Genetic Disorders PDF

TRANS 5.1...

TRANS 5.1 9/19/24 GENETIC DISORDERS Genes and Human Diseases Lifetime frequency of Genetic Diseases: Approx. 670 per 1000 *about 1% of all NB infants possess a gross chromosomal abnormality, and serious disease with a significant genetic component develops in approx. 5% of individuals younger than 25 years old 3 Broad Classifications of Human Genetic Disorders Single-Gene Disorders Chromosomal Disorders Complex Multigenic Disorders Mendelian Disorders / Monogenic dse Most common cause of abortion Polygenic / Multifactorial Single Gene Mutation Structural or Numerical Alteration Interactions between Multiple variant Cause forms of genes & environmental factors (in Autosomes & Sex Chromosomes) Mutations which cause the disease or *Polymorphisms predispose to the disease, & are Variations in genes which are common typically not present in the normal within the population population Each variant gene confers a small ↑ in disease risk, & no single susceptibility gene is necessary or sufficient to produce the disease Effects Large Effects Small Effects Frequency Rare Uncommon Common (Except in populations with selective forces) Penetrance High Penetrance High Penetrance Low Penetrance Presence of the mutation is associated with the It is only when several Polymorphisms are present disease in a large proportion of individuals in an individual that disease occur Inheritance Classic Mendelian Inheritance Non-Classic Mendelian Inheritance Multifactorial Inheritance Pattern *no single gene is necessary or sufficient Example Sickle Cell Anemia Down Syndrome (in areas where malaria is endemic) Atherosclerosis, DM, Hypertension, Hemoglobinopathy Turner Syndrome Autoimmune Diseases *Normal traits (Height & Weight) are also governed by Polymorphisms 4TH Category: Single-gene Disorders with non-classic pattern of Inheritance (Heterogenous group) Cause: Single Gene Mutation Inheritance Pattern: Non-classic Mendelian Inheritance Includes disorders resulting from: - Triple-repeat Mutation - Genomic Imprinting - Mutations in mitochondrial DNA (mtDNA) - Gonadal Mosaicism Mutations Point Mutations within Coding Sequences Definition: A permanent change in the DNA *May alter the code in triplet of bases & lead to the *Mutations that affect germ cells replacement of one amino acid by another in the gene product. Germ Cell Mutations Somatic Cells Mutations Missense Mutation Nonsense Mutation are transmitted to the Do not cause Hereditary Mutations which alter the change in AA codon to a Progeny & can give rise to diseases by are important meaning of the sequence of Chain Terminator or Inherited Diseases in the genesis of Cancers & the encoded CHON Stop codon Congenital Malformations AA Substitution Point Mutation Conservative Missense Nonconservative Missense If the substituted AA is Replaces the normal AA with a biochemically similar to the Biochemically different one original Typically, it causes little changes in the function of the CHON General Principles Relating to the Effects of Gene Mutations Type of Mutation Definition Effect on CHON Examples Point Mutations within Single base substitution with Can result in Missense Mutations Sickle cell anemia Coding Sequences a different base (Conservative or Nonconservative); (Nonconservative Missense Mutation) may cause Nonsense Mutations “Exons” “Alterations in DNA Sequence” leading to premature stop β0-Thalassemia codons & truncated proteins (Nonsense mutation) Mutations within Mutations affecting Promoter, May interfere with transcription or Thalassemia’s Noncoding Sequences Enhancer or Intron Regions result in defective splicing, leading to reduced or absent “Introns” gene expression Deletions and Insertions Removal or Addition of Base If not a multiple of three, causes Cystic fibrosis (3-base deletion Pairs in coding Sequence frameshift mutations; otherwise leading to loss of Phenylalanine) “Exons” results in the loss or gain of AA Alterations in CHON-Coding Structural changes Can lead to aberrant gain or loss 22q microdeletion syndrome, Genes other than Mutations (Amplification, Deletion, of protein function; often involves Philadelphia Chromosome Translocation) contiguous gene regions or (t(9;22) in Chronic Myeloid “Exons” somatically acquired in cancers Leukemia) Alterations in Non-Coding Changes affecting noncoding RNAs Affects regulation of gene Not specified RNAs (miRNA & lncRNA) expression rather than directly altering protein structure Trinucleotide-repeat Amplification of a sequence Dynamic mutations ↑ repeat Fragile X syndrome Mutations of 3 nucleotides, often involving number during gametogenesis, Guanine (G) & Cytosine (C) leading to abnormal gene expression or protein function NOTE: Hereditary Disorders → are derived from one’s parents & are transmitted in the germline through the generations (Familial) Congenital Disorders → implies “Born with”. Some Congenital diseases are not Genetic (Congenital Syphilis). Not all Genetic diseases are Congenital (Huntington Disease) MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Example: Sickle mutation affecting B-globin chain of Hgb - The nucleotide triplet CTC (or GAG in mRNA) which encodes Glutamic acid is changed to CAC (or GUG in mRNA) which encodes for Valine - Single AA substitution alters the physicochemical properties of Hgb, giving rise to Sickle cell anemia B-globin - Point mutation affecting the codon for Glutamine (CAG) creates a stop codon (UAG) if U is substituted for C - This change leads to premature termination of B- globin gene translation, and the short peptide that is produced is rapidly degraded - The resulting deficiency of B-globin chains can give rise to a severe form of anemia (B0-Thalassemia) Typical result: - Incorporation of a variable number of incorrect amino acids followed by truncation resulting from a premature stop codon Alterations in CHON-Coding Genes other than Mutations Coding genes undergo structural variations, such as: - Copy number changes → Amplification / Deletion / Translocation - That result in aberrant gain or loss of CHON Mutations within noncoding sequences function Point mutations or deletions involving these regulatory sequences may interfere with binding of transcription Structural changes may occur in the germline or be factors & thus leads to a marked reduction in or total lack acquired in somatic tissues of transcription In many instances, pathogenic germline alterations involve Example: Thalassemias a contiguous portion of a chromosome rather than a single Point Mutations within introns may lead to defective splicing gene (22q microdeletion syndrome) of intervening sequences. This in turn, interferes with Autism normal processing of the initial mRNA transcripts and - Pathogenic structural alterations was assessed resulting in a failure to form mature mRNA with the aid of next-generation sequencing (NGS) Therefore, translation cannot take place, and the gene technology for assessing genome-wide DNA copy products is not synthesized number variation at very high resolution Cancers Deletions and Insertions - Often contain somatically acquired structural 2 possible effects on the encoded CHON alteration, including amplifications, deletion, 1. If the number of base pairs involved is 3 or a translocation multiple of 3, the reading frame will remain intact, Philadelphia chromosome Translocation → t(9;22) between the and an abnormal