M1 – Human Genetics
Non-Mendelian Inheritance
Virginia A. Pallante, M.S. [email protected]
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Non-Mendelian Inheritance
• Mitochondrial Inheritance • Unstable Trinucleotide Repeats • Imprinting
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1 Mitochondrial Inheritance
• Nuclear DNA
• Also DNA in mitochondria
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Mitochondria contain mtDNA
• Thousands of mitochondria per cell • In each mitochondria there are several circular chromosomes containing mtDNA
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2 Mitochondrial Genome
•2 rRNAs • 22 tRNAs • 13 poly- peptides: subunits of enzymes of ox-phos
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Pedigree of Mitochondrial Inheritance
With rare exception only a mother transmits her mtDNA to her offspring. 6
3 Features of Mitochondrial Inheritance • Both sexes affected • All children of a mother with the disorder will have the disorder • No children of a father with the disorder will have the disorder • Reduced penetrance, variable expressivity, and pleiotrophy
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MERRF Myoclonus Epilepsy with Ragged Red Fibers
Quadriceps muscle histology 8
4 Replicative segregation
• Homoplasmy-same mutation in all mitochondria • Heteroplasmy-mutation present in only some mitochondria 9
Mitochondrial Inheritance: Homoplasmy
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5 Mitochondrial Inheritance: Heteroplasmy
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Anticipation and Parent of Origin Effects • Anticipation - phenomenon of disorder getting worse or having earlier age of onset in successive generations
• Parent of Origin Effects – sex of parent transmitting the disorder influenced severity or age of onset
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6 Trinucleotide Repeats
Tandemly repeated trinucleotides (i.e. CGG, CTG) within or adjacent to a gene that may increase or decrease in number during formation of egg or sperm cells and thus disrupt the functioning of the gene and lead to disease
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Disorders due to Unstable Trinucleotide Repeats
• Fragile X MR Syndrome (CGG) • Huntington Disease (CAG) • Myotonic Dystrophy 1 (CTG) • Friedreich Ataxia (GAA) • Spino-cerebellar ataxia (usually CAG) • Others
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7 Fragile X Syndrome • Moderate MR • Speech delay • Large head • Long face, prominent forehead and chin • Protruding ears • Large testes after puberty • Loose joints • Charac. behaviors 15
Fragile X Chromosome
• Fragile site at Xq27.3 observed in about 10- 40% males • No longer used for diagnostic testing
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8 Fragile X Syndrome • Gene identified and found to have a ‘CGG’ trinucleotide repeat region in the untranslated portion of exon 1
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Fragile X Syndrome
• Allele sizes – Normal: about 5-54 repeats – Premutation: about 55-200 repeats – Full: > 200 repeats • Change from phenotypically normal to affected state has only been observed following oogenesis – Expansion of premutation to full mutation may only occur during oogenesis
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9 Inheritance of Fragile X syndrome
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Fragile X Syndrome
• Males who carry the full mutation have mental retardation • About 50% of females who carry the full mutation have mental retardation • Transmitting males (carry a premutation) – their children are not at risk for MR, but their daughters will be at risk to have an affected child
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10 Fragile X Syndrome
• About 20% females who carry a premutation will develop premature ovarian failure
• About 30% of males who carry a premutation will develop Fragile X- associated tremor/ataxia syndrome (FXTAS) in adulthood
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Fragile X Syndrome
• Atypical X-linked inheritance • Due to amplified ‘CGG’ trinucleotide repeat in FMR-1 gene and subsequent methylation of this expansion • This results in silencing of FMR-1 transcription and leads to loss of FMRP • FMRP is RNA-binding protein and appears to be a nucleocytoplasmic shuttling protein
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11 Pathophysiology of Trinucleotide Repeat Conditions
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Fragile X Syndrome
• In women who carry a premutation allele the risk of expansion to a full mutation is related to: – Number of repeats in the premutation allele – Presence of AGG triplets imbedded in the CGG repeat segment
-CGGCGGAGGCGGCGGCGGCGGCGGCGG- -CGGCGGAGGCGGCGGCGGCGGCGGCGG-
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12 Huntington Disease
• Autosomal dominant with complete penetrance • Due to amplified ‘CAG” trinucleotide repeat • Allele sizes – Normal: less than 26 repeats – Intermediate: 27-35 repeats – Mutant: > 36 repeats –36-40 repeats: reduced penetrance –>41 repeats: full penetrance 27
