Inherited Genetic Disorders - Fall 2023 Lecture Notes PDF

Inherited Genetic Disorders CMB 704/DENT 604 – Fundamental Biochemistry Dr. Maryam Syed [email protected] Fall 2023 1 Learning Outcomes By the end of this lecture, students will be able to: 1. Recognize and define the different types of mutations 2. Read and draw a pedigree chart 3. Characterize...

Inherited Genetic Disorders CMB 704/DENT 604 – Fundamental Biochemistry Dr. Maryam Syed [email protected] Fall 2023 1 Learning Outcomes By the end of this lecture, students will be able to: 1. Recognize and define the different types of mutations 2. Read and draw a pedigree chart 3. Characterize each of the 5 types of inheritance patterns 4. Identify each of the 5 types of inheritance patterns when shown a pedigree chart 5. List the clinical features of the 3 types of Amelogenesis imperfecta and what the main cause is 6. Identify the genes and recall the normal role and the effect of the mutated gene in the subtypes of Amelogenesis imperfecta and the associated inheritance pattern 2 Lecture Outline • Mendelian genetics • Genetic diseases and mutations • Pedigree analysis • Patterns/Modes of inheritance • Inherited oral disorders • Amelogenesis imperfecta 3 Important Genetic Terminology • Gene: An inherited factor (encoded in the DNA) that helps determine a characteristic • Allele: One of two or more alternative forms of a gene • Locus: Specific place on a chromosome occupied by an allele • Genotype: Set of alleles possessed by an individual organism • Phenotype or trait: The appearance or manifestation of a characteristic • Heterozygote: An individual organism possessing two different alleles at a locus • Homozygote: An individual organism possessing two of the same alleles at a locus • Characteristic or character: an attribute or feature possessed by an organism • Autosome: Any of the 22 non-sex chromosomes • Sex chromosomes: Chromosomes responsible for sex determination 4 Mendelian Genetics 5 Mendelian Genetics Concept of a Gene: • 1860’s Gregor Mendel introduced new theory of inheritance • Experimental work with pea plants • Mendel believed heredity is the result of discrete units of inheritance • Every single unit (gene) is independent in it’s action in an individuals genome Gregor Mendel 6 Mendelian Genetics Concept of a Gene: • An individual inherits one gene from each parent • Individual will have pairing of two genes - alleles • If two alleles form a pair for a trait are identical: • Individual is homozygous for the trait • If two alleles form a pair for a trait are different: • Individual is heterozygous for the trait By Darryl Leja, National Human Genome Research Institute 7 Mendelian Genetics Mendel’s experimental results: • Selectively cross bred two plants (parental generation) which differed in a single trait • • Next generation, “F1” (first filial): • • Round peas vs wrinkled peas Individual plants exhibited one trait only – round peas Next generation, “F2” (second filial): • • Individual plants exhibited 3:1 ratio for trait 3 round pea plant : 1 wrinkled pea plant 8 Mendelian Genetics Mendel’s experimental results: • Genes made up of three possible pairings: • SS, Ss, ss • Big “S” represents dominant factor • Little “s” represents recessive factor 9 Genetic Disease and Mutations 10 Genetic Disease • A disease caused by abnormal expression of one or more genes in a person that result in a clinical phenotype • Causes for genetic defects • • • Chromosomal Mitochondrial Mutation in a gene, affecting the protein function/availability Monogenic (single gene) 2. Multifactorial/polygenic 1. • Hereditary disease: defective genes inherited from parents 11 Mutations • Defined as a permanent change in the DNA • Origin • • Somatic cells – cancer and some congenital malformations Germ cells – transmitted to progeny 12 Gene mutations 1. Suppress transcription 2. Produce abnormal mRNA 3. Defects carried over into translation 4. Interfere with protein synthesis 13 14 Point Mutation Result from substitution of a single base in the DNA • Coding portion of gene • • • • • Missense – result in substitution of one amino acid for another in the coded protein • • Conservative: similar chemical properties – function not affected Nonconservative : very different chemical properties – function altered • • Leads to a Stop codon – results in truncated protein Limited or no function depending on where STOP occurs • • Replaced base encodes same amino acid Lysine encoded by either AAG or AAA Nonsense Silent Noncoding portion of gene • • Promoter and enhancer regions Posttranslational processing – defective splicing 15 Patterns of Inheritance and Pedigree Analysis 16 Patterns of Inheritance • Individuals phenotype (observable characteristic or trait) is determined by genotype • Genotype is determined by alleles inherited from individual’s parents • Alleles control if a trait is dominant or recessive • Traits are dominant if only one copy of allele is required for expression of trait • Traits are recessive if two copies of an allele are required for expression of trait • Punnett square is a visual representation of inheritance 17 TABLE 3.6 Genotypic ratios for simple genetic crosses (crosses for a single locus Genotypic Ratio 1:2:1 1:1 Uniform progeny Genotypes of Parents Aa × Aa Genotypes of Progeny 1/ 4 AA : 1/2 Aa : 1/4 aa Aa × aa 1/ 2 Aa : 1/2 aa Aa × AA 1/ 2 Aa : 1/2 AA AA × AA All AA aa × aa All aa AA × aa All Aa Pedigree Analysis • Study of inheritance of genes in humans • Series of symbols represent different aspects of a pedigree • Phenotypic data from several generations • Determine if a trait is dominant or recessive and autosomal or sexlinked (After W. F. Bodmer and L. L. Cavalli-Sforza,Genetics, Evolution, and Man.Copyright © 1976 by W. H. Freeman and Company.) 19 Patterns of Inheritance Autosomal 1. Dominant • Recessive • X-linked 2. Recessive • Dominant • 3. Holandric (Y-Linked) 4. Mitochondrial Mutations 20 Evaluating a Pedigree • Transmission: • • • Sex Ratio: • • Vertical: Phenotype seen in generation after generation Horizontal: Phenotype seen in siblings but not in previous generations Number of males and females displaying phenotype: Equal or unequal? Segregation: Which parent passes on the trait and to whom? • • • Do fathers pass the condition to sons AND daughters? Do mothers pass the condition to sons AND daughters? What percentage of offspring are affected? Is it similar to the expected recurrence risk? Autosomal Dominant • Affected offspring usually have one affected parent (heterozygous; Aa) (AA x Aa) • Transmission: • • Sex ratio: • • Vertical Equal number of males and females affected Segregation: • Either parent passes on the trait to sons and daughters Autosomal dominant Autosomal Recessive • Parents of affected individuals are both heterozygotes (carriers; Aa) (Aa x Aa) • Transmission: • • Sex Ratio: • • Horizontal Equal number of males and females affected Segregation: • Either parent passes on the trait to sons and daughters Autosomal recessive Autosomal Dominant ■ Most often, affected offspring produced by union of an unaffected parent (AA) with an affected heterozygote (Aa). ■ ½ offspring will be unaffected A A A AA AA a aA aA Autosomal Recessive ■ Two carrier parents Aa x Aa ■ ¼ offspring will be affected X-Linked Dominant • Transmission: • • Sex Ratio: • • Vertical Twice as many females affected as males Segregation: • Affected female parent: 50% sons affected; 50% sons unaffected • 50% daughters affected; 50% daughters unaffected • • Affected male parent: All daughters affected • All sons unaffected • X-linked dominant X-Linked Recessive • Transmission: • • Sex ratio: • • Vertical with “skipped generations” More males than females affected Segregation: • Carrier female parent: 50% sons affected; 50% unaffected • 50% daughters carriers; 50% daughters noncarriers • • Affected male parent: All sons will be unaffected • All daughters will be carriers • X-linked recessive SEX-LINKED INHERITANCE COMPARISON OF MAJOR ATTRIBUTES ATTRIBUTE X-LINKED DOMINANT X-LINKED RECESSIVE Recurrence risk for heterozygous female x normal male mating 50% of sons affected 