Evidence of Oligogenic Inheritance in Nephronophthisis

Abstract

Nephronophthisis is a recessive cystic renal disease that leads to end-stage renal failure in the first two decades of life. Twenty-five percent of nephronophthisis cases are caused by large homozygous deletions of NPHP1, but six genes responsible for nephronophthisis have been identified. Because oligogenic inheritance has been described for the related Bardet-Biedl syndrome, we evaluated whether mutations in more than one gene may also be detected in cases of nephronophthisis. Because the nephrocystins 1 to 4 are known to interact, we examined patients with nephronophthisis from 94 different families and sequenced all exons of the NPHP1, NPHP2, NPHP3, and NPHP4 genes. In our previous studies involving 44 families, we detected two mutations in one of the NPHP1-4 genes. Here, we detected in six families two mutations in either NPHP1, NPHP3, or NPHP4, and identified a third mutation in one of the other NPHP genes. Furthermore, we found possible digenic disease by detecting one individual who carried one mutation in NPHP2 and a second mutation in NPHP3. Finally, we detected the presence of a single mutation in nine families, suggesting that the second recessive mutation may be in another as yet unidentified NPHP gene. Our findings suggest that oligogenicity may occur in cases of nephronophthisis.

Clinical and genetic characteristics of Japanese nephronophthisis patients

“…reported [11,12]. We also found compound heterozygosity across multiple NPHP genes in some of our Japanese nephronophthisis patients.…”

Identification of a Gene for Renal-Hepatic-Pancreatic Dysplasia by Microarray-Based Homozygosity Mapping

“…The first case was homozygous for an obligatory splice acceptor-site mutation (IVS26 ϩ 1 GϾA), and this child had no extrarenal manifestations of disease. 12 The second case was combined heterozygous for a frameshift mutation (435_438delAAGT) and a splice mutation (IVS24-1GϾC) in NPHP3 13 and was also heterozygous for a frameshift mutation in the NPHP4 gene. This child had liver fibrosis and reached end-stage renal disease at age 3 years.…”

The novel and independent association between single-point SNP of NPHP4 gene and renal function in non-diabetic Japanese population: the Takahata study

“…It is reported that NPHP sometimes accompanies simultaneous mutations in different NPHP genes. 21 Although the prevalence of renal abnormalities due to the mutation in other NPHP genes is low, there is a possibility that the difference in eGFR might be caused in part by the interaction between mutations in other NPHP genes.…”