Galloway-Mowat Syndrome 8

A number sign (#) is used with this entry because of evidence that Galloway-Mowat syndrome-8 (GAMOS8) is caused by homozygous mutation in the NUP133 gene (607613) on chromosome 1q42. One such family has been reported.

Biallelic mutation in the NUP133 gene can also cause nephrotic syndrome type 18 (NPHS18; 618177).

Description

Galloway-Mowat syndrome-8 is an autosomal recessive disorder characterized by impaired psychomotor development, poor overall growth with microcephaly, and early-onset progressive nephrotic syndrome associated with focal segmental glomerulosclerosis on renal biopsy. Some patients may have seizures, and some may die in childhood (summary by Fujita et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

Clinical Features

Nakazato et al. (2002) reported a consanguineous Japanese family in which 4 sibs had delayed psychomotor development apparent in infancy and subsequently developed progressive and severe renal disease in the first years of life. Fujita et al. (2018) provided follow-up of this family. The patients had strabismus, hypotonia, profoundly impaired intellectual development, and overall growth deficiency with relative microcephaly (about -2.6 SD). One patient was noted to have dysmorphic features, including narrow forehead, enamel hypoplasia, and deviation of the thumbs. Three patients developed seizures, including one patient with severe refractory epilepsy. Brain imaging of one child showed mild cortical atrophy, although imaging in another child was normal. Two patients had hearing impairment. The patients developed nephrotic syndrome with proteinuria and microscopic hematuria in the first years of life. Renal biopsies, when performed, showed focal segmental glomerulosclerosis, interstitial fibrosis, tubular atrophy, cystic dilatation, and focal foot process fusion or effacement. The renal disease was progressive, and the patients developed edema, uremia, and hypertension. Two patients died at ages 2 and 4 years, and the other 2 underwent successful renal transplantation. Neuropathologic examination in 1 patient, who later died at age 19 years, showed focal cortical dysplasia, abnormal tangential cortical lamination, dysmorphic neurons, loss of pyramidal cells in the hippocampus, abnormal dendritic arborization, and abnormalities in the cerebellum.

Inheritance

The transmission pattern of GAMOS8 in the family reported by Nakazato et al. (2002) and Fujita et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 affected members of a consanguineous Japanese family with GAMOS8, originally reported by Nakazato et al. (2002), Fujita et al. (2018) identified a homozygous splice site mutation in the NUP133 gene (607613.0004). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient cells showed that the mutation resulted in aberrant splicing and a significant reduction in NUP133 protein levels compared to controls. In vitro functional expression studies in HeLa cells showed that the mutant protein had impaired binding to NUP107 (607617), consistent with a loss of function. Expression of the mutation was unable to rescue the brain and renal tissue abnormalities observed in zebrafish embryos with morpholino knockdown of the nup133 gene.

Animal Model

Fujita et al. (2018) found ubiquitous expression of nup133 in various zebrafish embryos and adult tissue, with higher expression in the brain, testes, ovaries, skin, and kidney. Morpholino knockdown of the nup133 gene in zebrafish embryos resulted in small head and curved trunks, with later onset of edema and early death. The brain and renal tissue showed disorganization and underdeveloped glomeruli and abnormal podocytes.