Mkgrady8 Gpmdc 2 Genetics 4

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examples of inherited disorders that are not mendelian

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triplet repeats= fragile X syndrome, myotonic dystrophy, spinocerebellar ataxia, friedreich ataxia, synpolydactyly; genomic imprinting= prader willi and angelman syndrome; mitochondrial= LHON (Leber's hereditary optic neuropathy), MERRF (mito encephalomyopathy with lactic acidosis and stroke like episodes), and MELAS (myoclonic epilepsy and ragged red fibers)

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triplet expansion disorders: concepts

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anticipation= earlier onset of disease and increased severity of symptoms; gender of parent specific expansion= fragile X with expansion in meiosis I of female gametes, transmission is also affected by X chromosome inactivation; pre mutation versus full mutation= pre mutation in FMR1 gene can result in FXTAS or POI

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analysis of triplet expansions through what

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OCR analysis can be used for shorter repeats (for ex up to 115 CAG repeats in Huntington's disease); southern blotting for longer repeats (for ex in full mutation in fragile X syndrome)

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CAG triplet expansion disorders: what is it, examples

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polyglutamine disorders (expansion of CAG codon (glutamine))= toxic gain of function disorder; Huntington's disease (above 36 repeats show disease); spinocerebellar ataxia; this mutates a protein

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non CAG triplet expansion disorders: what is it, examples

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triplet expansions can occur in regions within and outside coding regions and affect gene function in different ways; fragile X syndrome is a CGG repeat; myotonic dystrophy is a CTG repeat; friedrich ataxia is a GAA repeat

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fragile X syndrome: what causes it, symptoms

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mutation of the FMR1 gene (Xp27.3) with >230 CGG repeats; this is an expansion of the 5' uTR which then causes the gene downstream of it to be hypermethelated and, as you know, this leads to inactivation of the gene; long ears, prominent ears, long face, hyperextendable MP joints, macroorchidism, neurological symptoms

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huntington's disease: what causes it, symptoms

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progressive disorder of cognitive, motor, and psychiatric disturbances; inheritance is autosomal dominant; expansion of CAG repeat in Huntingtin (HTT) gene with full penetrance at 40 or more repeats; ethical concerns about testing for unaffected individuals (no treatment available); affecting FUNCTION of protein NOT expression of it

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myotonic dystrophy: what is it, symptoms

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muscle weakness, especially of distal hand, leg, neck and face, myotonia (sustained muscle contraction), posterior subcapsular cataracts; inheritance is autosomal dominant; genetics= expansion of CTG repeat in non coding region of DMTK gene (dystrophia myotonica protein kinase) with full penetrance at 50 or more repeats; detectable by PCR or southern blotting; effect of mutation is unclear but may be related to improper processing of CMTK mRNA

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causes of triplet repeat expansion

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1. slippage of replication machinery; 2. unequal crossing over (recombination); triplet expansions occur during meiosis and can exhibit gender specificity; fragile X syndrome= expansion occurs predominantly during female meiosis; huntington disease= expansion occurs primarily in male meiosis

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what is epigenetics

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epigenetic modification of the genome and products (RNAs) through DNA methylation, histone acetylation, or translational regulation of mRNA by microRNAs; genome modification is a dynamic process through development, cellular differentiation, and X chromosome inactivation

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aberrant epigenetic modification examples

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cancer= inactivation of tumor suppressor genes by methylation (loss of heterozygosity); fragile X syndrome; genomic imprinting

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methylation of nucleotides in eukaryotes

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in eukaryotes only cytosine can be modified by methylation; this methylation always occurs in the context of CpG dinucleotide; consequences of this DNA methylation= alteration of chromatin structure, alteration of binding of proteins to DNA, alteration of gene expression patterns

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genomic imprinting definition

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involves an epigenetic modification of specific genomic regions that modulate expression based on parental origin of chromosomes; methylation of imprinted alleles inhibits their activity thus mutational events that inhibit the normally active alleles have significant clinical consequences; genomic imprinting= somatic cells have methylated alleles from a specific parent, at gamete formation the imprint is removed and all alleles are imprinted for the sex of the parent, when gametes form a zygote parent specific alleles are present; so PARENT OF ORIGIN SPECIFIC EXPRESSION OF GENES

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prader willi and angelman: the genetics

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ok so you have 2 chromosomes with 2 genes on each (so 4 genes total aka 2 pairs of the same gene); the chromosome from the mother has gene 2 methylated (inactivated) and the chromosome from the father has gene 1 methylated (inactivated) which leaves you with one functional gene1 and one functional gene2 so normal; problem arises when there is a deletion of one these 2 genes on one of the chromsomes; the thing is is that it is THE SAME deletion of the SAME 2 genes that results in two very different conditions depending on if it was the maternal or paternal chromosome having the deletion; these same conditions arise if there is uni parental disomy (aka UPD aka there was a trisomy of a chromosome and the cell was smart enough to boot one chromosome out but it doesn't know the difference between maternal and paternal so you might end with 2 paternal or 2 maternal) or if there was an imprinting error; ch 15

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clinical characteristics in prader willi

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not interested in eating early on but later has a real issue with overeating; mild intellectual disabilities; treatment= be careful with food intake

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clinical characteristics in angelman syndrome

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severe intellectual disability, happy demeanor (angel)

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mitochondrial disorders have the greatest effects in what tissues

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those that are energy greedy like muscle and brain tissue; these conditions are very rare

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mitochondrial disorder inheritance pattern

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from the mother only not because the sperm has no mito but because the egg has way way way more mito than the sperm

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what is heteroplasmy

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mito possess a circular genome physically separate from the nuclear genome; cells generally contain multiple mito; mito contain 2-10 copies of the mito genome; each cell may contain mito genomes that carry mutations in specific genes in a background of wild type genomes (heteroplasmy); the expression of a mutant phenotype will thus depend on the relative proportion of mutated versus wild type genomes; more mutant mito in a cell = greater severity of symptom in that cell

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leber's hereditary optic neuropathy presentation, genetics

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progressive blindness; there is no cure but antioxidant therapy may slow progression if caught early enough; 90% of individuals have mutations in one of the three genes on mtDNA genome and all are missense mutations in components of NADPH dehydrogenase complex; gender bias with 4:1 male:female; prenatal screening is complicated by hertoplasmy

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myoclonic epilepsy with ragged red fibers (MERRF): presentation, genetics

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myoclonus= involuntary muscle twitching followed by ataxia, epilepsy, weakness, and dementia; muscle biopsies reveal 'RAGGED RED FIBERS' when stained with trichrome stain; mitochondrial MT-TK gene encoding tRNA is mutated in 80% of cases (allelic heterogeneity); as in other mito disorders the phenotype depends on the degree of heteroplasmy, tissue distribution, and the threshold of mutation carrying mito

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mito encephalopathy, lactic acidosis, stroke like episodes: presentation, genetics

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generalized tonic clinic seizures, recurrent headaches, anorexia, and recurrent vomiting; 80% of those affected have mutation in MT-TL1 gene encoding tRNA

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conclusions: triplet expansion disorders occur due to

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expansion of unstable satellite repeats of 3 nucleotides

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conclusions: expansions may occur where, leading to what, an example

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in coding region, introns, or control regions of affected genes leading to differences in the mechanism by which each expansion leads to pathology; for example in fragile X syndrome the expansion leads to expansion of a PolyQ region in protein and aberrant protein activity

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conclusions: triplet expansion disorders display what

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genetic anticipation (earlier onset with more severe symptoms in subsequent generations)

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conclusions: genomic imprinting disorders are commonly associated with deletions of genes that display

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parent of origin patterns of expression

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conclusions: imprinting is associated with specific epigenetic modifications of

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parent specific chromosomal regions

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conclusions: mito disorders display what inheritance pattern and the severity of the phenotype is affected by what

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maternal inheritance patterns and the severity of the phenotype is affected by heteroplasmy