Nephronophthisis 20

A number sign (#) is used with this entry because of evidence that nephronophthisis-20 (NPHP20) is caused by homozygous or compound heterozygous mutation in the MAPKBP1 gene (616786) on chromosome 15q15.

Description

Nephronophthisis-20 is an autosomal recessive tubulointerstitial nephritis characterized by progressive renal fibrosis resulting in end-stage renal failure. The age at onset is relatively late compared to other forms of NPHP, and patients develop end-stage renal disease in the second or third decades. Unlike most other forms of NPHP, NPHP20 does not have features of a ciliopathy and patients do not appear to have extrarenal manifestations (summary by Macia et al., 2017).

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

Clinical Features

Macia et al. (2017) reported 8 patients from 5 unrelated families with NPHP20. The families were of various ethnic origins, including Norwegian, Turkish, Portuguese, and Italian: 4 of the families were consanguineous. The severity was variable: 5 patients from 3 families developed end-stage renal disease between 12 and 25 years of age, including 4 who underwent renal transplant, whereas 3 patients from the other 2 families did not have end-stage renal disease in their twenties. Renal biopsies and ultrasounds showed classic features of NPHP, including atrophic tubules with thickening of the basement membranes, massive interstitial fibrosis, interstitial infiltrates, and cysts. None of the patients had extrarenal manifestations or evidence of a ciliopathy, such as situs inversus or polydactyly. Some had variable additional features, including scoliosis, short stature, or facial dysmorphism, but it was unclear whether these were part of the NPHP20 phenotype. One patient had retinitis pigmentosa (RP43; 613810) associated with a known pathogenic RP mutation in the PDE6A gene (V685M; 180071.0004).

Inheritance

The transmission pattern of NPHP20 in the families reported by Macia et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 patients from 5 unrelated families with NPHP20, Macia et al. (2017) identified compound heterozygous or homozygous mutations in the MAPKBP1 gene (616786.0001-616786.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The patients were ascertained from a cohort of 141 NPHP families who underwent whole-exome sequencing. In vitro studies in various ciliated cells showed that MAPKBP1 did not associate with the cilia or centrosomes/basal bodies, and patient cells showed normal ciliary numbers, formation, and length. MAPKBP1 immunostaining at mitotic spindle poles was severely decreased in cells derived from 3 probands compared to controls. Transfection of the mutations into HeLa cells showed that all except the R544Q variant (616786.0004) impaired recruitment of MAPKBP1 to the spindle pole. Most of the variants, except R544Q, had decreased interaction with WDR62 (613583) and JNK2 (602896), although overall JNK signaling did not show significant changes from normal. All mutant fibroblasts, a kidney sample from 1 patient, and Mapkbp1-null murine cells showed evidence of an increased DNA damage response, with increased levels of nuclear gamma-phosphorylated H2AFX (601772) compared to controls.

Animal Model

Macia et al. (2017) found that Mapkbp1-null mice and zebrafish did not show any classic ciliopathy-associated phenotypes such as situs inversus, polydactyly (in the mouse), curved body axis (in the fish), or renal cysts. Only 1 of 8 mutant zebrafish showed dilated renal tubules associated with fibrosis.