WBR0118
| Author | [[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]] |
|---|---|
| Exam Type | ExamType::USMLE Step 1 |
| Main Category | MainCategory::Genetics |
| Sub Category | SubCategory::Musculoskeletal/Rheumatology |
| Prompt | [[Prompt::A 5-year-old boy is brought to the pediatrician's office by his parents for muscle weakness. The parents explain that when the child attempts to rise from the floor, he uses 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 likely to be observed in this patient?
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 3rd 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 G at the first position of the 4th codon in GGC causes a small frameshift mutation due to deletion of just 1 nucleotide. Small frameshift mutations account a smaller percentage of mutations that cause DMD. |
| Answer C | AnswerC::5'...ACA CCT TAC GGC CAT...3' |
| Answer C Explanation | AnswerCExp::This is a missense mutation due to replacement of G at the first position of the second codon by 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 1st and the 4th codons adjacent to each other. More than 60-70% of mutations in cases of DMD are characterized by large insertions or deletions that often involve more than one codon and disrupt the downstream 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 C at the second position of the first codon by A. |
| Right Answer | RightAnswer::D |
| 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. Gower's sign is defined as difficulty arising from a seated position that necessitates the use of hands to "walk up" one's own body to an upright position. Patients suspected to have DMD are usually first screened using creatine kinase (CK), which is markedly elevated among patients with DMD.
More than 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 is 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 cause Becker Muscular Dystrophy (BMD), a mild muscular dystophy with late onset, deletions that result in severely truncated proteins cause DMD. 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 likely to be observed in this patient. Verma S, Anziska Y, Cracco J. Review of Duchenne Muscular Dystrophy (DMD) for the pediatricians in the community. Clin Pediatr. 2010;49(11):1011-7 First Aid 2014 page 70]] |
| Approved | Approved::Yes |
| Keyword | WBRKeyword::Genetics, WBRKeyword::Gower sign, WBRKeyword::Gower's sign, WBRKeyword::Gower, WBRKeyword::Gower's, WBRKeyword::Mutation, WBRKeyword::Walk-up, WBRKeyword::Walk Up, WBRKeyword::Muscular dystrophy, WBRKeyword::Duchenne muscular dystrophy, WBRKeyword::Duchenne Muscular Dystrophy, WBRKeyword::DMD, WBRKeyword::Becker, WBRKeyword::Becker Muscular Dystrophy, WBRKeyword::Dystrophy, WBRKeyword::Large, WBRKeyword::Insertion, WBRKeyword::Deletion, WBRKeyword::Large insertion, WBRKeyword::Large deletion, WBRKeyword::Frameshift mutation, WBRKeyword::Frameshift Mutation |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |