Galloway-Mowat Syndrome 5

A number sign (#) is used with this entry because of evidence that Galloway-Mowat syndrome-5 (GAMOS5) is caused by homozygous mutation in the TPRKB gene (608680) on chromosome 2p13.

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 and ear abnormalities. Other features, such as arachnodactyly and visual or hearing 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 2 unrelated patients born of consanguineous Egyptian (patient B123) and European (patient B1144) families with GAMOS5. The patients presented with nephrotic syndrome with proteinuria around 4 years of age. One developed end-stage renal disease and died at age 6.8 years, whereas the other did not develop end-stage renal disease and was still alive with normal renal function at age 6. Renal biopsy of both patients showed focal segmental glomerulosclerosis (FSGS). Neurologic features included primary microcephaly, developmental delay with variable intellectual disability, spasticity, and ataxia. Brain imaging showed variable abnormalities, such as pachygyria, poor myelination, cerebral atrophy, and enlarged ventricles. Dysmorphic facial features included elongated face, epicanthal folds, hypertelorism, deep-set eyes, fleshy ear lobules, and prominent chin. One patient was noted to have deafness; this patient had an affected sib who presented with renal disease at 11 months of age and died at 13 months.

Inheritance

The transmission pattern of GAMOS5 in the families reported by Braun et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients, each born of consanguineous parents, with GAMOS5, Braun et al. (2017) identified homozygous missense mutations in the TPRKB gene (608680.0001 and 608680.0002). The mutations were found by whole-exome sequencing and high-throughput exon sequencing of gene members of the KEOPS complex after mutations in the OSGEP gene (610107) were identified. The mutations were unable to rescue the proliferation defect in human podocytes with shRNA-mediated knockdown of TPRKB, suggesting that the identified human disease alleles impaired protein functionality. However, the mutations did not abrogate intermolecular interactions among KEOPS complex proteins. Knockdown of TPRKB 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 TPRKB also decreased podocyte migration. Fibroblasts derived from 1 patient (patient B1144) showed increased phosphorylated H2AX (601772), consistent with activation of the DDR response. Braun et al. (2017) concluded that TPRKB 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 GAMOS5 families were part of a cohort of 91 GAMOS families who underwent genetic studies: mutations in 3 other genes of the KEOPS complex (LAGE3, OSGEP, and TP53RK) 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 tprkb gene in zebrafish larvae resulted in primary microcephaly and increased apoptosis in the brain compared to controls. Knockdown fish also showed early lethality. Mouse embryos with CRISPR/Cas9 knockdown of Tprkb also showed a microcephaly phenotype, with significantly shorter cerebral cortex lengths, cortex-midbrain midline lengths, and cortex widths compared to wildtype embryos. Neither mutant fish nor mutant mice had a renal phenotype, possibly a result of early lethality masking renal involvement that may have occurred in older animals.