Nephronophthisis 18

A number sign (#) is used with this entry because nephronophthisis-18 (NPHP18) is caused by homozygous or compound heterozygous mutation in the CEP83 gene (615847) on chromosome 12q22.

Description

Nephronophthisis-18 is an autosomal recessive disorder characterized by chronic tubulointerstitial nephritis resulting in end-stage renal disease in early childhood. Extrarenal manifestations, including intellectual disability or liver changes, may occur in some patients (summary by Failler et al., 2014).

For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100).

Clinical Features

Failler et al. (2014) reported 8 children from 7 families with early-onset nephronophthisis resulting in end-stage renal disease between 1 and 4 years of age. Four patients also had neurologic problems, including speech delay, intellectual disability, and/or hydrocephalus. One patient had retinitis, another had strabismus, and 2 had liver changes, including hepatic cytolysis, cholestasis, and portal septal fibrosis. Renal biopsies showed 2 types of histologic patterns: microcystic tubular dilatations associated with tubular atrophy and interstitial fibrosis, and atrophic tubules with thickening of the basement membranes and massive interstitial fibrosis. Two patients had hypertension.

Inheritance

The transmission pattern of NPHP18 in the families reported by Failler et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 patients from 7 families with nephronophthisis, Failler et al. (2014) identified homozygous or compound heterozygous mutations in the CEP83 gene (see, e.g., 615847.0001-615847.0007). The initial mutations were found by analyzing a cohort of 1,255 individuals with NPHP-related ciliopathies by applying exon-enriched targeting of up to 1,221 genes associated with cilia and 5 known distal appendage (DAP)-encoding genes. Seven of the patients carried a missense mutation or in-frame deletion on at least 1 allele, suggesting that some protein function may have been preserved in these patients. One patient with a more severe phenotype and multiple organ involvement was homozygous for a truncating mutation. Fibroblasts and tubular renal cells from 2 patients were consistent with altered DAP composition and assembly. Transfection studies of individual mutations in retinal epithelial cells showed that some of the mutations resulted in normal CEP83 localization but exerted a dominant-negative effect on CEP164 localization, whereas others resulted in CEP83 accumulation in the nucleus and failure to localize at the centrosome. Fibroblasts from 2 patients showed defects in ciliogenesis.