50% of daughters affected 50% of sons affected 50% of daughters heterozygous carriers Recurrence risk for affected male x normal female mating 0% of sons affected 100% of daughters affected 0% of sons affected 100% of daughters heterozygous carriers Transmission Pattern Vertical; disease phenotype seen in generation after generation Skipped generations may be seen, representing transmission through carrier females Sex Ratio Twice as many affected females as affected males (unless lethal) Much greater prevalence of affected males; affected homozygous females are rare Other Male-to-male transmission is not seen; expression is less severe in female heterozygotes than in affected males Male-to-male transmission not seen; manifesting heterozygotes may be seen in females Holandric (Y-linked) • Y chromosome contains very few genes • Transmission: • • Sex Ratio: • • All males Segregation: • • Vertical Only father to son transmission Rare • Y-chromosome infertility 32 Y-linked Mitochondrial Inheritance • Cellular organelles involved in energy production • mtDNA is subject to mutation • Cytoplasmic inheritance (not chromosomal) • mtDNA is inherited maternally 34 Mitochondrial Inheritance • All children of affected females will inherit the disease • All children of affected males will not inherit the disease • Why? 35 Mitochondrial Inheritance 36 Mitochondrial Inheritance 37 Incomplete Dominance • One dominant allele is not strong enough to overpower the recessive allele • Red flower + white flower = pink flower • Rare in humans • Familial hypercholesterolemia • Tay-Sachs Disease 38 Co-Dominance • Both alleles are dominant so they both show up in the phenotype • Human ABO blood group system • Sickle cell anemia 39 Inherited Oral Disorders 40 Inherited Genetic Dental Disorders • Genetic mouth/dental abnormalities (anomalies) are problems, dysfunctions and diseases of oral tissues and dentition caused by defective genes. • Many genetic dental/oral abnormalities indicate more complex disorders and are linked to inherited traits and defects, or result from spontaneous genetic mutations. 41 Inherited Oral Diseases Disorders affecting Oral Mucosa • Hereditary Hemorrhagic Telangiectasia • Multiple Endocrine Neoplasia Syndrome IIB • Neurofibromatosis • Peutz-Jeghers Syndrome • White Sponge Nevus Disorders of Teeth • Amelogenesis Imperfecta • Dentinogenesis Imperfecta • Dentin Dysplasia • Hypohidrotic ectodermal dysplasia • Hypophophatasia • Vitamin D deficient rickets Disorders Affecting Periodontium/Gingiva • Papillon-LeFèvre Syndrome • Cyclic Neutropenia Disorders affecting Jaw bones and Facies • Cherubism • Cleidocranial dysplasia • Gardner syndrome • Mandibulofacial dysostosis (Treacher-Collins syndrome) • Nevoid basal cell carcinoma syndrome • Osteogenesis Imperfecta • Aperts Syndrome • Crouzon Syndrome 42 Amelogenesis Imperfecta 43 Amelogenesis imperfecta • Disorder of tooth development • Causes teeth to be unusually small, discolored, pitted or grooved, prone to rapid wear and breakage • Defects vary among affected individuals • Can affect primary (baby) teeth and permanent (adult) teeth 44 Amelogenesis imperfecta • 4 types of AI – 17 Subtypes • Each form distinguished by specific dental abnormalities and pattern of inheritance • Can occur alone without any other symptoms • Can occur as part of a syndrome that affects multiple parts of the body 45 Amelogenesis imperfecta Frequency: • 1 in 700 northern Sweden • 1 in 14,000 United Sates Genetically inherited diseases are more commonly observed in genetically isolated populations and in cultures that practice consanguineous marriage. 46 Amelogenesis Imperfecta 1) Hypoplasia/Hypoplastic • Deficiency in the amount of enamel present • Characterized by • reduced tooth size, • thin enamel, • small spaces between teeth, • discoloration (yellow-brown) 47 Amelogenesis Imperfecta 2) Hypomineralization/Hypocalcified • • • A deficiency in the quality of enamel due to a failure in mineralization (considerable variation in severity). Resulting enamel layer may be normal thickness, but is more porous, rough, weak, and easily wears away after tooth eruption. Hypomineralized enamel is creamy white, yellow, or brown in color and is chalky in texture. 48 Amelogenesis Imperfecta 3) Hypomature/Hypomaturation • • • Failure to properly remove enamel matrix proteins and promote the hardening of the enamel layer. Enamel is pathologically soft. Enamel is present and may be white-ish on the surface. 49 Amelogenesis imperfect – enamel defects of three basic types Hypoplastic Hypocalcified Hypomaturation • Enamel has abnormal thickness or pitting, but normal hardness • Defect in enamel matrix formation • Enamel has normal thickness, but is soft and chalky. • Defect in enamel mineralization • Enamel has normal thickness, but abnormal hardness • Mild forms exhibit “snow-capped” incisal edges • Severe forms lose their translucency • Defect in enamel maturation 50 Amelogenesis imperfecta • Mutations in AMELX, ENAM, MMP20 and FAM83H genes • AMELX, ENAM, MMP20 involved in making proteins essential for normal tooth development • Enamel: hard, calcium-rich protective outer layer • FAM83H: believed to be involved in enamel formation • 50% of cases are attributed to these gene mutations • • Mostly FAM83H mutation Remaining 50%: genetic cause unknown 51 Amelogenesis imperfecta FAM83H Inheritance Pattern: • FAM83H mutation, usually autosomal dominant • FAM83H protein found in ameloblasts (produce tooth enamel) involved in formation of enamel • Mutations  Produce short protein • Normal protein = cytoplasm • Mutant protein = nucleus • 52 Amelogenesis imperfecta Inheritance Pattern: • Mutations in MMP20 gene = autosomal recessive • Carriers do not show signs and symptoms • Enamelysin – • Key role in removing proteins no longer needed to allow enamel to harden Cleaves amelogenin and ameloblastin into smaller pieces, easier to remove • Mutation causes incomplete removal of proteins, resulting in soft enamel with crystal structure • 53 Amelogenesis imperfecta Inheritance Pattern: • Mutations in ENAM gene = autosomal recessive • Carriers do not show signs and symptoms • Enamelin (ENAM) – • Key role in formation and growth of crystals in developing enamel • Mutations reduce amount of protein or produce short protein missing critical regions for function 54 Amelogenesis imperfecta Inheritance Pattern: • 5% caused by AMELX gene mutation = X-linked pattern • Males experience more severe dental abnormalities • Amelogenin – Key function: Separates and supports the mineral crystals in enamel formation • Mutations lead to abnormal protein, interfere with formation and organization of enamel crystals OR no protein produced at all • Teeth have structural defects, distinctive pattern of vertical grooves • 55 Summary • A human will inherit 23 chromosomes from its mother and 23 from its father; together, these form 23 pairs of chromosomes that direct the inherited characteristics of the individual. • If the two copies of a gene inherited from each parent are the same, that individual is said to be homozygous for the gene; if the two copies inherited from each parent are different, that individual is said to be heterozygous for the gene. • Incomplete dominance is the expression of two contrasting alleles such that the individual displays an intermediate phenotype. • Codominance is a variation on incomplete dominance in which both alleles for the same characteristic are simultaneously expressed in the heterozygote. 56 Summary • Autosomal Dominant Each affected person has an affected parent • Occurs in every generation • • • Autosomal Recessive Both parents of an affected person are carriers • Not typically seen in every generation X-linked Dominant Females more frequently affected • Can have affected males and females in same generation • Males more frequently affected • Affected males often present in each generation • • • • X-linked Recessive Mitochondrial Can affect both males and females, but only passed on by females • Can appear in every generation • • Y-Linked Appear only in males • All male offspring of affected male are affected • 57