Nephrotic Syndrome, Type 11

A number sign (#) is used with this entry because of evidence that nephrotic syndrome type 11 (NPHS11) is caused by homozygous or compound heterozygous mutation in the NUP107 gene (607617) on chromosome 12q15.

Biallelic mutation in the NUP107 gene can also cause Galloway-Mowat syndorme-7 (GAMOS7; 618348).

Description

Nephrotic syndrome type 11 is an autosomal recessive disorder of the kidney with onset in the first decade of life. The disorder is progressive and usually results in end-stage renal disease necessitating renal transplantation, although some patients may have a slightly milder phenotype (summary by Miyake et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).

Clinical Features

Miyake et al. (2015) reported 9 patients from 5 unrelated families of East Asian descent with early-onset steroid-resistant nephrotic syndrome. Four of the families were of Japanese origin and 1 was of Korean origin; 3 of the families had previously been reported by Kitamura et al. (2006). In 4 families, the patients developed nephrotic syndrome between 2 and 3 years of age, and end-stage renal disease became apparent before age 10. Two sisters from a Korean family had a slightly later age at onset, around 10 to 11 years of age, and renal function was relatively well preserved to age 34 years. Renal biopsy showed focal segmental glomerulosclerosis and minimal-change nephrotic syndrome. Six patients who underwent renal transplant had no recurrence of disease after transplant. None of the patients had neurologic phenotypes.

Braun et al. (2018) reported a boy, born of consanguineous Turkish parents (family A3825), with onset of NPHS11 at age 4.5 years, which progressed to end-stage renal disease at age 5. Renal biopsy showed diffuse mesangial sclerosis. The patient also had cleft lip and palate.

Inheritance

The transmission pattern of NPHS11 in the families reported by Miyake et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 9 affected individuals from 5 unrelated families of East Asian descent with NPHS11, Miyake et al. (2015) identified compound heterozygous mutations in the NUP107 gene (607617.0001-607617.0004). All patients carried a D831A mutation (607617.0001) on 1 allele, and haplotype analysis was consistent with a founder effect. In vitro studies showed that 3 of the 4 mutations impaired NUP107 binding to NUP133 and NUP107 incorporation into the nuclear pore complex. However, patient lymphoblastoid cells showed no apparent loss of the nuclear pore complex, suggesting residual NUP107 function. Miyake et al. (2015) hypothesized that defective NUP107 function could result in functional impairment of podocytes that are progressively destroyed by increased filtration pressure after birth, resulting in damage to the glomerulus. The authors postulated that NPHS11 is caused by a structural abnormality, since there is no recurrence of the disorder after renal transplant.

In a boy with NPHS11 from a Turkish family (A3825), Braun et al. (2018) identified a homozygous missense mutation in the NUP107 gene (Y889C; 607617.0007). The patient also had cleft lip and palate.

Animal Model

Miyake et al. (2015) found that zebrafish with an in-frame deletion mimicking the human missense mutation D831A (607617.0001) had underdeveloped glomeruli with hypoplastic or poorly organized capillary vessels and mesangial regions. Electron microscopy showed abnormally shaped foot processes, collapse of the capillary lumen, and thickened basement membrane, suggesting that the mutation caused renal abnormalities. Mutant zebrafish developed edema and died around days 5 and 6.

Braun et al. (2018) found that morpholino knockdown of nup107 in Xenopus embryos resulted in abnormal pronephros morphology, consistent with a defect in glomerulogenesis. Expression of human wildtype NUP107 rescued the defect. CRISPR/Cas9-mediated knockout of the nup107 gene in zebrafish embryos resulted in developmental abnormalities, including small eyes, body axis curvature, and edema, as well as early lethality.