CHON lacking or gaining one or BCR & ABL genes in Chronic Myeloid Leukemia more amino acids will be synthesized Alterations in noncoding RNAs (ncRNAs) ncRNAs serve important regulatory functions. miRNAs & lncRNAs Trinucleotide-repeat Mutations *Belong to a special category of genetic anomaly Characterized by: Amplification of a sequence of 3 nucleotides Fragile X Syndrome (FXS) - There are 250 to 4000 tandem repeats of the sequence CGG within the regulatory region of a gene called Familial Mental Retardation 1 (FMR1) 2. If the number of affected coding bases is not a In normal populations the number of repeats is small, multiple of 3, this will result in an alteration of the averaging 29 reading frame of the DNA strand → producing a Such expansions of the Trinucleotide sequences prevent Frameshift Mutation normal expression of the FMR1 gene, thus giving rise to intellectual disability. Another distinguishing feature: They are Dynamic (the degree of amplification increases during Gametogenesis) These features influence the pattern of inheritance & the phenotypic manifestations of the diseases caused by this class of mutation MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Summary expected to result from new mutations. Many new Mutations can interfere with gene expression at various mutations seem to occur in germ cells of relatively levels older fathers - Clinical features can be modified by variations in Transcription may be expressed by gene deletions and Penetrance and Expressivity. point mutations involving promoter sequences Incomplete Penetrance Variable Expressivity Abnormal mRNA processing may result from mutations individuals inherit the trait is expressed differently affecting Introns or Splice Junctions or both mutant gene but are among individuals Translation is affected if a nonsense mutation creates a phenotypically normal stop codon (Chain Termination Mutation) within an Exon. Penetrance indicates that 50% of those who carry the Some pathogenic point mutations may lead to expression gene express the trait of normal amounts of a dysfunctional CHON. (manifestations of Neurofibromatosis type1 range from brownish spots on the skin to multiple skin tumors and Mendelian Disorders skeletal deformities). The mechanisms are not fully It is estimated that every individual is a carrier of several understood, but they most likely result from effects of other deleterious genes; most of these genes are recessive and genes or environmental factors that modify the phenotypic therefore do not have serious phenotypic effects. expression of the mutant allele. (the phenotype of a patient 80 – 85% of these mutations are Familial with sickle cell anemia – resulting from mutation at the B- 15 – 20% represent new mutations acquired de novo by an globin locus – is influenced by the genotype at the a-globin affected individual locus because the latter influences the total amount of Hgb Most mutations in Autosomal genes produce partial expression made). The influence of environmental factors is in the heterozygote & full expression in the Homozygote. exemplified by individuals heterozygous for familial Traits hypercholesterolemia (FH). The expression of the disease Dominant Recessive in the form of atherosclerosis is conditioned by the dietary intake of lipids NOTE: Codominance - HLA / MHC & Blood group Ags - In many conditions the age at onset is delayed; Homozygous Heterozygous symptoms and signs may not appear until adulthood (Huntington Disease) full expression partial expression Molecular mechanisms of Autosomal Dominant Disorders Sickle Cell Anemia Sickle Cell Trait depend on the nature of the Mutation and the Type of Substitution of normal HbA by HbS CHON affected. All Hgb is abnormal Only a proportion of Hgb is AbN Even with normal saturation Red cell sickling occurs Loss-of-Function of O2 the disorder is fully only under unusual Most mutations lead to the reduced production of a gene expressed circumstances product or give rise to a dysfunctional or inactive CHON (sickling deformity of all red (exposure to lowered O2 *Whether such a mutation gives rise to dominant or recessive cells & hemolytic anemia) tension) disease depends on whether the remaining copy of the gene is Pleiotropism Genetic Heterogeneity capable of compensating for the loss Single mutant gene may Mutations at several lead to many end effects genetic loci may produce Patterns of Autosomal Dominant Diseases the same trait 1. Sickle Cell Anemia Profound Childhood Deafness Not only does the point A homogeneous clinical Gain-in-Function mutation in the gene give entity, results from many - rise to HbS, which different types of autosomal predisposes the RBC to recessive mutations Hemolysis, but also the *recognition of genetic abnormal RBCs tend to heterogeneity not only is important cause a logjam in small in genetic counseling but also is vessels, inducing, splenic relevant in the understanding of fibrosis, organ infarcts, & the pathogenesis of some bone changes common disorders (DM) Transmission Patterns of Single-Gene Disorders *Mutations involving single genes typically follow 1 of 3 patterns of inheritance Autosomal Dominant Disorders - Manifested in the Heterozygous state - At least 1 parent of an index case is usually affected - Both males and females are affected Basic Rule: when an affected person marries an unaffected one, every child has 50% chance of having the disease Autosomal Recessive Disorders Characteristics: Makes up the largest category of Mendelian Disorders - With every autosomal dominant disorder, some - Manifested in the Homozygous state proportions of patients do not have affected *Occur when both alleles at a given gene locus are mutated parents. Such patients owe their disorder to new - *include almost all inborn errors of metabolism mutations involving either the egg or the sperm from which they were derived. Their siblings are Characteristic Features neither affected nor at increased risk for disease 1. The trait does not usually affect the parent of the development. The proportion of patients who affected individual, but siblings may show the develop the disease as a result of a new mutation disease is related to the effect of the disease on 2. Siblings have one chance in four of having the trait reproductive capability. If a disease markedly (the recurrence risk is 25% for each birth) reduces reproductive fitness, most cases would be MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 3. If the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected individual (proband) is the product of a Consanguineous Marriage Distinguishing feature from Autosomal Dominant disease - The expression of the defect tends to be more uniform - Complete penetrance is common - Onset is frequently early in life - Although new mutations associated with recessive disorders do occur, they are rarely detected clinically *(since the individual with a new mutation is an asymptomatic heterozygote, several generations may pass before the descendants of such a person mate with other heterozygotes and produce affected offspring) - Many of the mutated genes encode enzymes. *In heterozygotes, equal amount of normal and defective enzyme are synthesized. Usually the natural “Margin of Safety” ensures that cells with half the usual complement of the enzyme function normally. X-Linked Disorders - All sex-linked disorders are X-linked - Almost all are Recessive NOTE: X-linked Dominant Conditions - Are caused by dominant disease-associated alleles on the X chromosome Is transmitted by: - An affected heterozygous female to half her sons & half her daughters, and - An affected male parent to all his daughters but none of his sons (if mother is unaffected) Example: - Vitamin D-resistant Rickets - Alport Syndrome MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Table 5.4 Biochemical & Molecular Basis of Some Mendelian Disorders - A minor pathway producing small quantities of M1 Biochemical & Molecular Basis of Single-Gene and M2 also exists (Mendelian) Disorders 3 Major Biochemical Consequences of an Enzyme Defect Result from alterations involving single genes Accumulation of the Substrate Genetic defect may lead to: - Depending on the site of block, may be - Formation of an abnormal CHON accompanied by accumulation of 1 or both - Reduction in the output of the gene product intermediates *virtually any type of CHON may be affected in Single- - Moreover, an increased concentration of gene disorders and by a variety of Mechanisms Intermediate 2 may stimulate the minor pathway 4 Categories Based on the Mechanisms involved in and thus lead to an excess of M1 and M2 Single-gene Disorders - Under these conditions tissue injury may result if Enzyme Defects and their Consequences the precursor, the intermediates, or the products of Mutations may result in the synthesis of an enzyme with alternative minor pathways are toxic in high reduced activity or a reduced amount of a normal enzyme concentrations *deficiency of galactose-1-phosphate uridyltransferase leads to the accumulation of galactose and consequent tissue damage *Excessive accumulation of complex substrates within the lysosomes as a result of deficiency of degradative enzymes is responsible for Lysosomal Storage Disease Metabolic block & a decreased amount of end product - Melanin deficiency may result from lack of tyrosinase, which is necessary for the biosynthesis of melanin from its precursor, tyrosine, resulting in Albinism - If the end product is a feedback inhibitor of the enzymes involved in the early reactions, the deficient of the end product may permit overproduction of intermediates and their catabolic products, some of which may be injurious at high Figure 5.5 A possible Metabolic Pathway in which a concentrations. → Lesch-Nyhan Syndrome substrate is converted to an end product by a series of Failure to inactivate a tissue-damaging substrate Enzyme reactions. M1, M2 products of a Minor Pathway - AAT deficiency → individuals who have an - A substrate is converted by intracellular enzymes inherited deficiency of serum a1-antitrypsin are (1,2,3) into an end product through intermediates 1 unable to inactivate neutrophil elastase in their &2 lungs - The final product exerts feedback control on - Unchecked activity of this protease leads to enzyme 1 destruction of elastin in the walls of lung alveoli, leading eventually to Pulmonary Emphysema MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Defects in Membrane Receptors & *reduction of Fibrillin Transport Systems content below a certain Transport is achieved by: Receptor-mediated Endocytosis threshold weakens the CT (Haploisufficiency) Familial Hypercholesterolemia (FH) 2 fundamental Mechanisms of by which loss of Fibrillin - Reduced synthesis or function of LDL receptors leads to Clinical Manifestations of Marfan Syndrome leads to defective transport of LDL into the cells 1. Loss of structural support in microfibril-rich CT and secondarily to excessive cholesterol synthesis 2. Excessive activation of TGF-B signaling by complex intermediary mechanisms - TGF-B Bioavailability Cystic Fibrosis - Bone overgrowth and myxoid changes in mitral - Transport system for chloride and bicarbonate ions valves → cannot be attributed to changes in tissue in exocrine glands, sweat ducts, lungs, and elasticity pancreas is defective - Fibrillin-1 controls the bioavailability of TGF-B - Reduced or altered forms of Fibrillin-1 give rise to *impaired Anion Transport leads to serious Injury to the abnormal and excessive activation of TGF-B, since lungs and Panreas normal microfibrils sequester TGF-B Alterations in Structure, Function, or - Excessive TGF-B signaling, in turn leads to Quality of Nonenzyme CHONs inflammation, has deleterious effects on vascular Widespread secondary effects smooth muscle development, and increases the activity of Metalloproteases, causing loss of ECM Sickle cell disease This schema is supported by 2 sets of Observations - Defects in the structure of the globin genes that 1. 1st, gain-of-function mutations in the RGF-B type II affect the amount of globin chains synthesized receptor give rise to a related syndrome → Marfan Thalassemias Syndrome Type II (MFS2). Furthermore, patients - Associated with reduced amounts of structurally with germline mutations in one isoform of TGF-B normal a-globin or B-globin chains (TGF-B3), present with an inherited predisposition Osteogenesis imperfecta to Aortic Aneurysm and other cardiovascular - Defect in collagen manifestations similar to those found in patients Hereditary Spherocytosis with classic marfan syndrome - Defect in Spectrin 2. 2nd , Angiotensin Receptor II blockers, which inhibit Muscular Dystrophies TGF-B activity, markedly reduce the aortic root - Defect in Dystrophin diameter in mouse models of marfan syndrome Genetically Determined Adverse Reactions Ehlers-Danlos Syndromes EDS to Drugs Those Enzyme deficiencies are unmasked only after exposure of the affected individual to certain drugs Pharmacogenetics G6PD - Under normal condition, deficiency does not result in disease, but on administration of an antimalarial drug primaquine, a sever hemolytic anemia results Disorders Associated with Defects in Structural CHON *below affects the CT, involve multiple organs Marfan Syndrome A disorder of CT, manifested principally by changes in the Skeleton, Eyes, Cardiovascular System Prevalence: 1 in 5000 70 – 85% are Familial, transmitted by Autosomal Dominant PATHOGENESIS Results from an inherited defect in Fibrillin-1 NOTE: Fibrillin - A major component of Microfibrils in the ECM - Provide a scaffold on which tropoelastin is deposited to form elastic fibers - Microfibrils are particularly abundant in Aorta, Ligaments, Ciliary Zonules that support the lens Isoforms of Fibrillin (Homologous forms) Fibrillin-1 Fibrillin-2 encoded by FBN1 encoded by FBN2 *mapped on Chromosome 15q21.1 & 5q23.31 Defective Fibrillin-1 Defective Fibrillin-2 Most are Missense Less common Mutations that give rise to abnormal Fibrillin-1 Marfan Syndrome Congenital Contractural Arachnodactyly Autosomal dominant Autosomal dominant disorder disorder Inhibit polymerization of Characterized by Skeletal -ADD THE CLINICAL FEATURE PAGE 149- Fibrillin fibers (dominant negative effect) Abnormalities MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Disorders associated with Defects in Receptor CHONs - A diverse range of cellular organelles and molecules are degraded by autophagy including complex lipids, Familial Hypercholesterolemia polyubiquitinated CHONs, Mitochondria, and fragments of the ER. Caused most commonly by mutations in the gene encoding - Autophagy is essential for turnover of mitochondria by a the receptor for LDL process termed Mitophagy Result: Inadequate removal of plasma LDL by the