Non-Mendelian Inheritance II

Non-Mendelian Inheritance II: Dynamic Mutations and Triplet

Repeat Diseases

Triplet Repeat Diseases

Newly identified type of genetic alteration

Dynamic disorders. Involve expansion of a set of 3 nucleotide sequences: CAG, CGG, GAA.

Approximately 10 such diseases are known, including: Fragile X, Huntingtons, Myotonic Dystrophy, and Freidrich Ataxia.

"Rules":

(1) Severity of the phenotype is highly correlated with the degree of expansion of the triplet repeat.
(2) Expression increases with subsequent generations (genetic anticipation). If dad had the disease at 50, son will get it at 30, and the grandson will get it as an infant.
(3) Usually specific to either maternal or paternal meiosis (the worsening of the phenotype is sex specific).
(4) Affects both males and females.

Fragile X syndrome

One of the most common causes of mental retardation, with a prevalence of 1/2000 – 1/6000.

Clinical: mental retardation, autism, large testicles, characteristic facial findings (long face, big ears), premature ovarian failure.

Inheritance: "Sherman Paradox" – not a classic x-linked recessive disorder (now known to be x-linked dominant):

(1) Excess of affected females.

(2) Unaffected transmitting males (asymptomatic carrier males).

(3) Ý severity per generation (anticiptation).

Molecular etiology: The Fragile X gene is FMR1. Though it’s function is uncertain, it is known to express in the CNS. This gene contains unstable (stable in most people) expandable CGG trinucleotide repeat in the 5’ UTR (untranslated region) of exon 1. The repeat exists in three states: Normal (5-50 repeats), Pre-mutation (60-200 repeats), Full mutation (>200 repeats). Note: >200 repeats causes excessive methylation of the FMR1 gene, which shuts off protein production.

The three states explains a number of the clinical observations:

(1) A pre-mutation mother may have an unaffected son (carrier) who then has daughters with the disease.
(2) This also explains the worsening of the condition by generation (as the triplet repeat expands).

Expansion occurs in female meiosis only. As such, expansion is not seen in males. This explains the male carriers.

Never occurs from normal Þ full mutation without passing through the pre-mutation state.

The likelihood that a pre-mutation will expand to a full mutation is greater for pre-mutations with higher repeat numbers.

Huntington Disease

Inheritance: Autosomal dominant trait, complete penetrance, variable expressivity.

Prevalence: 3/100,000 – 7/100,00

Clinical: progressive dementia, involuntary movements (chorea), psychiatric distrubances.

Age of onset and clinical course are variable (onset <20 y/o rapid onset and decline, onset >60 y/o slower progression). Death occurs within ten years.

If heterozygous, will manifest evidence of the disease if live long enough.

90% familial, 5% of cases become symptomatic 1^st decade of life.

Pathology: neuronal loss and gliosis of caudate and putamen.

Molecular basis: Huntington gene, locus 4p16.3. Real function unknown. All inherited through affected father.

HD is caused by an unstable expansion of CAG repeat within the open reading frame of the gene.

The three stages are: Normal (10-29 repeats), Pre-mutation (29-36 repeats), HD (37-120 repeats). Varies by family.
CAG codes for glutamine. Polyglutamine expansion causes a new/toxic function.
Greater expansion = earlier onset of symptoms (Faster toxic build up?).
Expansion only occurs through males who carry a pre-mutation.

Myotonic Dystrophy

Myotonic = unable to relax muscles.

The most common autosomal muscular dystrophy.

Incidence: 1/7-8000

Clinical: progressive weakness of face, neck, extremities. Myotonia, cataracts, diabetes, cardiac arrhythmias.

Variable age of onset: prenatal – 60s. 20-25 y/o most common.

Congenital Myotonic Dystrophy – most severe presentation. Pre-natal onset, many die as neonates (25% mortality).

Always inherited through mother.

Long term survivors are mentally retarded.

Genetics: Autosomal dominant; ß function of myotin protein kinase gene.

Gene location = 19q.

Three stages: Normal (5-40 repeats), Pre-mutation (50-100 repeats), MD (>100 repeats).
There is a strong correlation to expansion size and severity of phenotype.
Expansion always through mother. There are very few (if any) new mutations.

Friedrich’s Ataxia

Clinical: progressive limb ataxia, dysarthria, hypertrophic cardiomyopathy, pyramidal weakness in legs.

Genetics: Chromosome 9, GAA repeat, Autosomal recessive.

Expansion occurs in introns!!!

SUMMARY:

Disease	Inheritance	Expansion through…	Location of expansion
Fragile X syndrome	X-linked Dominant	Mother	5’ Untranslated region
Huntington Disease	Autosomal Dominant	Father	Exon
Myotonic dystrophy	Autosomal Dominant	Mother (congenital form)	3’ Untranslated region
Friedrich’s Ataxia	Autosomal Recessive	Both (because autosomal recessive)	Intron