Nephrotic Syndrome, Type 15

A number sign (#) is used with this entry because of evidence that nephrotic syndrome type 15 (NPHS15) is caused by homozygous or compound heterozygous mutation in the MAGI2 gene (606382) on chromosome 7q21.

Description

NPHS15 is an autosomal recessive renal disorder characterized by onset of impaired kidney function with proteinuria in the first months of life. The disease course and severity varies widely. Some patients show rapid progression to end-stage renal failure necessitating transplant, whereas others have a more benign course that can be managed with medication. Renal biopsy tends to show glomerular sclerosis and effacement of podocyte foot processes (summary by Bierzynska et al., 2017).

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

Clinical Features

Bierzynska et al. (2017) reported 3 children, including 2 sisters (patients 175 and 175S) born of consanguineous parents and an unrelated child (patient 180), with NPHS15. The patients presented with proteinuria and hypoalbuminemia within the first 4 months of life. The disease course varied. Patient 175 had rapid disease progression, resulting in end-stage renal failure necessitating renal transplant at age 3.5 years, whereas patient 175S had a more benign course and had not had renal transplant by age 2.3 years. Patient 180 had persistent proteinuria with only mild renal impairment until age 9 years; he did not need a renal transplant. Renal biopsy of patient 175 showed marked glomerular lobulation with fibrosis or global sclerosis, and interstitial fibrosis. Renal biopsy of patient 180 showed minimal change disease and 2 of 59 glomeruli with global sclerosis. Electron microscopy showed diffuse podocyte foot process effacement with a normal glomerular basement membrane. Patient 175S had some minor cardiac abnormalities, including mild peripheral branch pulmonary stenosis and patent foramen ovale, possibly unrelated to the renal disorder. Patient 180 had polydactyly and pyloric stenosis, but no other features of a characterized syndrome.

Inheritance

The transmission pattern of NPHS15 in the families reported by Bierzynska et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with NPHS15, Bierzynska et al. (2017) identified homozygous or compound heterozygous frameshift mutations in the MAGI2 gene (606382.0001-606382.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient kidney biopsies showed absence or decrease of MAGI2 immunostaining, consistent with a loss of function. Nephrin (NPHS1; 602716) expression was also decreased or showed altered localization in patient biopsies compared to controls. Patient 175, who had the most severe phenotype with rapid progression to end-stage renal disease in early childhood, also carried a heterozygous variant of unknown significance (G1425A) in the LAMB2 gene (150325). The patients were ascertained from a cohort of 187 patients with childhood-onset steroid-resistant nephrotic syndrome who underwent whole-exome sequencing.

Animal Model

Ihara et al. (2014) found that Magi2-null mice did not show obvious gross abnormalities at birth, but had neonatal lethality; all died within a few days after birth. Mutant mice had significantly impaired renal function, with anuria, increased plasma creatinine, and abnormal morphology of foot processes. Foot processes were shortened, the interdigitating network was not well organized, and the slit diaphragms showed impaired structure due to fusion and/or adhesion of foot processes. Immunohistochemical studies showed loss of Magi2, nephrin (NPHS1; 602716), and dendrin (DDN; 610588) at the slit diaphragm of mutant mice. These changes were associated with increased cathepsin L (CTSL; 116880), which is reported to be critical for rearrangement of the actin cytoskeleton in podocytes, and altered expression of adhesion molecules at the slit diaphragm.

Balbas et al. (2014) found that Magi2-null mice were viable and born at normal ratios, but they presented with early-onset progressive proteinuria and severe noninflammatory proliferative glomerulopathy with collapsing and crescent-like features within a few weeks after birth. Ultrastructural studies showed diffuse podocyte injury, followed by rapid and severe podocyte loss. The onset of glomerular dysfunction was associated with a decrease in protein abundance of nephrin as well as proliferation of extracapillary epithelial cells. All mutant mice died of renal failure by 3 months of age. The findings indicated that MAGI2 is essential for kidney filter maintenance and preservation of podocytes, and suggested that early loss of nephrin contributes to the renal dysfunction in Magi2-null mice.