Liver - This serves as a quality control system whereby dysfunctional mitochondria are degraded - Mutations in LDL Receptor Gene (LDLR) → 80 - - Because of the accumulation of undigested 85% of cases → One of the most frequently macromolecules in the lysosomes, the rate at which occurring Mendelian Disorder → Heterozygote: lysosomes process organelles delivery by frequency: 1 in 200 individuals 2-3x elevation of autophagocytic vacuoles is markedly reduced plasma cholesterol level (leading to tendinous - This lead to persistence of dysfunctional and leaky xanthomas and premature atherosclerosis)→ mitochondria with poor calcium-buffering capacity and homozygote: 5 – 6x elevations in plasma altered membrane potentials in the lysosomes cholesterol levels → skin xanthomas and coronary, - Damaged mitochondria generate free radicals and cerebral, and peripheral vascular atherosclerosis release molecules that trigger the intrinsic pathway of apoptosis. may develop at an early age (MI may occur before - Impaired autophagy gives rise to secondary age 20) accumulation of autophagic substrates including Mutations in 2 other genes involved in clearance of plasma LDL ubiquitinated and aggregate-prone polypeptides (alpha- - ApolipoCHON B-100 (ApoB) → The ligand for LDL synuclein and huntingtin CHON) receptor on the LDL particle (5 – 10% of cases) - This provides a molecular link between - ProCHON convertase Subtilisin / Kexin type 9 (1 – 2% of neurodegenerative disorders and lysosomal storage cases) → this enzyme (aka PCSK9), reduces expression diseases (Gaucher Disease) of LDL receptors by downregulating their recycling and -BALIKI LANG NI “3 GENERAL APPROACHES TO THE consequent degradation in lysosomes TREATMENT OF LYSOSOMAL STORAGE DISEASES”- *each of these 3 types of mutations impairs hepatic clearance of Important genetic risk factor for Parkinson Disease LDL and increases serum levels of cholesterol, giving rise to - Carrier state for Gaucher disease premature Atherosclerosis and a greatly increased risk of MI - *all patients with Gaucher disease develop -Baliki lang “NORMAL CHOLESTEROL METABOLISM Parkinson disease AND TRANSPORT”- Niemann-Pick Type C Disease Disorders Associated with Enzyme Defects - Increased risk for Alzheimer disease Lysosomal Storage Diseases Lysosomes – key components of the Intracellular Digestive System Lysosomes play critical role in: Contains hydrolytic enzymes which have 2 special 1. Autophagy, resulting from the fusion with the properties: autophagosome 1. They function in the acidic milieu of the lysosomes 2. Immunity, because they fuse with phagosomes 2. These enzymes constitute a special category of 3. Membrane Repair, through fusion with the plasma secretory CHON that are destined not for the membrane extracellular fluids but for intracellular organelles Identified Lysosomal storage disease: approx. 70 Lysosomal enzymes (acid hydrolases) are synthesized in These may result from: the ER and transported to the golgi apparatus - Abnormalities of lysosomal enzymes or CHONs - Within the golgi complex they undergo a variety of involved in substrate degradation posttranslational modifications (attachment of terminal - Endosomal sorting mannose-6-phosphate group to some of the - Lysosomal membrane integrity oligosaccharide side chanes) - Phosphorylated mannose residues serve as an “address Categories of Lysosomal storage disorders based on the label” that is recognized by specific receptors found on biochemical nature of the substrates and the accumulated the inner surface of the golgi membrane. metabolites - Lysosomal enzymes bind these receptors and are thereby segregated from the numerous other secretory Distribution of the stored material / organs affected, is CHON within the golgi. determined by: - Subsequently, small transport vesicles containing the 1. The tissue where most of the material to be receptor-bound enzymes are pinched off from the golgi degraded is found and proceed to fuse with the lysosomes 2. The location where most of the degradation - Thus, the enzymes are targeted to their intracellular normally occurs abode, and the vesicles are shuttled back to the golgi Example: (Fig 5.9). - Brain is rich in gangliosides. Defective hydrolysis of Lysosomal enzymes catalyze the breakdown of a variety of gangliosides (GM1 & GM2 gangliosidoses), results complex macromolecules. These large molecules may be primarily in accumulation within neurons and consequent derived from the metabolic turnover of intracellular neurologic symptoms organelles (autophagy), or they may be required from - Defects in degradation of mucopolysaccharides affect outside the cells by phagocytosis (Heterophagy) virtually every organ because mucopolysaccharides are widely distributed in the body An inherited deficiency of a functional lysosomal - Cells of the mononuclear phagocyte system are enzyme gives rise to 2 pathologic consequences especially rich in lysosomes and are involved in the (FIG 5.10) degradation of a variety of substrates, organs rich in 1. Primary Accumulation phagocytic cells (spleen and liver) are frequently - Catabolism of the substrate of the missing enzymes enlarged in several forms of lysosomal storage disorders remains incomplete - Leading to the accumulation of the partially degraded *CATEGORIES OF LYSOSOMAL STORAGE DISEASE insoluble metabolite within the lysosome BASED ON THE BIOCHEMICAL NATURE OF THE - Stuffed with incompletely digested macromolecules, ACCUMULATED METABOLITE lysosomes become large and numerous enough to - Glycogenoses interfere with normal cell functions. - Sphingolipidoses (Lipidoses) 2. there is a tight linkage between autophagy, mitochondrial - Mucopolysaccharidoses (MPSs) functions, and lysosomes. - mucolipidoses MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Table 5.6 Lysosomal Storage Diseases *because the mutant CHON is misfolded, it induces the Tay-Sachs Disease “Unfolded CHON Response” GM2 Gangliosidosis: Hexosaminidase a-subunit Deficiency *if such misfolded enzymes are not stabilized by A group of 3 lysosomal storage diseases chaperones, they undergo proteasomal degradation, caused by deficiency of the enzyme: B-Hexosaminidase leading to accumulation of toxic substrates and Resulting in: Inability to catabolize GM2 ganglioside intermediates within neurons 2 isoenzymes of B-Hexosaminidase Hex A Hex B Treatment on trial: Molecular Chaperone Therapy Consist of 2 subunits Homodimer of B-subunit *therapy involves the use of synthetic chaperones that can Alpha & Beta cross the BBB, bind to the mutated CHON, and enable its Degradation of GM2 gangliosides requires 3 polypeptides proper folding encoded by 3 distinct genes (HEXA; on chromosome 15) → encodes for a-subunit of Hex A & Hex B → (GM2A; on chromosome 5) → encodes the activator of Hexosaminidase The phenotypic effects of mutations affecting these genes are fairly similar because they result from accumulation of GM2 gangliosides. *the underlying enzyme defect, however, is different for each Tay-Sachs Disease - Most common form of GM2 Gangliosidosis result from: Mutations in the α-subunit locus on chromosome 15 *that cause a severe deficiency of Hexosaminidase - prevalent among Jews (Ashkenazic) origin - Carrier rate: 1 in 30 Molecular Basis for Neuronal Injury resulting from Hexosaminidase Deficiency *more than 100 mutations have been described in the HEXA a-subunit gene → most affect CHON