Galloway-Mowat Syndrome 7

A number sign (#) is used with this entry because of evidence that Galloway-Mowat syndrome-7 (GAMOS7) 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 nephrotic syndrome type 11 (NPHS11; 616730).

Description

Galloway-Mowat syndrome-7 (GAMOS7) is an autosomal recessive disorder characterized by developmental delay, microcephaly, and early-onset nephrotic syndrome (summary by Rosti et al., 2017).

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

Clinical Features

Rosti et al. (2017) reported 5 patients from 2 unrelated consanguineous families, one of which was of Turkish descent, with a nephrotic syndrome similar to Galloway-Mowat syndrome. The patients had microcephaly (-5 to -9 SD), poor overall growth with short stature, and mildly delayed intellectual development with speech delay, although most could attend special schools. Two sibs from 1 family (MIC-670) developed progressive nephrotic syndrome in the first decade, manifest as proteinuria, hypoalbuminemia, edema, and hypercholesterolemia. Renal biopsy showed focal segmental glomerulosclerosis. One patient underwent renal transplantation at age 16 years after developing renal failure. The 2 younger sibs in this family did not have proteinuria at ages 7 years and 20 months, respectively, but were being closely monitored. The single patient in the second family (MIC-5233) developed proteinuria at age 12 years, and renal biopsy showed IgA nephropathy. All patients had similar dysmorphic features, including sloping forehead, bitemporal narrowing, smooth philtrum, and micrognathia. Some patients had skeletal anomalies, including clinodactyly, bifid thumb, cubitus valgus, hallux valgus, pectus excavatum, and kyphoscoliosis. Brain imaging showed simplified gyri and sulci, and reduced frontal cortex volume. All patients carried the same NUP107 mutation (607617.0006).

Bierzynska et al. (2017) reported 3 sibs (patients 45, 46, and 47), and an unrelated patient (patient 48), all born of consanguineous Pakistani parents, with GAMOS7. Clinical details were limited, but all had neurologic involvement, including developmental delay, learning difficulties, and microcephaly. Two of the sibs had eczema. Patients developed renal disease in the first or second decade; 1 patient was diagnosed and in end-stage renal failure at age 14 years. Renal biopsy, when available, showed focal segmental glomerulosclerosis. One patient underwent successful renal transplantation with no disease recurrence.

Braun et al. (2018) reported 5 unrelated consanguineous families in which multiple individuals had onset in the first or second decade of steroid-resistant nephrotic syndrome that was associated with extrarenal manifestations, namely short stature, microcephaly, and intellectual disability. One patient had a ventricular septal defect, and 2 had arachnodactyly and high-arched palate. All affected individuals carried the c.303G-A mutation, which was demonstrated to be a South Asian founder allele. Two families were of Pakistani descent, and the others were Turkish, Indian, and Arabic, respectively. A patient from a family (A1830) of European descent who was compound heterozygous for a frameshift and an in-frame 3-bp deletion in the NUP107 gene also had nephrotic syndrome with microcephaly, intellectual disability, and dilated cardiomyopathy. Renal findings in these patients included focal segmental glomerulosclerosis, effacement of podocyte foot processes, tubular atrophy, interstitial fibrosis, proteinuria, and end-stage renal disease.

Inheritance

The transmission pattern of GAMOS7 in the families reported by Braun et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 2 unrelated consanguineous Turkish families with GAMOS7, Rosti et al. (2017) identified a homozygous c.303G-A transition in the last coding base of exon 4, predicted to result in a splicing defect or a met101-to-ile (M101I) substitution (607617.0006). The mutation, which was found by homozygosity mapping followed by direct gene sequencing, segregated with the disorder in both families. Analysis of patient fibroblasts showed that the mutation resulted in the skipping of exon 4, which would result in a frameshift and nonsense-mediated mRNA decay. Patient cells showed about a 90% reduction in NUP107 protein levels compared to controls, as well as a reduction in NUP133 levels, consistent with a loss of function. High-resolution microscopy of patient fibroblasts showed a 40% decrease in density of nuclear pores. Rosti et al. (2017) noted that this homozygous variant had been reported by Alazami et al. (2015) in a patient (11DG0417) with developmental delay and early-onset focal segmental glomerulosclerosis who also had microcephaly (-5.7 SD) and intellectual disability, suggesting an allele-specific phenotype.

Bierzynska et al. (2017) identified the homozygous c.303G-A mutation in the NUP107 gene in 3 sibs, born of consanguineous Pakistani parents, with GAMOS7. An unrelated patient, born of consanguineous Pakistani parents, carried a homozygous missense mutation in the NUP107 gene (C442Y; 607617.0008). The mutations were found by whole-exome sequencing of a large cohort of patients. Functional studies of the variants and studies of patient cells were not performed.

Braun et al. (2018) identified a homozygous c.303G-A mutation in the NUP107 gene in affected members of 5 consanguineous families with GAMOS7. One of the families was a large multigenerational Pakistani family (PN-1), whereas the others were of Pakistani, Turkish, Indian, and Arabic descent, respectively. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. It was found in heterozygous state in 1 of 245,544 alleles in the gnomAD database. The mutation represents a South Asian founder allele. Patient lymphoblastoid cells with the M101I mutation showed reduced or absent levels of NUP107, NUP160, NUP133, and NUP37 compared to controls. In vitro functional expression studies showed that the NUP107 mutations were unable to rescue abnormal kidney morphology in nup107-null Xenopus embryos, consistent with a loss of function. CRISPR/Cas9-mediated knockout of NUP107 in human podocytes increased the formation of filopodia and was associated with increased CDC42 (116952) activity, suggesting alteration of actin and cytoskeletal dynamics. 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. The patients were part of a large study in which various nucleopore (NUP) genes were found to be mutated in NPHS, suggesting a common pathogenic pathway.