7. The pedigree below is of a family with Huntington disease, a dominant conditi

Question

7. The pedigree below is of a family with Huntington disease, a dominant condition that leads to dementia. The numbers indicate the number of tri-nucleotide repeats associated with the alleles of the Huntington's gene in each individual. In this family, the individual with light stippling developed the disease at age 75. His two sons developed more severe symptoms that appeared at ages 48 and 55, respectively. The affected grandchildren were diagnosed with the disease in their 30's. 18, 17 36, 20 17,15 18, 41 21, 16 17,44 17, 10 17.46 i. What is happening to the Huntington's gene in this family? ii. What process(es) might lead to this result? ili. How does age of onset of disease correlate with the expanding nucleotide repeat?

Explanation / Answer

1) Huntington's disease or Huntington's chorea is a neurodegenerative disease. It is caused due to an autosomal dominant mutation in an individual's Huntingtin gene which results in expansion of a trinucleotide repeat CAG. Normally individuals with fewer less than 36 repeats of this codon CAG are normal. But, in this family, it is found that in successive generations, the number of this tri nucleotide repeats in Huntingtin gene is increasing .

ii) This condition is caused due to an autosomal dominant mutation in Huntingtin gene which causes increased CAG repeats. The codon CAG codes for an amino acid Glutamine. So, increased CAG repeats in Huntingtin gene causes overproduction of the amino acid Glutamine in Huntingtin protein , which has severe negative impact in brain cells. They are found to interfere with Transcription factor sp1 and with TFIID, a component in transcription machinery. So, this imapirs transcription in brain cells and ultimately results in neurodegeneration.

iii) Since, the disease is autosomal dominant, the offspings of effected parent has a 50 % chance of inheriting the mutated gene. They are at a higher risk of Huntington's disease. So, in such cases, the huntingtin gene of the offspring has already an increased CAG repeats (ie, in normal condition itself they show increased CAG repeats). Hence the symptoms of the disease appears in successive generations much earlier than they appeared in their ancestral population.

This is the reason why, in this family the first generation showed symptoms at the age of 75, while in second generation it appeared by the age of 48, 55. And in third generation, the grand children was diagnosed with the disease in early 30's.

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