folding MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Neuron → ballooned with cytoplasmic vacuoles, each Niemann-Pick Disease Type C representing a markedly distended lysosome filled with gangliosides Distinct at the biochemical and genetic levels and is more common than Type A and B combined Ganglion cells (in retina)→ swollen with GM2 ganglioside → at the margins of the macula → Cherry-red spot in the Due primarily to defect in nonenzymatic lipid transport Macula → representing accentuation of the normal color of Cause: Mutations in NPC1 & NPC2 the macular choroid contrasted with the pallor produced by NPC1 NPC2 the swollen ganglion cells in the remainder of the retina responsible for 95% of “CHARACTERISTIC BUT NOT PATHOGNOMONIC ” cases -BALIKI LANG “CLINICAL FEATURES- membrane bound soluble Neimann-Pick Disease Types A & B *both are involved in the transport of free cholesterol from the lysosomes to the cytoplasm Characterized by: Lysosomal accumulation of Sphingomyelin *is clinically heterogeneous. May present as Due to: Inherited deficiency of Sphingomyelinase - Hydrops fetalis and stillbirth - Neonatal hepatitis Type A Type B - or most commonly, as a chronic form characterized Severe infantile form with Organomegaly but by progressive neurologic damage extensive neurologic generally no CNS involvement, marked involvement. Clinical Features visceral accumulations of - Marked ataxia Sphingomyelin & Px usually survive into - Vertical supranuclear gaze palsy progressive wasting and adulthood - Dystonia early death within the first 3 - Dysarthria years of life - Psychomotor regression Common in Ashkenazi Jews Gaucher Disease The gene for acid Sphingomyelinase maps to chromosome 11q15.4 ; and is one of the imprinted gene that is Refers to a cluster of autosomal recessive disorders preferentially expressed from the maternal chromosome as resulting from mutations in the gene encoding a result of Epigenetic silencing of the paternal gene Glucocerebrosidase Pattern of Inheritance: Autosomal Recessive Most common lysosomal storage disorder *heterozygotes who inherit the mutant allele from the mother can develop Niemann-Pick Disease The affected gene encodes glucocerebrosidase, an enzyme that normally cleaves the glucose residue from ceramide As a result, glucocerebrosides accumulate principally in phagocytes (in some subtypes also in CNS). Glucocerebrosides are continually formed from the catabolism of Glycolipids derived mainly from the cell membranes of senescent Leukocytes and RBCs *pathologic changes in Gaucher Disease are caused not just by the burden of storage material but also by activation of Mac and the consequent secretion of cytokines (IL-1, IL- 6) and TNF 3 Clinical Subtypes of Gaucher Disease Type I / Chronic Nonneuronopathic form 99% of cases Storage of Glycocerebrosides is limited to the Mononuclear Phagocytes throughout the body without involving the Brain Splenic and Skeletal involvements dominate this pattern Found principally in Jews of European stock Reduced but detectable levels of Glucocerebrosidase Type II / Acute Neuronopathic Form Infantile Acute Cerebral Pattern Mononuclear Phagocyte System → Accumulation of Has no predilection of Jews. Sphingomyelin within lysosomes *affected cells become enlarged, sometimes to 90um in Virtually no detectable Glucocerebrosidase activity in the diameter, due to the distention of lysosomes with tissues. sphingomyelin and cholesterol Hepatosplenomegaly is also seen in this form of Gaucher Lipid-laden phagocytic Foam cells → widely distributed in disease, but the clinical picture is dominated by progressive the spleen, liver, Lymph nodes, Bone marrow, tonsils, GIT, CNS involvement leading to death at an early age lungs Type III / Vacuolation and ballooning of neurons → constitute the Intermediate between types I and II dominant histologic change, which in time leads to cell Have the systemic involvement characteristic of Type I but death and loss of brain substance have progressive CNS Disease That usually begins in adolescence or early adulthood Retinal Cherry-red spot → MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 95% 4% Source of the Extra Chromosome 21 Meiotic Nondisjunction in Presence of a the Ovum Robertsonian Translocation of the Long Arm of Chromosome 21 to another Acrocentric Chromosome (22 or 14) Maternal in Origin *Inherited usually from the Mother *Translocated Frequently but not always familial NOTE: In cells with Robertsonian Translocation - The genetic Material normally found on long arms of 2 pairs of chromosomes is distributed among only 3 chromosomes - This affects chromosome pairing during Meiosis, and as a result the gametes have a high probability of being Aneuploid 1% → Mosaic - Have a mixture of cells with 46 or 47 chromosomes - Mosaicism is a result from Mitotic nondisjunction of Chromosome 21 during an early stage of Embryogenesis - Symptoms are viable and milder, depending on the proportion of abnormal cells Effect of Maternal Age in producing Down Syndrome - Meiotic Nondisjunction → Strong Influence - Translocation & Mosaic → No Effect Diagnostic Clinical Features - Flat Facial Profile - Oblique Palpebral Fissures -BALIKI LANG NI CLINICAL FEATURES- - Epicanthic Folds *are usually evident, even at birth Mucopolysaccharidoses - Simian Hand Creases - *Severe Mental Retardation Other Clinical Features Mucopolysaccharidoses - Congenital Heart Disease (approx. 40% of cases) Most frequent form: Atrioventricular Septal Defect (43%) Ventricular Septal Defects (32%) Glycogen Storage Diseases (Glycogenoses) Atrial Septal Defects (19%) Result from a hereditary deficiency of 1 of the enzymes Tetralogy of Fallot (6%) involved in the synthesis or sequential degradation of *responsible for the Majority of deaths in infancy and early glycogen childhood (other congenital malformation, like Atresia of the Depending on the normal tissue or organ distribution of the Esophagus and Small bowel are also common) specific enzyme, glycogen storage in these disorders may be limited to a few tissues, may be more widespread while - High Risk of Developing Leukemia (Acute) not affecting all tissues, or may be systemic Acute B Lymphoblastic Leukemias (20-fold increased risk) Acute Myeloid Leukemias (500-fold increased risk) *Acute Megakaryoblastic Leukemia - Neuropathologic Changes (Alzheimer Disease) Disorders Associated with Defects in CHONs that All patients older than age 40 Regulate Cell Growth - Abnormal Immune Responses leading to recurrent NOTE: infections and thyroid autoimmunity - *T-cell functions is usually affected Complex Multigenic Disorders Molecular Basis of Down Syndrome Gene Dosage - Majority of CHON coding denes mapped to Chromosomal Disorders chromosome 21 are overexpressed - Includes: Amyloid-Beta precursor CHON (APP) - Aggregation of APP is the critical initiating event in Normal Karyotype the development of Alzheimer disease and could contribute to the early onset of Alzheimer Disease. Structural Abnormalities of Chromosomes Mitochondrial Dysfunction - Approx. 