Molecular Genetics & Genetic Disorders PDF

MOLECULAR GENETICS & GENETIC DISORDERS NORLELAWATI BINTI A TALIB 2425 LECTURES OBJECTIVES o Explain the molecular basis of genetics, including the structure, function, and expression of genes. o Describe different types of mutations and their consequences on human health...

MOLECULAR GENETICS & GENETIC DISORDERS NORLELAWATI BINTI A TALIB 2425 LECTURES OBJECTIVES o Explain the molecular basis of genetics, including the structure, function, and expression of genes. o Describe different types of mutations and their consequences on human health. o Discuss the classification and examples of genetic disorders, including their molecular pathogenesis and inheritance patterns. o Introduce diagnostic techniques and molecular tools used in studying genetic disorders ACTIVITIES Foundation of Molecular Genetics Molecular Diagnostics and Emerging Tools Genetic Disorders -Chromosomal Disorders Genetic Disorders --Mendelian inheritance etc GENETIC DISORDERS PART 2 INTRODUCTION TO GENETIC DISORDERS Diseases Caused By Abnormalities In The Genome. Can Involve Single Genes, Multiple Genes, Chromosomes, Or Mitochondria. Classification of Genetic Disorders 1. Chromosomal Disorders. 2. Single-gene (Mendelian) Disorders. 3. Polygenic (Multifactorial) Disorders. 4. Disorders With Non-classic Inheritance. Single-gene (Mendelian) Disorders. Mutation in a single gene - large Single mutation with many effects end effects , (pleiotropism) Autosome: partial expression several genetic loci but (heterozygous) & full expression produce the same trait (homozygote) (genetic heterogeneity). Usually, Dominant or recessive Other factors may also traits influence the phenotype Some cases: Codominance (both expression: allele of a gene pair contribute to Compensatory genes phenotype) eg blood group Ag, Environmental factors HLA antigen. Inheritance patterns: Autosomal dominant, autosomal recessive, X- linked.  MENDELIAN DISORDERS o Mutations in a single gene - have large effects o Autosomal genes -partial expression(heterozygote) & full expression (homozygote) o Dominant or Recessive traits o Dominant: Expressed when one allele copy is present (e.g., AA or Aa). o Recessive: Expressed when both alleles are present (e.g., aa) o Some cases: Codominance (both allele of a gene pair contribute to phenotype) eg. blood group Ag, HLA antigen. o Pleiotropism - single mutation with many end effects o Genetic heterogeneity) -several genetic loci  produce same trait o Other factors may that influence phenotype expression: o Compensatory genes o Environmental factors  Types of Mendelian Inheritance Main Features Example Affects males and females equally. Autosomal Affected individuals have at least one affected Marfan syndrome Dominant parent. Familial 50% chance of passing the trait to offspring.. hypercholesterolemi Variable expressivity and incomplete penetrance Huntington disease may occur. Autosomal Affects males and females equally. Alpha and Beta- Recessive Requires two mutant alleles (homozygous) for the thalassaemia phenotype to be expressed. Cystic fibrosis Parents are typically asymptomatic carriers. Phenylketonuria 25% chance of the offspring being affected if both parents are carriers. X-Linked Affects males predominantly (XY: no second X to Hemophilia A and B Recessive compensate for the mutation). G6PD deficiency Carrier females may be asymptomatic or have mild Duchenne muscular symptoms. dystrophy No male-to-male transmission (mutation is on the X chromosome).  