Duchene\'s muscular dystrophy is an X-linked disease characterized by gradual we

Question

Duchene's muscular dystrophy is an X-linked disease characterized by gradual weakening and wasting of muscle tissue. Usually the disease appears by 6 years of age and the patients are unable to walk by age 12. Death usually results from respiratory failure or infection, when the diaphragm muscles become affected. The gene for Duchene's muscular dystrophy has been cloned, and you are sequencing it to determine the defect. You obtain the following results- the coding stand sequence is shown.

Wild type:

5' CAG CTG CCC GAT TAT AGC GAG 3'

Mutant:

5' CAG CTG T AGC GAG CAA CAT 3'

What is the molecular defect (i.e. mutation) at the DNA level in this disease?

It is caused by a mutation of dystrophin gene.

Using the codon chart, determine the amino acid sequence encoded by each gene segment.   For this problem, remember that the sequence above is the coding sequence; in other words, the sequence above is that of the mRNA (with Ts instead of Us).

Wild type:    

Muscular dystrophy:

What is the defect in muscular dystrophy at the protein level?

UAU UAC UGC UUA UCA UAA Stop UGA Stop A UUG CUU cuC CUA CUG AUU AUCÌlle ACC! AAC? AGC| |C AUA AUG ACGAAGAGG GUU GUC GUA GUG Leu UCGUAG Stop UGG Trp G CCU CAU CGU CAC CCA CCG ACU CGA Gin CAG AAU AGU Ser ACA GCU GAU GGU GCC GAC Ala Gly GGA GCG GAG

Explanation / Answer

Ans. #1. Molecular defect (Mutation): Insertion of one or more nucleotides in the open reading frame of a gene may lead to frameshift mutation. Frameshift mutation is the insertion or deletion of on ‘n’ (here, n = 1) residues in the reading frame of mRNA, where n is NOT divisible by 3. It thus changes the reading frame of mRNA because the reading frame is shifted by a number not equal to 3 or its multiple – which is the basic unit (triplet codon) of translation.

#2. The sequence and polarity of mRNA is exactly the same as that of coding strand, except T in DNA is replaced by U in mRNA.

#A. Coding strand Wild type DNA: 5’- CAGCTGCCCGATTATAGCGAG—3’

            mRNA:            5’- CAGCUGCCCGAUUAUAGCGAG- 3’

            Protein (AA) sequence: Gln-Leu-Pro-Asp-Tyr-Ser-Glu

#B. Coding strand Wild type DNA: 5’- CAGCTGTAGCGAGCAACAT—3’

            mRNA:            5’- CAGCUGUAGCGAGCAACAU - 3’

            Protein (AA) sequence: Gln-Leu-STOP

Defect: There’s appearance of a STOP codon in the mRNA, thus causing premature termination of mRNA translation. The resultant mutant protein is non-functional because of having fewer amino acids than the wild-type protein.

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