Galloway-Mowat Syndrome 4

A number sign (#) is used with this entry because of evidence that Galloway-Mowat syndrome-4 (GAMOS4) is caused by homozygous or compound heterozygous mutation in the TP53RK gene (608679) on chromosome 20q13.

Description

Galloway-Mowat syndrome is a renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities, and delayed psychomotor development. Most patients have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable. Most patients die in the first years of life (summary by Braun et al., 2017).

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

Clinical Features

Braun et al. (2017) reported 4 patients from 3 unrelated consanguineous families with GAMOS4. The families were of European/South African/Indian descent (family B77), Thai descent (patient N2984), and Moroccan descent (patient N2194). All patients presented with nephrotic syndrome with proteinuria in the first year of life followed shortly by end-stage renal disease resulting in death by age 3 years. Renal biopsy of the 2 sibs showed focal segmental glomerulosclerosis (FSGS) and diffuse mesangial sclerosis (DMS). Neurologic features included primary microcephaly, developmental delay with speech delay, seizures, hypotonia, and spasticity. Brain imaging showed variable abnormalities, such as polymicrogyria, poor myelination, cerebral atrophy, and cerebellar hypoplasia. Most patients had dysmorphic facial features, including large ears and hypertelorism. One patient was noted to have short stature, tapered fingers, feeding difficulties, and abnormally pigmented skin macules, whereas another had evidence of impaired vision.

Inheritance

The transmission pattern of GAMOS4 in the families reported by Braun et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 3 unrelated families with GAMOS4, Braun et al. (2017) identified homozygous or compound heterozygous mutations in the TP53RK gene (608679.0001-608679.0004). The mutations were found by whole-exome sequencing and high-throughput exon sequencing of gene members of the KEOPS complex (of which TP53RK is one) after mutations in the OSGEP (610107) gene were identified. The mutations were unable to rescue the proliferation defect in human podocytes with shRNA-mediated knockdown of TP53RK, suggesting that the identified human disease alleles impaired protein functionality. Both mutations found in family B77 (608679.0001 and 608679.0002) abrogated the molecular interaction between TP53RK and TPRKB (608680). Knockdown of TP53RK using shRNA in human podocytes resulted in inhibition of nascent protein synthesis, decreased cell proliferation, activation of the unfolded protein response with endoplasmic reticulum (ER) stress and upregulation of the ER-associated proteasomal degradation system, and increased apoptosis associated with activation of the DNA damage response (DDR). Knockdown of TP53RK also disrupted the formation of the sublamellar actin network in human podocytes and decreased podocyte migration. Braun et al. (2017) concluded that TP53RK mutations impair both the canonical and noncanonical functions of the KEOPS complex, resulting in several potential pathogenic mechanisms, including translational attenuation, activation of DDR signaling, increased apoptosis, and defects in actin regulation, which would have major effects on neurons and podocytes. The GAMOS4 families were part of a cohort of 91 GAMOS families who underwent genetic studies: mutations in 3 other genes of the KEOPS complex (LAGE3, 300060; OSGEP, and TPRKB) were also identified; mutations in these 4 genes were found in a total of 32 GAMOS families.

Animal Model

Braun et al. (2017) found that CRISPR/Cas9-mediated knockdown of the Tp53rk gene in mouse embryos resulted in smaller head size, with shorter cerebral cortex lengths, cortex-midbrain midline lengths, and cortex widths compared to wildtype embryos, although the differences from controls were not significant.