Types of Mendelian Inheritance Main Features Example X-Linked Affects both males and females, but females are Rett syndrome Dominant more likely to survive due to their second X. Fragile X syndrome Affected males pass the trait to all daughters (dominant aspects). but no sons. Y-Linked Affects only males, as Y chromosome is Y-linked infertility (Holandric) transmitted from father to son. (deletions or (Y chromosome is small and carries fewer genes mutations in the AZF (~50–60 protein-coding genes), mostly related to (Azoospermia Factor) ) male sex determination and spermatogenesis.) Hairy Ears Autosomal dominant inheritance Eg. Pedigree tree  Variation in Penetrance & Expressivity In Autosomal Dominant o Incomplete penetrance : individuals inherit the mutant gene but are phenotypically normal o Variable expressivity: if a trait is seen in all individuals carrying the mutant gene but is expressed differently among. o Explanation: o Gene-gene interactions o Environment o Details mutation Autosomal Dominant Disorders (some common examples) Expansion of CAG trinucleotide repeats HTT gene  an abnormal huntingtin protein,damages brain cells. Mostly involves quantity or arrangement of large structural proteins, regulator proteins and receptors, deficiency in proteins which are in short Tumor genes: supply even in health Short-supply protein deficiency syndromes Structural proteins: Structural proteins: Structural proteins: Receptor/channel problems: Short-supply protein deficiency syndromes Mechanism of some example Autosomal Dominant Disorders System Disease name (Mutated Mechanism Gene) Nervous Neurofibromatosis disrupt tumor suppressor proteins, leading (NFI & NF2 ) to uncontrolled nerve cell growth. GIT Familial Polyposis Coli abnormal Wnt signaling, promoting (APC) uncontrolled growth of colon polyps. Haemat0 Hereditary Spherocytosis weaken the red cell membrane, leading to (Spectrin, ankyrin) haemolysis Skeletal Achondroplasia constitutive receptor activation, inhibiting (FGFR3) bone growth and causing dwarfism. Metabolic Familial impair LDL uptake, causing elevated Hypercholesterolemia cholesterol levels. (LDLR) Mechanism of some example Autosomal Dominant Disorders Disease name (Mutated Gene) Neurofibromatosis (NFI & NF2 ) Familial Polyposis Coli (APC) Normal tarso short limbs Hereditary Spherocytosis (Spectrin, ankyrin) Achondroplasia (FGFR3) Familial Hypercholesterolemia (LDLR) Autosomal Recessive inheritance Eg. Pedigree tree Autosomal Recessive Disorders (some common examples) Deficiencies or defects in highly specialized proteins Deficiencies or defects in highly specialized proteins Deficiencies or defects of highly specialized proteins (enzymes, transport proteins), or hemoglobinopathies. Age of onset frequently in early life. Major hemoglobin problems Clinical features > more uniform (than AD). Complete penetrance is common. Disorders are commonly severe. Mechanism of some common examples Autosomal Recessive Disorders System Disease name (Mutated Mechanism Gene) Metabolic Cystic Fibrosis (CFTR) impair chloride ion transport, causing thick mucus in lungs and digestive organs. Phenylketonuria (PAH) deficient phenylalanine hydroxylase, causing toxic phenylalanine accumulation Haematology Sickle Cell Disease (HBB) abnormal hemoglobin (HbS), leading to red blood cell deformation and vaso-occlusion Thalassemias (Alpha, Beta) reduce or absent globin chain synthesis, (HBA1/HBA2 and HBB) leading to anemia.  Some common examples Autosomal Recessive D System Disease name (Mutated Gene) Metabolic Cystic Fibrosis (CFTR) Phenylketonuria (PAH) Haematology Sickle Cell Disease (HBB) Thalassemias (Alpha, Beta) (HBA1/HBA2 and HBB) X-linked Recessive inheritance eg Family tree  Most X linked disorders are recessive. Males > much more likely to be affected. Can be transmitted through healthy female carriers An affected male will transmit the mutant gene to all his daughters but to none of his sons. (Absent father to son transmission) X-linked Recessive Disorders (some common examples) System Disorder Mechanism of Disease Haemapoietic Hemophilia A(F8) deficiency of clotting factor VIII, causing impaired blood clotting. Haemapoietic G6PD Deficiency (G6PD) reduced glucose-6-phosphate dehydrogenase, leading to red cell hemolysis under oxidative stress. Neuromuscular Duchenne Muscular leading to progressive muscle Dystrophy (DMD) degeneration. SUMMARY OF SELECTED MENDELIAN DISORDERS INTRODUCTION TO GENETIC DISORDERS Diseases Caused By Abnormalities In The Genome. Can Involve Single Genes, Multiple Genes, Chromosomes, Or Mitochondria. Classification of Genetic Disorders 1. Chromosomal Disorders. 