WBR0118

Author	PageAuthor::William J Gibson
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Musculoskeletal/Rheumatology, SubCategory::General Principles
Prompt	[[Prompt::A 5-year-old boy is brought to the physician by his parents for muscle weakness. When the child attempts to rise from the floor, he must use his hands and arms to “walk up” his own body. The boy undergoes genetic evaluation where portions of the DMD gene are subject to sanger sequencing of DNA. Assuming that all codons are exons of critical regions within the gene and the first three nucleotides constitute the first codon, which of the following DNA sequences is most commonly observed with this patient's condition? Reference Sequence: 5'...ACA GCT TAC GGC CAT...3']]
Answer A	AnswerA::5'...ACA GCT TAG GGC CAT...3'
Answer A Explanation	[[AnswerAExp::This is a nonsense mutation due to replacement of C to G at the 3rd position of the 3rd codon. The mRNA sequence will be read in a 5' to 3' fashion, and it will thus be identical to the reference sequence shown in the vignette with the exception of U replacing T. Thus, the first codon will be UAG, which is a stop codon that does not code for any amino acid but rather stops the process of mRNA transcription leading to a nonsense mutation.]]
Answer B	AnswerB::5'...ACA GCT TAC GCC ATT...3'
Answer B Explanation	AnswerBExp::The deletion of the G at the first position of the 4th codon in GGC causes a small frameshift mutation due to deletion of just 1 nucleotide.
Answer C	AnswerC::5'...ACA CCT TAC GGC CAT...3'
Answer C Explanation	AnswerCExp::This is a missense mutation due to replacement of the first G in the second codon by a C.
Answer D	AnswerD::5'...ACA CAT TCC AAT ATC...3'
Answer D Explanation	[[AnswerDExp::This sequence reflects the deletion of three codons (9 nucleotide) from the reference sequence 5'...ACA [GCT TAC GGC] CAT...3', making the first and the 4th codons adjacent to each other. 60% of mutations in cases of DMD are characterized by large insertions or deletions that often involve more than one codon and disrupt the reading frame.]]
Answer E	AnswerE::5'...AAA GCT TAC GGC CAT...3'
Answer E Explanation	AnswerEExp::This is a missense mutation due to replacement of the second C in the first codon by an A.
Right Answer	RightAnswer::B
Explanation	[[Explanation::Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disorder caused by mutations in the DMD gene, the largest gene known to the human genome, that normally encodes the protein dystrophin, a 427-kDNA cytoskeletal protein. DMD is the most common muscular dystrophy in children. It is characterized by progressive symmetric weakness and gait disturbance at early childhood, especially starting the age of 2 years. Nonetheless, diagnosis is often delayed till 5-6 years when symptoms become more pronounced. Common sign and symptoms include waddling, toe walking, lordotic posture, difficulty climbing stairs, calf pseudohypertrophy, Achilles tendon contractures, and positive Gower's sign, defined as difficulty arising from a seated position necessitating the patient uses his hands to "walk up" his own body to an upright position. Patients suspected to have DMD are usually first screening using creatine kinase (CK), which is usually markedly elevated among patients with DMD. Approximately 60-70% of mutations of the DMD gene are large insertions or deletions, whereas the remaining 30-40% are point mutations or small frameshift mutations. Frameshift mutations refer to the insertion or deletion of nucleotides that shift the reading frame of the mRNA. Severity of muscular dystrophy phenotype is caused by whether there was a reading frame disruption (mutation involving critical regions) vs. preservation (mutation not involving critical region) caused by the large deletions and insertions in the gene exons. While in-frame deletions that result in synthesis of semi-functional proteins causes Becker Muscular Dystrophy (BMD), a mild muscular dystophy with late onset, deletions that result in severely truncated proteins cause DMD. In this patient, the deletion of three codons (9 nucleotide) from the reference sequence 5'...ACA [GCT TAC GGC] CAT...3' is a large deletion, thus being the DNA sequence most commonly observed in this patient. Educational Objective: A frameshift is a genetic mutation caused by indels (insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. References: Nowak KJ, Davies KE. Duchenne muscular dystrophy and dystrophin. pathogenesis and opportunities for treatment. EMBO Rep. 2004;5(9):872-6 First Aid 2014 page 70]]
Approved	Approved::Yes
Keyword	WBRKeyword::Genetics, WBRKeyword::Mutation, WBRKeyword::Muscular Dystrophy, WBRKeyword::Duchenne Muscular Dystrophy, WBRKeyword::DMD
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