Trinucleotide Repeats

Question 1

Characteristics of Fragile-X Syndrome

Answer 1

most common inherited cause of mental retardation, phenotypes often not severe, large ears, adult males have large testes

50% of females are retarded and/or demonstrate the fragile site, 20% of males are transmitting males but are phenotypically and cytogenetically normal

Question 2

FMR-1 Gene

Answer 2

causes fragile-X, close to site of apparent breakage

has a trinucleotide repeat in one of its non-coding regions, and when this gets long, the CpG island near the promoter gets methylated, and less protein is formed

Question 3

Describe the lenghts of trinucleotide repeats in FMR and how they relate to disease

Answer 3

28 repeats is normal

55-200 gives is a premutation but also has a normal phenotype

>200 repates causes mental retardation

Question 4

expnsion of the trinucleotide repeats in FMR-1

Answer 4

premutations - meiotically unstable in oogenesis and tend to expand, mitotically stable

full mutations - meiotically unstable in oogenesis and also mitotically unstable, which leads to mosaicism for size of expanded repeat

Question 5

Are premutation carriers really carriers?

Answer 5

40% of male premutation carriers develop tremor/ataxia syndrome after age 50, ANS and memory problems

20% of female permutation carriers develop primary ovarian failure

Question 6

anticipation

Answer 6

the appearance of a genetic trait at an earlier age or with greater severity in successive generations

Question 7

diseases with repeat segments in non-coding regions

Answer 7

Fragile-X Syndrome

Myotonic Dystrophy

Friedreich’s Ataxia

Question 8

diseases with repeat segments in coding regions

Answer 8

spinal and bulbar muscular atrophy

Huntington Disease

Question 9

Friedreich’s Ataxia

Answer 9

most common inherited ataxia, autosomal recessive, mapped to chromosome 9 - frataxin

associated with expansion of GAA repeat in the first intron

onset typically before 20 years

ataxia of all four limbs, cerebellar dysarthria, absent reflexes, sensory loss, pyramidal signs, cardiomyopathy, skeletal deformities, glucose inolerance/diabetes

Question 10

myotonic dystrophy

Answer 10

autosomal dominant, CTG repeat in 3’ untranslated region of protein kinase

progressive weakness and myotonia, cataracts, arrhythmia, hypogonadism, male pattern baldness, cognitive impairment

usual onset 20-30 years of age

Question 11

repeat length and severity of myotonic dystrophy

Answer 11

increased repeats makes it higher risk of getting the disease and at a younger age

Question 12

complete androgen insensitivity syndrome

Answer 12

“testicular feminization” - mutations in androgen receptor (X-linked)

affects only 46,XY males - sex-limited, normal external genitalia, blind vagina, presence of testes, absent uterus and ovaries

normal testosterone production, failure of virilization at puberty, aromatization of androgens to estrogens, no neurologic disease

Question 13

SBMA - Kennedy Disease

Answer 13

slow progressive loss of spinal cord and bulbar motor neurons, weakness of skeletal and facial musculature

onset during third decade

striking gynecomastia is the first sign, reduced fertility and testicular atrophy

X-linked recessive

Question 14

Cause of SBMA

Answer 14

tinucleotide repeat in the androgen receptor gene, same gene that produces andorgen insensitivity

expansion of the trinuclear repeate, evidence of feminization

CAG repeat causes a polyglutamine tract in exon 1, expansion results in increase from 11-34 to 40-62

expansion more often in male meioses

gain of function effect

Question 15

trinucleotide repeat diseases

Answer 15

Fragile-X Syndrome

Myotonic dystophy

Friedreich’s Ataxia

SPinall and Bulbar Muscular Atrophy

Huntington Disease

Spinocerebellar Ataxia Type 1

Dentatorubral-Pallidoluysian Atrophy

Machado-Joseph Disease