Background: Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in 9 genes (NPHP1-9) have been identified. NPHP can be associated with retinal degeneration (Senior-Løken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis.
Methods: To identify a causative gene for the subset of patients with associated liver fibrosis, we performed a genome-wide linkage search in a consanguineous family with 3 affected patients using 50K SNP microarrays and homozygosity mapping.
Results: We obtained a significant maximum parametric lod score of Zmax=3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67. When examining a world-wide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether 4 novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in 5 of them. Mutations of MKS3/TMEM67, found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6 are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded 7 different (4 novel) mutations in 5 patients, 4 of which presented also with congenital liver fibrosis.
Conclusions: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.