10% of the overexpressed genes are Cytogenetic Disorders Involving Autosomes directly or indirectly involved in regulation of Trisomy 21 Down Syndrome Mitochondrial Functions Most common Chromosomal disorders (1 in 700 births) - Mitochondria are abnormal both morphologically Major cause of Intellectual Disability and functionally in several tissues (Cristae are Most Common cause of Trisomy: Meiotic Nondisjunction broken or swollen); Mitochondrial stress with ROS *parents have a normal Karyotype & are normal in all aspect and Activation of Apoptosis MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 facial structures, Thymus, and Parathyroid are Noncoding RNAs derived - Chromosome 21 has the highest density of Targets of TBX1 lncRNAs whose target sequences are widely - PAX9 → A gene that controls the development of expressed on other chromosomes, making the task the palate, parathyroid and thymus of identification of genes whose products dictate Diagnosis: Detection of the Deletion the phenotype of trisomy 21 exceedingly difficult *may be suspected on Clinical Grounds Next-Generation Sequencing (NGS) Modality: FISH - Non-invasive Screening Test for Prenatal diagnosis of Trisomy 21 Other Trisomies - Trisomies involving chromosomes 8, 9, 13, 18 & 22 Trisomy 18 (Edwards Syndrome) & Trisomy 13 (Patau Syndrome) - They share several karyotypic and clinical features with trisomy 21 - Most cases result from: Meiotic Nondisjunction - Extra copy of chromosome 13 or 18 - Is associated with increased maternal age - Malformations are much more severe and wide ranging - Rarely do infants survive beyond the first years of life (usually few weeks to months) Chromosome 22q11. 2 Deletion Syndrome Encompasses a spectrum of disorders that result from a Small deletion of band q11.2 on the long arm of chromosome 22 *in a very small number of cases, there is a deletion of Cytogenetic Disorders involving Sex Chromosomes 10p13-14 Imbalances in sex chromosomes are more common than Frequency: 1 in 4000 births autosomal imbalances because they are typically better *fairly common but often missed because of variable tolerated clinical features 2 Factors that are peculiar to the Sex Chromosomes Clinical Features 1. Lyonization or Inactivation of all but one X - Congenital Heart Defects Chromosome - Abnormalities of the Palate 2. The modest amount of genetic material carried by - Facial Dysmorphism the Y Chromosome - Developmental Delay NOTE: Lyon Hypothesis Mary Lyon (1961) - Variable degrees of T-Cell Immunodeficiency 1. Only 1 of the X Chromosomes is genetically active - Hypocalcemia 2. The other X Chromosome of either Maternal or - Increased risk for Psychotic Disorders Paternal origin undergoes Heteropyknosis (is (Schizophrenia (25%), Bipolar disorders, Attention rendered Inactive) deficit hyperactivity Syndrome (30 – 35%)) 3. Inactivation of either the Maternal or the Paternal X DiGeorge Syndrome Velocardiofacial Syndrome chromosome occurs at random among all the cells Clinical Features of the Blastocyst (on or about day 5.5 of Embryonic Life) -Thymic Hypoplasia -Facial Dysmorphism 4. Inactivation of the same X Chromosome persists in With T-cell (Prominent Nose, all the cells derived from each precursor cell Immunodeficiency Retrognathia) Barr Body / X-chromatin -Parathyroid Hypoplasia -Cleft Palate - Inactivated X chromosome seen in the Interphase giving rise to Hypocalcemia -Cardiovascular Anomalies nucleus as a darkly staining small mass in contact -Cardiac malformations -Learning Disabilities with the nuclear membrane affecting the outflow tract -Immunodeficiency (less -Mild Facial Anomalies frequent) Molecular Basis of X Inactivation Atopic disorders (Allergic XIST gene Rhinitis) & Autoimmunity - Product is a lncRNA that is retained in the nucleus, (Thrombocytopenia) may where it “coats” the X-chromosome that it is also be seen transcribed from and initiates a gene-silencing Molecular Basis process by chromatin modification and DNA - Deleted region is large (approx. 1.5Mb) methylation - Includes 30 – 40 genes - XIST allele is switched off in the active X - Clinical heterogeneity, with predominant chromosome immunodeficiency (DiGeorge Syndrome) and predominant dysmorphology and cardiac *Genes on Xp (30%) & Xq (3%) escape Inactivation malformations in other cases, probably reflects the variable position and size of the deleted segment *Patients with Monosomy of the X chromosome (Turner from this genetic region syndrome) have severe somatic and gonadal abnormalities - If a single dose of X-linked genes were sufficient, n TBX1 detrimental effect would be expected in such cases - A T-box transcription factor - Most closely associated with the phenotypic *although 1 X chromosome is inactivated in all cells during features of this syndrome embryogenesis, it is selectively reactivated in Oogonia - This gene is expressed in the pharyngeal before the 1st meiotic division. Thus, it seems that both X mesenchyme and endodermal pouch from which MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 chromosomes are required for normal growth as well as *in some patients the testicular tubules are totally atrophied Oogenesis and replaced by pink, Hyaline, Collagenous Ghosts. The tips of short and long arms of X and Y Chromosomes *apparently normal tubules are interspersed with atrophic have regions of homology that recombine during Meiosis tubules and are therefore inherited as Autosomal loci. For this reason, they are called Pseudoautosomal regions. *in some patients, all tubules are primitive and appear These genes also escape X inactivation. These embryonic, consisting of cords of cells that never mechanisms ensure that males and females have developed a lumen or progressed to mature equivalent doses of genes that map on X and Y spermatogenesis chromosomes. Y Chromosome *Leydig cells appear prominent, as a result of the atrophy - Determines the male sex and crowding of the tubules and elevation of Gonadotropin - The gene that dictates testicular development concentrations. (SRY → Sex-determining region Y gene) is located Laboratory Tests on its distal short arm FSH (& LH) : consistently ↑ - MSY → Male-specific Y region → has 75CHON Mean Plasma Estradiol : ↑ coding genes. All are believed to be testis-specific Testosterone : variable ↓ and are involved in spermatogenesis NOTE: Estrogen:Testosterone ratio - All Y chromosome deletions are associated with - Determines the degree of Feminization in individual cases Azoospermia Karyotypes X Chromosome Classic Most common (47, XXY) - Has 840 coding genes Karyotype (90% of cases) Features common to all sex chromosome disorders - Results from Nondisjunction during the Meiotic - Cause subtle, chronic problems relating to sexual Divisions in the Germ cells of one of the parents development and fertility - Maternal and Paternal nondisjunction at the 1st - Often difficult to diagnosis at birth (many are 1st meiotic division is roughly equally involved recognized at the time of puberty) *NO PHENOTYPIC DIFFERENCE BETWEEN THOSE - The greater the number of X chromosomes, both WHO RECEIVE THE EXTRA X CHROMOSOME FROM male and female, the greater the likelihood of THEIR FATHER AND THOSE WHO RECEIVE IT FROM Intellectual Disability THEIR MOTHER Klinefelter Syndrome *Advanced Maternal Age (>40yrs old) is a risk factor Best defined as: Male Hypogonadism that occurs when Mosaic Patterns 46,XY / 47, XXY (15%) there are 2 or more X chromosomes & 1 47,iXq,Y or more Y chromosome. cells with structurally abnormal X Incidence / Frequency: 1 in 660 live male births chromosome One of the most frequent forms of genetic diseases involving the As is the case with normal females, all but one X sex chromosomes as well as one of the most common causes of chromosome