1. Huntington disease (HD) is an inherited neurodegenerative disorder, character
ID: 3508514 • Letter: 1
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1. Huntington disease (HD) is an inherited neurodegenerative disorder, characterized by the gradual, irreversible impairment of psychological, motor, and cognitive functions. Symptoms typically appear in middle age, but onset can occur at almost any age. The course of the disease can last 15 to 20 years. The molecular basis of the disease is becoming better understood. The genetic mutation underlying HD has been traced to a gene encoding a protein (M 350,000) of unknown function. In individuals who will not develop HD, a region of the gene that encodes the amino terminus of the protein has a sequence of CAG codons (for glutamine) that is repeated 6 to 39 times in succession. In individuals with adult-onset HD, this codon is typically repeated 40 to 55 times. In individuals with childhood-onset HD, this codon is repeated more than 70 times. The length of this simple tri-nucleotide repeat indicates whether an individual will develop HD, and at approximately what age the first symptoms will occur A small portion of the amino-terminal coding sequence of the 3,143-codon HD gene is given below. The nucleotide sequence of the DNA is shown, with the amino acid sequence corresponding to the gene below it, and the CAG repeat is shaded. Translate the genetic code and outline a PCR-based test for HD that could be carried out using a blood sample. Assume the PCR primer must be 25 nucleotides long. By convention, unless otherwise specified a DNA sequence encoding a protein is displayed with the coding strand (the sequence identical to the mRNA transcribed from the gene) on top such that it is read 5' to 3', left to right. a. 307 A GTCCTTC 358 18 QF QQ Q Q Q Q Q Q Q 409 35 QQ P PP P P PP P 460 CCGCCTCCTCAGCTTCCTCAGCCGCCGCCGExplanation / Answer
Amino acid sequence for the given sequence: methionine, alanine, threonine, leucine, glutamine, lysine, leucine, methionine, lysine, alanine, phenylalanine, glutamine, serine, leucine, lysine, serine, phenylalanine, glutamic acid, glutamic acid, phenylalanine, glutamic acid (23 times repeated), proline (11 times repeated), glutamine, leucine, proline, glutamic acid, proline, proline, proline.
It should be kept in mind that when DNA is translated to m-RNA then T is replaced by Uracil U. Then the sequence is given as follows:
5'
AUGGCGACCCUGGAAAAGCUGAUGAAGGCCUUCGAGUCCCUC
M A T L E K L M K A F E S L
AAGUCCUUCCAGCAGUUCCAGCAGCAGCAGCAGCAGCAGCAG
K S F Q Q F Q Q Q Q Q Q Q Q
CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAA
Q Q Q Q Q Q Q Q Q Q Q Q Q Q
CAGCCGCCACCGCCGCCGCCGCCGCCGCCGCCGCCGCAG
Q P P P P P P P P P P P Q
CUUCCUCAGCCGCCGCCG 3'
L P Q P P P
The sequence of amino acid is same as that of the above given sequence.
For diagnosis of HD the prerequisite is the family history of such condition and then required is the physical and psychological condition of the individual. For performing a blood test PCR is the best technique to be used and the results are not confirmatory but they can be used as an aid to confirm the disease occurence in future i.e., in age group of 30-50 years. In this case the primer used is 25 nucleotide long. For the disease to occur atleast 25 successive repetitions are required and in this case there are only 23 successive repetitions so the individual is not prone to HD. If the repetitions are above 25 ranging to 70 then basing on the range the occurence of disease can be assumed. This is not a confirmatory test but only an aid to assume the occurence of disease.
Apart from this test fMRI, CT PET scans can be performed which visualise the atrophic changes of brain tissue as the disease progresses.
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