Genotype and clinical phenotype analysis of autosomal recessive polycystic kidney disease caused by the novel compound heterozygous mutation of PKHD1 gene
10.3760/cma.j.cn441217-20231016-01025
- VernacularTitle:PKHD1基因新型复合杂合突变致常染色体隐性遗传多囊肾病的基因型和临床表型分析
- Author:
Junlan YANG
1
;
Siqi PENG
;
Zhiyuan WEI
;
Bin WANG
;
Fengmei WANG
;
Xiaobing WANG
;
Xiaoliang ZHANG
Author Information
1. 东南大学医学院，南京210009
- Keywords:
Polycystic kidney, autosomal recessive;
Mutation;
Genetic association studies;
PKHD1 gene
- From:
Chinese Journal of Nephrology
2024;40(6):451-457
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To analyze the mutation pathogenicity of the novel compound heterozygous mutation in the PKHD1 gene causing autosomal recessive polycystic kidney disease (ARPKD) family, expand the PKHD1 gene mutation database, and explore the genotype-phenotype correlations of PKHD1 gene mutation causing ARPKD. Methods:Clinical data and peripheral blood of a patient with ARPKD caused by the novel compound heterozygous mutation in the PKHD1 gene and their family members were collected. High-throughput sequencing was used to detect pathogenic mutations in the proband, and PCR amplification and Sanger sequencing were used to verify the pathogenic mutations in the family. AlphaFold software was applied to predict changes in protein structure in the present or absent mutations, and the pathogenicity of mutations was analyzed. Results:The patient was a young male who underwent splenectomy due to liver cirrhosis and hypersplenism at age 7. He developed end-stage renal disease at age 22, requiring maintenance peritoneal dialysis, and died of severe pneumonia and septic shock at age 24. Genetic testing revealed three compound heterozygous mutations in the PKHD1 gene inherited from his parents: a missense mutation (c.5935G>A) inherited from the father and a missense mutation (c.1187G>A) and a novel splice mutation (c.6332+1_6332+2insG) from the mother. The single missense mutation allele likely contributed to the prolonged survival. c. 6332+1_ 6332+2insG is a novel splicing mutation that has not been reported in the past, which can lead to early termination of protein translation. This discovery expands the PKHD1 gene mutation database. c. 1187G>A (p.S396N) and c.5935G>A (p.G1979R) occur in the PA14 and G8 domains of the protein, respectively, and are associated with early and severe liver phenotypes in patients. Conclusions:The mutation types and amino acid localization of the PKHD1 gene are associated with the heterogeneity of clinical phenotypes in ARPKD patients. Analyzing structural changes in proteins before and after mutations can help understand the pathogenicity at a molecular level, establishing genotype-phenotype correlations and providing valuable insights for assessing prognosis and identifying high-risk ARPKD patients early.