2. Single-gene (Mendelian) Disorders. 3. Polygenic (Multifactorial) Disorders. 4. Disorders With Non-classic Inheritance.  Single Gene Disorders With Non-Classic Inheritance Classified into 4 groups: 1. Diseases caused by trinucleotide-repeat mutations (eg. Fragile X syndrome) 2. Disorders caused by mutations in mitochondrial genes(eg. Leber Hereditary Optic Neuropathy). 3. Defective genomic imprinting (eg Prader-Willi and Angelman syndromes) 4. Disorder associated with Gonadal mosaicism. Single gene disorders with non classic inheritance : Triplet repeat mutations o Caused by excessive repetition of a specific three-nucleotide sequence. o Leads to protein misfolding and functional impairment. o Ex: Fragile X syndrome, Huntington dis, myotonic dystrophy (~40 diseases) o Triplet repeat mutations: long repeated sequence of three neucleotides. Often share G and C. o Neurogenerative/Mental retardation dominate the clinical features. o Fragile X: Common cause of familial mental retardation. o Genetic anticipation -severity increases with each successive generation that inherits them.  Triplet repeat mutations: Fragile X Syndrome (also X-linked disorder). o FXS is caused by an expansion of CGG repeats in the 5' untranslated region (UTR) of the FMR1 gene on the X chromosome (Xq27.3) o N: 10-55 repeats, FXS: 200-4000 repeats. o Premutation repeats: 55-200. o CGC repeats can be amplified during oogenesis (not spermatogenesis) full mutations is passed on to the progeny (off spring). o “Dynamic mutation”.  Triplet repeat mutations: Fragile X Syndrome (also X-linked disorder). o 200 repeats : FXS o hypermethylation of the FMR1 promoter (DNA methylation =Epigenetic) o silences gene transcription, o affect the production of Fragile X Mental Retardation Protein (FXMP) o FXMP is crucial for synaptic plasticity and mRNA transport in neurons.  Single gene disorders with non classic inheritance : Mutation in mitochondrial genes o Inherited exclusively from the mother (maternal inheritance). o Affects high-energy requiring tissues mtDNA 37 genes (13 oxidative like the brain, muscles, and eyes. phosphorylation,22 tRNA, o Example: Leber Hereditary Optic 2rRNA) mtDNA is inherited Neuropathy (LHON) exclusively from the mother (sperm mitochondria o Mitochondrial mutation affecting degraded after fertilization) Genetic complex I of the electron lineage/anthropology. transport chain. o Causes progressive vision loss due to optic nerve degeneration.  Single gene disorders with non classic inheritance : Defective Genomic Imprinting GENOMIC IMPRINTING o Defective genomic imprinting - certain genes are expressed Loss of functional alleles in a parent-specific manner. Only one allele (either (deleted, epigenetic error or maternal or paternal) is inactivated) active, while the other is silenced (epigenetically o parent- specific gene silenced). expression is disrupted Occurs due to epigenetic genetic disorders modifications like DNA methylation/Histone modification. IMPRINT is reset during gametogenesis –according to sex  Single gene disorders with non classic inheritance : Defective Genomic Imprinting Prader-Willi Syndrome Loss of the paternal copy of imprinted genes on chromosome 15q11-q13. (N: paternal allele is active, while the maternal allele is silenced); disrupt expression Angelman Syndrome -Loss of the maternal copy of imprinted genes on chromosome 15q11-q13 (N: Maternal allele is active, paternal allele is silenced)  Single Gene Disorders With Non Classic Inheritance : Disorder Associated With Gonadal Mosaicism mutation occurs post- zygotically in the germline (sperm or egg cells) but not in somatic cells. individual appears phenotypically normal but can pass the mutation to offspring.. Example: Duchenne Muscular Dystrophy (DMD) (15% of cases) THANK YOU