undergoes inactivation in patients with Hypogonadism in males Klinefelter Syndrome. Clinical Features can be attributed to 2 major factors 1. Aneuploidy & the impact of ↑ gene dosage by the Why do patients have Hypogonadism & associated features? Supernumerary X Explained by the genes on the X chromosome that escape 2. Presence of Hypogonadism Lyonization and in the pattern of X inactivation Clinical Features Pathogenic Mechanism involved: - Most patients have a distinctive body Habitus with 1. Uneven dosage compensation during X an ↑ in length between the soles & the pubic bone, inactivation → 35% of X-linked genes escape w/c creates the appearance of an elongated body inactivation. Thus there is an extra dose of these - Eunuchoid body habitus with abnormally long legs genes compared with normal males in whom only - Small atrophic testes often associated with a small 1 copy of the x chromosome is active. penis Overexpression of one or more of these genes - Lack of secondary male characteristics (deep leads to Hypogonadism. A similar mechanism may voice, beard, and male distribution of pubic hair) also dictate some somatic features. The Short- - Gynecomastia may be present stature HomeobOX (SHOX) gene that maps on the - Cognitive abilities range from average to below pseudoautosomal region of Xp is one of the genes average with modest deficit in verbal skills that is not subject to X-inactivation. An extra copy particularly those that are used in reading and of this growth-related gene is probably responsible language comprehension for the tall stature and long legs typical of the syndrome. It should be noted that most genes Development of Comorbid Conditions whoe expression is upregulated in the syndrome lie - Increased incidence of Type 2 DM outside the X chromosome. This implies that the - Metabolic Syndrome that gives rise to Insulin Resistance supernumerary X Chromosome can regulate gene - Higher risk for Congenital Heart Disease (Mitral expression on autosome Valve Prolapse (seen in 50% of adults) 2. Gene encoding the Androgen receptor → which - Higher prevalence of Atrial and Ventricular Septal testosterone mediates its effects. The androgen Defects receptor gene maps to the X chromosome & - Increased incidence of Osteoporosis and Fractures contains highly polymorphic CAG (trinucleotide) due to sex hormone imbalance repeats. The functional response of the receptor to - 20 – 30-fold higher risk of Developing Extragonadal any particular dose of androgen is dictated, in part, germ cell tumors, mostly mediastinal Teratomas by the number of CAG repeats, as receptors with - Breast cancer and autoimmune diseases (SLE) shorter CAG repeats are more sensitive to An important genetic cause of Reduced Spermatogenesis androgens than those with long CAG repeats. In & Male Infertility the syndrome, the X chromosome bearing the androgen receptor allele with the shortest CAG repeat is preferentially inactivated. In XXY males MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 with ↓ testosterone levels, expression of androgen receptors with long CAG repeats exacerbates the Principal Clinical Features in Adolescents and Adults Hypogonadism and appears to account for certain At puberty aspects of the Phenotypes (SMALL PENIZE SIZE) - Failure to develop normal secondary sex Turner Syndrome characteristics (Genitalia remain infantile, breast Results from: Complete or Partial monosomy of the X development is inadequate, there is little pubic chromosome hair) - Normal mental status (but subtle defects in Characterized by: Hypogonadism in Phenotypic Females nonverbal, visual-spatial information processing) Frequency: 1 in 2000 live-born Females Most common Sex Chromosome abnormality in Females Important in establishing Diagnosis in an adult 3 Types of Karyotypic Abnormalities in Turner Syndrome - *Shortness of stature (rarely exceeding 150cm in 1. 57% → are missing an entire X chromosome → 45,X height) Karyotype - *Amenorrhea 43% → (1/3) 14% have structural abnormalities of the X Turner syndrome is the single most important cause of chromosomes; (2/3) 29% are mosaics primary amenorrhea → approx. 1/3 of the cases 2. common feature of the structural abnormalities is to produce partial monosomy of the X chromosome 50% of patients develop autoantibodies that react with the Thyroid Gland → up to ½ of these develop clinically Structural abnormalities of the X chromosome manifested Hypothyroidism - Isochromosome of the long arm →46,X,i(X)(q10) → resulting in the loss of the short arm Comorbidities - Deletion of portions of both long and short arms → Glucose Intolerance, Obesity, Nonalcoholic fatty liver 46,X,r(X) → resulting in the formation of a ring disease, insulin resistance chromosome Some have full-fledged metabolic syndrome - Deletion of portions of the short or long arm → 46X,del(Xq) or 46X,del(Xp) *occurrence of Insulin resistance is significant because 3. Mosaic patients have a 45,X cell population along with therapy with growth hormone, commonly used in these one or more Karyotypically normal or abnormal cell types patients, worsens insulin resistance Karyotypes that Mosaic Turner Females may have: Molecular Basis - 45,X / 46,XX In 80% of cases, X chromosome is maternal in origin - 45,X / 46,XY *suggesting that there is an abnormality in paternal - 45,X / 47,XXX gametogenesis - 45,X / 46,X,i(X)(q10) -BALIKI LANG NI SIYA- *It is important to appreciate the Karyotypic Heterogeneity associated with Turner Syndrome because it is responsible for significant variations in phenotype Hermaphroditism & Pseudohermaphroditism *in patients in whom the proportion of 45,X cells is high, the phenotypic changes are more severe than in those who have readily detectable mosaicism → the later may have Single-Gene Disorders with Nonclassic Inheritance an almost normal appearance and may present only with primary amenorrhea. A very small number of patients are Diseases caused by Trinucleotide-Repeat Mutations able to conceive *Expansion of Trinucleotide repeats *are associated with: Neurodegenerative Disorders 5 – 10% of Turner syndrome have Y chromosome Fragile X Syndrome FXS sequences either as a complete Y (45,X / 46,XY Karyotype) or as fragments of Y chromosomes translocated on other Fragile X-Associated Fragile X-Associated chromosomes Tremor / Ataxia Syndrome Primary Ovarian Failure These patients are at higher risk for development of Gonadal Tumor (Gonadoblastoma) Clinical Features Mutations in Mitochondrial Genes During Infancy (Leber Hereditary Optic Neuropathy) - Edema of the dorsum of the hand and foot due to Feature unique to mtDNA: Maternal Inheritance lymph stasis and sometimes swelling of the Nape *because Ova contain numerous Mitochondria within their of the neck (related to markedly distended abundant Cytoplasm, whereas Spermatozoa contain few lymphatic channels → producing Cystic Hygroma) Mothers transmit mtDNA to all their offspring (male & female) Developed Infants Daughters, but not sons, transmit the DNA further to their - Swelling subside but often leave bilateral Neck progeny webbing & persistent looseness of skin on the back Other features of Mitochondrial Inheritance of the neck Human mtDNA contains 37 genes - Congenital heart disease (25 – 50% of patients) - 22 are transcribed into tRNA - Left-sided cardiovascular abnormalities - 2 are transcribed into rRNA (particularly preductal coarctation of the