A 5-year-old boy is being evaluated for progressive muscle weakness that has resulted in numerous recent falls. There is no family history of muscle disorders. Physical examination reveals bilateral calf enlargement. When the patient is asked to stand, he uses his hands and arms to help push himself to an upright position. Serum creatine kinase is 12,600 U/L (normal: 30-170 U/L). Molecular tests reveal a large muscle protein that is defective due to the loss of 508 amino acid residues. Genetic analysis reveals a single base substitution within exon 48 of the gene encoding this muscle protein. This patient's gene mutation has most likely resulted in which of the following mRNA codon changes?

Question

A 5-year-old boy is being evaluated for progressive muscle weakness that has resulted in numerous recent falls.  There is no family history of muscle disorders.  Physical examination reveals bilateral calf enlargement.  When the patient is asked to stand, he uses his hands and arms to help push himself to an upright position.  Serum creatine kinase is 12,600 U/L (normal: 30-170 U/L).  Molecular tests reveal a large muscle protein that is defective due to the loss of 508 amino acid residues.  Genetic analysis reveals a single base substitution within exon 48 of the gene encoding this muscle protein.  This patient's gene mutation has most likely resulted in which of the following mRNA codon changes?

Quizplus · Accepted Answer

11ec160b_376f_5fe6_9249_a1d32ceeaa39_MD0001_00 This young boy with progressive proximal muscle weakness, calf pseudohypertrophy, Gowers sign, and elevated creatine kinase likely has Duchenne muscular dystrophy, an X-linked recessive disorder caused by mutations in the dystrophin gene. Although Duchenne muscular dystrophy is most commonly caused by deletions resulting in frameshift mutations, nonsense mutations may also occur, leading to the formation of a truncated dystrophin protein. After messenger RNA (mRNA) is produced from DNA and posttranscriptionally modified, it is transported to the cytoplasm for translation into protein. mRNA is composed of groups of 3 sequential nucleotide bases known as codons. These nucleotide triplets code for specific amino acids and signal for the initiation (eg, start codon [AUG]) or termination of translation (eg, stop codons [UAA, UAG, UGA]). In this case, a single base substitution from UCA (serine) to UGA has introduced a premature stop codon in the middle of the protein sequence (nonsense mutation), resulting in early termination of protein synthesis. Dystrophin normally links with actin fibers and provides mechanical reinforcement to glycoprotein complexes in the plasma membrane of skeletal muscle cells. Consequently, dystrophin dysfunction leads to increased breakdown of the sarcolemma, muscle fiber degeneration, and the clinical findings described above. (Choices A and C) Changing CUU (leucine) to AUU (isoleucine) or UAC (tyrosine) to CAC (histidine) would result in an amino acid substitution at one position (missense mutation). The function of this protein may be altered depending on a variety of factors, but the ultimate size of the protein will remain the same. Missense mutations that result in the substitution of a new amino acid with similar chemical properties are called conservative mutations. (Choice B) Changing UAA to UAG would not affect protein structure or function because both of these sequences are stop codons. Stop codons are normally located at the end of the translated region of mRNA. (Choice E) Changing UUU to UUC would not affect the protein as both sequences code for phenylalanine. Point mutations that do not change the amino acid sequence of a protein are called silent mutations. Educational objective: Duchenne muscular dystrophy presents with progressive proximal muscle weakness in young boys due to increased muscle fiber degeneration. It is caused by frameshift mutations (most common) or nonsense mutations in the dystrophin gene that lead to the formation of a truncated, defective protein. Nonsense mutations introduce premature stop codons (eg, UAA, UAG, UGA) in the coding sequence of mRNA. __________ References: Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center. (http://www.ncbi.nlm.nih.gov/pubmed/20485447)

A 5-Year-Old Boy Is Being Evaluated for Progressive Muscle Weakness