Genetics1.nonmendelian.mcv/vcu

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Non-Mendelian Inheritance (3)

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1. Mitochondrial Inheritance

2. Unstable Trinucleotide Repeats

3. Imprinting

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What are some features of Mitochondrial DNA and inheritance?

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-DNA also exists in the mitochondria
-There are thousands of mitochondria per cell
-In each mitochondria there are several circular chromosomes containing mtDNA

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Mitochondrial Genome

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-2 rRNAs

-22 tRNAs

-13 poly-peptides: subunits of enzymes of ox-phos

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Pedigree of Mitochondrial Inheritance

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With rare exception only a mother transmits her mtDNA to her offspring.

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Features of Mitochondrial Inheritance

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-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 (single gene has multiple phenotypes)

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Example of Mitochondrial inheritance disease.

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MERRF Myoclonus Epilepsy with Ragged Red Fibers

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Replicative segregation - Mitochondrial disease lineage.

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1. Homoplasmy-same mutation in all mitochondria (all progeny are affected) OR all mitochondria are the same - normal

2.Heteroplasmy-mutation present in only some mitochondria (some progeny are affected)

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Anticipation and Parent of Origin Effects

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Anticipation - phenomenon of disorder getting worse or having earlier age of onset in successive generations (in the CCS problem, or when affected individuals get Huntington's symptoms sooner than the previous generation)

Parent of Origin Effects – sex of parent transmitting the disorder influenced severity or age of onset

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Trinucleotide Repeats

Non-Mendelian inheritance

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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

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-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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Fragile X Syndrome (allele)

FMR-1 gene identified and found to have a ‘CGG’ trinucleotide repeat region in the untranslated portion of exon 1

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Allele sizes (approximate):

-Normal: about 5-54 repeats

-Premutation: about 55-200 repeats

-Full: > 200 repeats

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Fragile X Syndrome (male and female transmission)

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Non Mendelian X-linked condition

-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 metal retardation, but their daughters will be at risk to have an affected child

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Fragile X Syndrome (onset of changes)

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-Change from phenotypically normal to affected state has only been observed following oogenesis

-Expansion of premutation to full mutation may only occur during oogenesis (i.e. when inherited from the mother). Remember that children of male carriers will only produce daughters who can pass on the disease.

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Fragile X Syndrome (overview and causes)

One of the most common causes of inherited mental retardation and neuropsychiatric disease in human beings, affects as many as one in 2000 males and one in 4000 females.

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-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

-Approximately 15-25% of individuals with fragile X syndrome also are diagnosed with mild to moderate autism and autism spectrum disorders.

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Huntington Disease overview

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-Autosomal Dominant

-Progressive disorder of motor, cognitive, and psychiatric disturbances

-Incidence of ~ 1/20,000

-Mean age of onset is 35-44 years; range of 15 to 70+ years

-Median age of survival is 15-18 years after diagnosis

-Neuronal loss in basal ganglia

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Huntington Disease overview cont.

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-Inherited from father = earlier onset of 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

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Trinucleotide Disease Mechanisms

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-Expansion of trinucleotide repeat

-Interference with normal degradation and/or transport of protein

-Interference with transcription, RNA processing, translation

-Still learning…..hope is that better understanding will lead to better treatments

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Genetic Imprinting definition

Is this different from Parent of Origin Effect?

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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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Examples of Parent of Origin Effects

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1. Fragile X Syndrome
-Expansion of premutation to full mutation only when inherited from mother

2. Huntington disease
-Earlier age of onset when inherited from father

3. Myotonic dystrophy
-Earlier age of onset and increased severity when inherited from mother

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Implications of Imprinting

Imprinting is independent of the classical Mendelian inheritance.

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-Imprinted genes are either expressed only from the allele inherited from the mother or father (parent-of-origin specific)

-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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PWS & AS both involve chromo 15q11-13

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Uniparental disomy also causes some cases of PWS & AS

-If maternal UPD (paternal deletions/no paternal contribution at 15q11-13) → PWS

-If paternal UPD (maternal deletions/no maternal contribution at 15q11-13) → AS

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Molecular Mechanisms for Imprinting

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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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Prader-Willi Syndrome (PWS) - review for Jackson-Cook

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-Hypotonia in infancy

-Mental retardation

-Voracious appetite, obesity

-Short stature

-Small hands and feet

-Hypogonadism

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Angelman Syndrome (AS) - review for Jackson-Cook

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-Mental retardation

-Short stature

-Spasticity

-Seizures

-“Happy puppet syndrome”

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Myotonic Dystrophy

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-Muscles have trouble relaxing
-Shake hands test
-Over the time the muscles go lax
-Most common form of MD in adults
-Progressive muscle wasting & atrophy, myotonia, cataracts, develop. delay, and cardiac conduction defects

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Myotonic Dystrophy Continued

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-greater # of repeats = increased severity and earlier onset
-when inherited from MOM = increased severity and earlier onset (ANTICIPATION)
-Variable expressivity
-Incidence of ~ 1/8000
-Mean age of onset is 20-25 years
-Autosomal dominant with late onset

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DM Type 2

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-Due to expanded ‘CCTG’ repeat in the Zinc Finger Protein 9

-Need genetic testing to distinguish between DM 1 and DM 2

-Can't tell clinically the difference from type 1 and type 2

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Disease Mechanisms for Conditions Caused by Unstable Trinucleotide Repeats

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-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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Trinucleotide Disease Mechanisms

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-Expansion of trinucleotide repeat

-Interference with normal degradation and/or transport of protein

-Interference with transcription, RNA processing, translation

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Define Maternal Disomy

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-Inherited both copies from Mom

-bad because you need genes from mom and dad to be normal

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Praeder Willi and Angelman Syndrome. What about parental activation?

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PWS - need chromosome from Dad with active Praeder Willi Gene

AS- need chromosome from Mom with active AS gene

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When do mistakes in these processes occur?

Isodisomy

Unidisomy

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Isodimoy - mistake in M2

Unidisomy - mistake in M1