A 16-year-old girl with a history of anemia since childhood is evaluated for a genetic abnormality after several members of her family are also found to be anemic. It is determined that she has a point mutation in the β globin gene, which has resulted in the substitution of guanine (G) with cytosine (C) in the mRNA sequence shown below (+1 position indicates start codon). Which of the following cellular processes is most likely impaired due to this patient's gene mutation?

Question

A 16-year-old girl with a history of anemia since childhood is evaluated for a genetic abnormality after several members of her family are also found to be anemic.  It is determined that she has a point mutation in the β globin gene, which has resulted in the substitution of guanine (G) with cytosine (C) in the mRNA sequence shown below (+1 position indicates start codon).  Which of the following cellular processes is most likely impaired due to this patient's gene mutation?

Quizplus · Accepted Answer

11ec160b_377d_b7e6_9249_1d82e8efd893_MD0001_00 This patient has β thalassemia due to a mutation in the β globin gene just before the methionine start codon (AUG) that is most likely disrupting translation initiation. Eukaryotic translation initiation requires the assembly of ribosomal subunits (60S and 40S), mRNA, initiation factors, initiator tRNA charged with methionine, and guanosine-5'-triphosphate (GTP). The small ribosomal subunit (40S) initially binds to the 5' cap of mRNA and scans for the start codon, which is positioned near the beginning of the mRNA and is surrounded by the Kozak consensus sequence. This short sequence identifies the specific AUG codon that serves as the initiator of translation (analogous to the Shine-Dalgarno sequence in bacteria). Mutations affecting the Kozak consensus sequence can significantly impair protein translation and have been identified in patients with α and β thalassemias. (Choice A) Co-translational protein targeting is mediated by the N-terminal amino acid sequence of an elongating polypeptide. This localization signal is recognized by a signal recognition protein that helps transport the ribosome to the rough endoplasmic reticulum (ER). Mutations affecting the signal sequence would be found after the start codon (AUG). (Choice C) Peptide bond formation is catalyzed by peptidyl transferase, an RNA enzyme ("ribozyme") that resides in the large ribosomal subunit. A defect in rRNA coding for ribosomes would interfere with this process. (Choice D) During polypeptide elongation, the ribosome moves 3 nucleotides toward the 3' end of mRNA, advancing peptidyl tRNA from the A site to the P site (translocation). Translocation is catalyzed by elongation factor 2 and requires GTP hydrolysis. (Choice E) Termination of polypeptide synthesis occurs at stop codons. Mutations in stop codons (nonstop mutations) can result in continued and inappropriate translation of mRNA into the 3'-untranslated region, producing an excessively long, nonfunctional polypeptide. Educational objective: The Kozak consensus sequence occurs on eukaryotic mRNA and helps initiate protein translation by identifying the proper methionine start codon (AUG). __________ References: Diversity of preferred nucleotide sequences around the translation initiation codon in eukaryote genomes. (http://www.ncbi.nlm.nih.gov/pubmed/18086709) Beta-thalassemia. (http://www.ncbi.nlm.nih.gov/pubmed/20098328)

A 16-Year-Old Girl with a History of Anemia Since Childhood