PKHD1-Mutationsspektrum bei pädiatrisch betreuten Patienten mit autosomal-rezessiver polyzystischer Nierenerkrankung (ARPKD)

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of renal- and liver related morbidity and mortality in neonates and infants, occurring 1 in 20000-40000 live births. Principal histological manifestations involve the fusiform dilatation of renal collecting ducts and hepatobiliary ductal plate malformations. The clinical spectrum is widely variable. About 30 to 50% of affected individuals die in the neonatal period, while others survive into adulthood. ARPKD is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene on chromosome 6p12, which is among the largest human genes known until today. This is the first study analysing mutations and the mutation detection rate in the PKHD1 gene of pediatric ARPKD-patients. The study population consisted of 186 patients from 127 unrelated families. The DNA of each patient was screened for mutations in 66 encoding exons of the longest open reading frame of the PKHD1 gene by DHPLC and sequencing. The significance of each new sequence variation was evaluated by screening a control group of healthy individuals, performing a segregation analysis, and by using bioinformatical methods as well. The mutation detection rate was about 77%. Two mutations were found in 58% families, as could be expected in an autosomal-recessive disorder. One mutation was discovered in 39% families. Conclusively, 96% of patients had at least one mutation, confirming the diagnosis of ARPKD and establishing DHPLC screening as a powerful diagnostic tool in pediatric patients suspected with ARPKD. 78% of the pathogenic variations were missense mutations, only 22% were characterised as truncating ones. No patient carried two truncating mutations corroborating that one missense mutation is indispensable for survival of newborns. More than three quarters of the mutations were “private mutations”, i.e. were detected in one family only. Due to these private mutations and a great number of compound heterozygotes a correlation between genotype and phenotype is hard to establish. This study attempted for the first time to link all known recurrent mutations to date to four different clinical courses.