aortal and - 13 encode subunits of the respiratory chain bicuspid aortic valve, are seen most frequently) enzymes - Aortic root dilatation is present in 30% of cases Because mtDNA encodes enzymes involved in Oxidative - 100-fold higher risk of aortic dissection Phosphorylation, mutations affecting these genes exert their deleterious effects primarily on the organs most *Cardiovascular abnormalities are the most important dependent on oxidative phosphorylation cause of increased mortality in children with Turner - CNS, Skeletal Muscle, Cardiac Muscle, Liver, Syndrome Kidneys MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 *organs less dependent on Oxidative phosphorylation *Regardless of the Mechanism, it is believed that such marking of - Skin (Epidermis), Cartilage, Adipose tissue, CT, paternal & maternal chromosomes occurs during gametogenesis, and thus it seems that from the moment of conception some RBC, Lymphatic tissues, Cornea of eye (avascular chromosomes remember where they came from. with low energy demand), Bone (BM has higher energy needs) Estimated range of Imprinted genes: 200 – 600 Each mitochondrion contains thousands of copies of *Imprinted genes may occur in isolation, but more commonly mtDNAs, and typically deleterious mutations of mtDNA they are found in groups that are regulated by common cis- acting elements called Imprinting control regions affect some, but not all, of these copies. Prader-Willi Syndrome Angelman Syndrome Thus, tissues and, indeed, individuals may harbor both Cause wild-type and mutant mtDNA → Heteroplasmy del (15) (q11.2q13) Interstitial Deletion of Band q12 in the long arm of A minimum number of mutant mtDNAs must be present in Chromosome 15 *In most cases the breakpoints area the same, causing a 5-Mb Deletion a cell or tissue before oxidative dysfunction give rise to a Microdeletion on: disease → Threshold Effect Paternal Chromosome 15 Maternal Chromosome 15 *threshold is reached most easily in the metabolically active tissues *Phenotypically distinct During cell division, mitochondria and their contained DNA Characterized by: are randomly distributed to the daughter cells. Thus when Intellectual disability Intellectual disability a cell containing normal and mutant mtDNA divides, the Short Stature Microcephaly proportion of the normal and mutant mtDNA in daughter Hypotonia Ataxic gait, cells is extremely variable Profound Hyperphagia Seizures, Obesity Inappropriate Laughter Small hands & feet (“Happy Puppets” → because *the expression of disorders resulting from mutations in Hypogonadism of their Laughter & Ataxia) mtDNA is quite variable *a comparison of these 2 syndromes clearly demonstrates the Parent-of-Origin effects on gene function Figure 5.27 Pedigree of Leber Hereditary Optic Neuropathy All progeny of an affected male (shaded square) are normal, but all children, male & female, of the affected female (shaded circle) manifest disease to a variable degree Leber Hereditary Optic Neuropathy Cause: Mutation in mtDNA - Neuromascular system - Neurodegenerative disease that manifests as progressive bilateral loss of Central Vision - Visual impairment is first noted between ages 15 and 35, leading eventually to blindness Cardiac conduction defects & Minor Neurologic Manifestations have also been observed in some families Genomic Imprinting Description: A phenomenon, in which there is differential modification and/or expression of homologous alleles or chromosome regions depending on the parent from whom the genetic material is derived. NOTE: We all inherit 2 copies of each autosomal gene, carried on homologous Maternal & Paternal chromosomes *Important functional differences exist between the Paternal allele & the Maternal allele differences result from an Epigenetic process → Imprinting *in most cases, imprinting selectively inactivates either the maternal or paternal Allele Maternal Imprinting Paternal imprinting Transcriptional Silencing of Inactivated Maternal allele Paternal allele Occurrence of Imprinting: Ovum or Sperm *Before Fertilization, & then is stably transmitted to all somatic ells through Mitosis - As with other instances of epigenetic regulation, imprinting is associated with differential patterns of DNA Methylation at CG nucleotide - Other mechanisms include Histone H4 Deacetylation & Methylation MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Angelman Syndrome Prader-Willi Syndrome Molecular Bases 3 Mechanisms involved in the process of Genomic Imprinting Deletions 65 – 70% Conversely, a distinct gene that also maps to A gene or set of genes on the maternal the same region of chromosome 15 is imprinted chromosome 15q12 is imprinted (Silenced), and on the paternal chromosome. Only the maternal thus the only functional alleles are provided by derived allele of this gene is normally active. the paternal chromosome. When these are lost Deletion of this maternal gene on chromosome as a result of a deletion, the person develops 15 gives rise to Angelman syndrome Prader-Willi Syndrome Uniparental Disomy 20 – 25% Have 2 Paternal copies of Chromosome 15 Have 2 maternal copies of Chromosome 15 - Inheritance of both chromosomes of a pair from one parent - Net effect is the same (the person does not have a functional set of genes from the nonimprinted chromosome) Defective Imprinting 1- 4% Maternal chromosome carries the Paternal Imprint Paternal chromosome carries the Maternal imprint *hence, there are no functional alleles Genetic Basis Affected Gene: UBE3A gene Affected Gene: No single gene has been implicated is a ubiquitin ligase that is involved in catalyzing - Instead, a series of genes located in the the transfer of activated ubiquitin to target 15q11.2-q13 interval (which are CHON substrates imprinted on the maternal chromosome UBE3A gene → maps within the 15q12 region, and expressed from the paternal is imprinted on the paternal chromosome, and chromosome) are believed to be is expressed from the maternal allele primarily involved in specific regions of the brain - These include the SNORP family of genes that encode small nucleolar Absence of UBE3A inhibits synapse formation RNAs and synaptic plasticity - These RNAs are noncoding molecules that are involved in posttranscriptional The imprinting is tissue-specific in the UBE3A is modifications of ribosomal RNAs and expressed from both alleles in most tissues other small nuclear RNAs Loss of SNORP functions is believed to contribute to Prader-Willi Syndrome, but the precise mechanisms are unclear NOTE: Bases on Molecular Diagnosis - Assessment of Methylation status of marker genes - FISH Parent-of-Origin Effects - have been identified in a variety of inherited diseases such as Huntington Disease & Myotonic Dystrophy & in Tumorigenesis Indications for Analysis of Acquired Genetic Alterations Gonadal Mosaicism PCR and Detection of DNA Sequence Alterations Molecular Genetic Diagnosis NOTE: Diagnostic Methods and Indications for Testing - Molecular Analysis of Genomic Alterations Laboratory Considerations Fluorescence in Situ Hybridization (FISH) Indications for Analysis of Inherited Genetic Alterations MEDCSI1 GENERAL PATHOLOGY TRANS 1.1 Cytogenomic Array Technology Polymorphic Markers and Molecular Diagnosis Epigenetic Alterations RNA Analysis Next-Generation Sequencing (NGS) Bioinformatics Clinical Applications of Next-Generation DNA Sequencing Future Applications - - - - - NOTE: