An 8-year-old boy of Ashkenazi Jewish ancestry is brought to the office after developing reduced sensitivity to pain, impaired tear formation, and orthostatic hypotension. Familial dysautonomia is suspected due to the patient's symptoms and heritage. This disorder is caused by loss of function of the IKAP protein, which is essential for development and survival of sensory and autonomic neurons. IKAP gene sequencing reveals a single nucleotide substitution that causes a guanine residue to be replaced by adenine at the highlighted position in the normal gene sequence shown below. Exon sequences are represented by capital letters and introns by lowercase letters. Which of the following is the most likely effect of this mutation?

Question

An 8-year-old boy of Ashkenazi Jewish ancestry is brought to the office after developing reduced sensitivity to pain, impaired tear formation, and orthostatic hypotension.  Familial dysautonomia is suspected due to the patient's symptoms and heritage.  This disorder is caused by loss of function of the IKAP protein, which is essential for development and survival of sensory and autonomic neurons.  IKAP gene sequencing reveals a single nucleotide substitution that causes a guanine residue to be replaced by adenine at the highlighted position in the normal gene sequence shown below.  Exon sequences are represented by capital letters and introns by lowercase letters.  Which of the following is the most likely effect of this mutation?

Quizplus · Accepted Answer

11ec160b_3775_efa2_9249_29c38334f0c7_MD0001_00 Following transcription, pre-mRNA is the initial transcript that contains both intron and exon sequences. Before leaving the nucleus, pre-mRNA must be processed to mature mRNA by 3 post-transcriptional modifications: 5' methylguanosine capping, addition of a 3' polyadenine (Poly A) tail, and splicing. Splicing is performed by spliceosomes, which are complexes of small nuclear ribonucleoproteins (snRNPs) and other proteins that assemble on pre-mRNA. Spliceosomes remove introns containing GU at the 5' splice site and AG at the 3' splice site. Initially, the 5' end of intron 1 (splice donor site) is cleaved and joined to the branch point. The freed 3'-OH of exon 1 then forms a phosphodiester bond with the 5'-phosphate at the splice acceptor site, joining exons 1 and 2. Mutations at splice sites may result in inappropriate removal of exons and retention of introns. This often leads to the formation of proteins with impaired structure and function as described in the case above. (Choice A) Polyadenylation of the 3' end of mRNA is performed by the enzyme polyadenylate polymerase. This process stabilizes mRNA and helps it exit the nucleus. (Choices B and D) In eukaryotes, translation is initiated when the small ribosomal subunit attaches to the 5' cap of mRNA and then scans for the AUG start codon within the Kozak consensus sequence. The 5' cap also protects against exonucleases and helps stabilize mRNA in the cytosol. (Choice E) Termination of polypeptide synthesis occurs at the 3 stop codons (UAA, UAG, UGA) in mRNA. Mutations in stop codons (nonstop mutations) can result in continued and inappropriate translation of mRNA into the 3'-untranslated region, producing an extremely long, nonfunctional polypeptide. Educational objective: Splicing is performed by spliceosomes, which remove introns containing GU at the 5' splice site and AG at the 3' splice site. Splice site mutations may result in inappropriate removal of exons and retention of introns, leading to the formation of dysfunctional proteins. __________ References: Familial dysautonomia is caused by mutations of the IKAP gene. (http://www.ncbi.nlm.nih.gov/pubmed/11179021) RNA splicing: disease and therapy. (http://www.ncbi.nlm.nih.gov/pubmed/21628314) The pathobiology of splicing. (http://www.ncbi.nlm.nih.gov/pubmed/19918805)

An 8-Year-Old Boy of Ashkenazi Jewish Ancestry Is Brought to the Office