Passage
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common heterogeneous disorders, with a reported incidence of 1 in 1,000 people. The primary pathology is the development of numerous fluid-filled renal cysts that ultimately expand and severely impair kidney function. By age 60, approximately 50% of patients with ADPKD progress to end-stage renal disease (ESRD) and kidney failure. Clinical complications include high blood pressure, urinary tract infections, and cysts in other organs such as the liver and pancreas.Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, which codes for the protein polycystin-1 (PC1) . The remaining 15% of cases are caused by mutations in the PKD2 gene, which codes for the protein polycystin-2 (PC2) . The PC2 protein functions as a mechanically activated calcium (Ca²⁺) channel in ciliated renal epithelial cells. PC1 and PC2 interact via their C-terminal cytoplasmic tails to form a heteromer that modulates intracellular calcium homeostasis. Disruption of calcium signaling as a result of mutations in either PKD1 or PKD2 is associated with increased cell growth and cyst formation in ADPKD patients.To identify individuals with mutations in PKD1 and PKD2, researchers analyzed phenotypic and genetic data from patients with established renal disease, as shown in Table 1.Table 1 Comparison of Renal Disease Onset and Symptom Severity in Various Patient Groups
Next, researchers examined how phenotypic disease severity was affected by both the position of the mutations in PKD1 (5′ or 3′ end) and the type of mutation in PKD1 or PKD2. In Figure 1, disease severity is given as the cumulative probability of renal survival as a function of age.
Figure 1 Probability of maintaining healthy kidney physiology as a function of age, analyzed by mutation type and position
Adapted from Cornec-le gall E, Audrézet MP, Chen JM, et al. J Am Soc Nephrol. 2013;24(6) :1006-13.
-Which of the following DNA mutations would always lead to truncated PC1 if observed in the coding strand of the PKD1 gene shown below?

Question

Passage
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common heterogeneous disorders, with a reported incidence of 1 in 1,000 people. The primary pathology is the development of numerous fluid-filled renal cysts that ultimately expand and severely impair kidney function. By age 60, approximately 50% of patients with ADPKD progress to end-stage renal disease (ESRD) and kidney failure. Clinical complications include high blood pressure, urinary tract infections, and cysts in other organs such as the liver and pancreas.Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, which codes for the protein polycystin-1 (PC1) . The remaining 15% of cases are caused by mutations in the PKD2 gene, which codes for the protein polycystin-2 (PC2) . The PC2 protein functions as a mechanically activated calcium (Ca²⁺) channel in ciliated renal epithelial cells. PC1 and PC2 interact via their C-terminal cytoplasmic tails to form a heteromer that modulates intracellular calcium homeostasis. Disruption of calcium signaling as a result of mutations in either PKD1 or PKD2 is associated with increased cell growth and cyst formation in ADPKD patients.To identify individuals with mutations in PKD1 and PKD2, researchers analyzed phenotypic and genetic data from patients with established renal disease, as shown in Table 1.Table 1 Comparison of Renal Disease Onset and Symptom Severity in Various Patient Groups

Next, researchers examined how phenotypic disease severity was affected by both the position of the mutations in PKD1 (5′ or 3′ end) and the type of mutation in PKD1 or PKD2. In Figure 1, disease severity is given as the cumulative probability of renal survival as a function of age.

Figure 1 Probability of maintaining healthy kidney physiology as a function of age, analyzed by mutation type and position
Adapted from Cornec-le gall E, Audrézet MP, Chen JM, et al. J Am Soc Nephrol. 2013;24(6) :1006-13.
-Which of the following DNA mutations would always lead to truncated PC1 if observed in the coding strand of the PKD1 gene shown below?

Quizplus · Accepted Answer

11ecba2d_0f90_b872_a3bf_f75fd9935175_MD0008_00 When DNA is transcribed, the noncoding DNA strand is read by RNA polymerase to produce a complementary 5′ to 3′ mRNA strand. As a result, the mRNA transcript is always identical to the coding DNA strand with one exception: RNA has uracil instead of thymine. Transcription is followed by translation (protein synthesis), a process in which the ribosome reads the mRNA transcript in a 5′ to 3′ direction until a stop codon (UAA, UAG, or UGA) is recognized, causing translation termination and polypeptide release. Mutations are changes in the DNA sequence that arise from errors in replication or from mutagen exposure (manmade or environmental). A nonsense mutation is a point mutation in which a single nucleotide change creates a premature stop codon, causing early translation termination and production of a truncated (shortened) protein. The insertion of an adenine nucleotide after the second nucleotide in the PDK1 coding sequence produces TGA, which corresponds to UGA in mRNA. This is a nonsense mutation that results in truncated PC1. (Choice A) A G→T substitution at the second nucleotide does not produce a premature stop codon. Instead, this is either a silent or a missense mutation, meaning the nucleotide change corresponds to the same amino acid as in the original sequence or to a different amino acid, respectively. (Choice B) Frameshift mutations result from the insertion or deletion of a number of nucleotides not divisible by three. These mutations change the reading frame of the transcript, giving rise to proteins with altered amino acid sequences. They may also generate truncated proteins if a downstream stop codon is present in the new reading frame. Deletion of the guanine nucleotide at the fifth position changes the reading frame but does not generate a stop codon. (Choice C) Insertion of three cytosine nucleotides after the third nucleotide generates neither a nonsense mutation nor a frameshift mutation with a downstream stop codon. Instead, the resulting polypeptide will simply contain one additional amino acid that corresponds to the CCC triplet. Educational objective: Various types of DNA mutations can alter the protein product of a gene. Truncated proteins result from nonsense mutations and frameshift mutations with a downstream stop codon (UAA, UAG, UGA) in the new reading frame.

Passage Autosomal Dominant Polycystic Kidney Disease (ADPKD) Is One of the the Most