Huntington Disease
• Parent of origin affect – Earlier age of onset associated with inheritance from an affected father – Likely due to greater expansion during spermatogenesis • Protein, huntingtin, has polyglutamine track due to expanded CAG repeats and this confers new protein function: the protein accumulates in the nucleus of neurons and has some toxic effect
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13 Pathophysiology of Trinucleotide Repeat Conditions
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Myotonic Dystrophy (DM)
• Most common form of MD in adults • Progressive muscle wasting & atrophy, myotonia, cataracts, develop. delay, and cardiac conduction defects • Variable expressivity • Incidence of ~ 1/8000 • Mean age of onset is 20-25 years • Autosomal dominant with late onset
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14 Myotonic Dystrophy (DM) •DM Type 1 – Due to expanded ‘CTG’ repeat in Dystrophia-Myotonica Protein Kinase gene – Allele sizes • Normal: 5-35 repeats • Fully penetrant: > 50 repeats – ↑ number of repeats →↑earlier age of onset and ↑ severity – Neonatal onset with maternal transmission due to greater expansion during oogenesis
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Myotonic Dystrophy Type 1
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15 Myotonic Dystrophy (DM)
•DM Type 2 – Due to expanded ‘CCTG’ repeat in the Zinc Finger Protein 9 – Need genetic testing to distinguish between DM 1 and DM 2
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Pathophysiology of Trinucleotide Repeat Conditions
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16 Disease Mechanisms for Conditions Caused by Unstable Trinucleotide Repeats
• Expansion of trinucleotide probably results from “slippage” during DNA replication • Expansions may – Cause a loss of protein function – Confer novel properties to the RNA – Confer novel properties to the protein
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Slipped Mispairing Mechanism
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Imprinting
The differential expression of a gene depending on the sex of the parent from which it is inherited (i.e. the parental origin of the gene
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18 Implications of Imprinting
• Sensitive period during development • Stable during mitosis • Affects gene expression • Erased in germ cell line • Only portions of the genome • Form of gene regulation
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Imprinting: erased in germ cell line
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19 Imprinting: only portions of the genome
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Examples of Parent of Origin Effects
• Fragile X Syndrome • Huntington disease • Myotonic dystrophy
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20 Evidence of Imprinting in Humans
• Hydatidiform moles (diploid paternal) – Absent, disorganized fetal tissue – Over-development of extra-embryonic membranes
• Ovarian teratomas (diploid maternal) – Embryonic tissue – No placental tissue 44
Evidence of Imprinting in Humans
• Triploidy – Dygynic (2 mat; 1 pat) • Small embryos; very small placenta – Diandric (2 pat; 1 mat) • Malformed embryos; over-development of extra- embryonic membranes
• Maternal genes → embryo • Paternal genes → extra-embryonic membranes
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21 Prader-Willi Syndrome (PWS)
• Hypotonia in infancy • Mental retardation • Voracious appetite, obesity • Short stature • Small hands and feet • Hypogonadism
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Angelman Syndrome (AS)
• Mental retardation • Short stature • Spasticity •Seizures • “Happy puppet syndrome”
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22 PWS & AS both involve chromo 15q11-13
Deletions account for ~ 70% cases of PWS & AS • If paternal deletion of 15q11-13 → PWS • If maternal deletion of 15q11-13 → AS
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Causes of PWS and AS
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23 PWS & AS both involve chromo 15q11-13
Uniparental disomy also causes some cases of PWS & AS • If maternal UPD (no paternal contribution at 15q11-13) → PWS • If paternal UPD (no maternal contribution at 15q11-13) → AS
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Trisomy Rescue: a proposed mechanism for UPD
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25 Molecular Mechanisms for Imprinting • Involves methylation of regulatory sequences of genes during gametogenesis
– Methylation of C residues of CpG dinucleotides – Methylation often represses or turns off gene function
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Imprinting
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26 Non-Mendelian Inheritance
• Mitochondrial Inheritance • Unstable Trinucleotide Repeats • Imprinting
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