Galloway-Mowat Syndrome 3

A number sign (#) is used with this entry because of evidence that Galloway-Mowat syndrome-3 (GAMOS3) is caused by homozygous or compound heterozygous mutation in the OSGEP gene (610107) on chromosome 14q11.

Description

Galloway-Mowat syndrome is a renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, 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

Chen et al. (2007) reported an infant with Galloway-Mowat syndrome. Prenatal ultrasound late in gestation revealed intrauterine growth retardation, microcephaly, and oligohydramnios. Postnatally, the infant had hypotonia, a sloping forehead, hypertelorism, epicanthal folds, microphthalmos, low-set floppy ears, small midface, high-arched palate, and micrognathia. At age 1 month, he showed developmental delay, proteinuria, and hypoalbuminemia. Brain MRI showed gyral abnormalities, frontal pachygyria, and deficient myelination. He died of multiple organ failure at age 2 months.

Edvardson et al. (2017) reported 2 sibs, born of consanguineous Arab Muslim parents, with GAMOS3 resulting in death between 6 and 8 years of age. Soon after birth, both patients showed dysmorphic features, failure to thrive, acquired microcephaly, and hypotonia. They had severely delayed psychomotor development with very few words; 1 patient was never able to sit unsupported. Both also developed a renal tubulopathy with decreased serum magnesium due to renal wasting. One of the patients developed a hypertensive crisis and the other also had hypocalcemia. Dysmorphic features were somewhat variable, but included upturned nose, downward slanting palpebral fissures, high-arched palate, microphthalmia, nystagmus, strabismus, pectus excavatum, and cryptorchidism. Brain imaging of 1 patient showed cerebellar atrophy, whereas brain imaging of the other patient showed nonspecific leukodystrophy. One patient had hypoplastic left heart, aortic coarctation, coloboma, arachnodactyly, and ichthyosis, which may have resulted from a concurrent 1q21.1 duplication of several genes that occurred only in this patient and not in the sib.

Braun et al. (2017) reported 28 patients from 24 families with GAMOS3. Several of the patients had previously been reported (Lin et al., 2001; Chen et al., 2005; Chen et al., 2007; Chen et al., 2011; Bailey and Georges, 2007). The families were of multiple ethnic origins, including Caucasian European, Turkish, Jordanian, Iranian, and American Indian, but almost half were of Taiwanese or East Asian descent; only 3 of the families were consanguineous. Most patients developed nephrotic syndrome with proteinuria in the first days or months of life followed shortly by end-stage renal disease, although 1 patient presented at age 3.5 years and another at age 13 years and did not have end-stage renal disease. Two sibs from 1 family (KW) did not have renal disease at ages 2.5 years and 7 months, respectively. Renal biopsy, when performed, usually showed focal segmental glomerulosclerosis (FSGS) or diffuse mesangial sclerosis (DMS); several biopsies showed diffuse foot process effacement. Almost all patients had primary microcephaly, developmental delay with speech delay, seizures, hypotonia, and spasticity. Brain imaging showed variable abnormalities, including gyral anomalies with lissencephaly, simplified gyral patterns, pachygyria, poor myelination, cerebral atrophy, dilated ventricles, atrophic corpus callosum, and cerebellar hypoplasia. Two sibs in 1 Turkish family (PN553) did not have microcephaly or significant neurologic deficits. Most patients had variable dysmorphic facial features, including narrow forehead, large low-set ears, floppy ears, micrognathia, beaked nose, epicanthal folds, hypertelorism, and deep-set eyes. Other common features included intrauterine growth retardation, short stature, camptodactyly, arachnodactyly, clenched hands, dislocated hips, edema, and visual or hearing impairment. Most of the patients died before 3 years of age.

Prenatal Findings

Chen et al. (2005) noted that oligohydramnios may be an associated prenatal sonographic finding in GAMOS, and Chen et al. (2011) found that intrauterine growth retardation, microcephaly, and oligohydramnios are significant ultrasound findings in fetuses affected by GAMOS. Brain gyral abnormalities, poor myelination, and cerebellar atrophy can also be observed by imaging during fetal development.

Inheritance

The transmission pattern of GAMOS3 in the families reported by Braun et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous Arab Muslim parents, with GAMOS3, Edvardson et al. (2017) identified a homozygous missense mutation in the OSGEP gene (R325Q; 610107.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family. Expression of the homologous mutation in yeast (R376Q) into yeast depleted of kae1 (the ortholog of OSGEP) failed to fully rescue the t6A synthesis defect, compared to expression of the wildtype allele. Edvardson et al. (2017) concluded that decreased t6A synthesis resulting from the R325Q mutation interfered with global protein production, resulting in a severe neurologic disorder.

In affected members of 24 families with GAMOS3, Braun et al. (2017) identified homozygous or compound heterozygous mutations in the OSGEP gene (see, e.g., 610107.0001-610107.0008). The mutation in the first family (B57) (I14F; 610107.0004) was found by a combination of homozygosity mapping and whole-exome sequencing. Subsequent mutations were identified by whole-exome sequencing and high-throughput exon sequencing of the OSGEP gene. Several of the OSGEP mutations were recurrent and represented founder alleles in certain populations (610107.0001, 610107.0002, 610107.0004, and 610107.0008). Complementation studies showed that the GAMOS3 OSGEP mutations were unable to restore growth defects or t6A levels in kae1-null yeast, and the mutations fell into 2 functional classes: either hypomorphic or amorphic alleles. The mutations were also unable to rescue the proliferation defect in human podocytes with shRNA-mediated knockdown of OSGEP. These findings indicated that the identified human disease alleles impaired protein functionality. However, none of the OSGEP mutations abrogated intermolecular interactions among KEOPS complex proteins, of which OSGEP is one. Knockdown of OSGEP using shRNA in human podocytes resulted in decreased t6A levels, inhibition of nascent protein synthesis, decreased cell proliferation, activation of the unfolded protein response with 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 OSGEP also disrupted the formation of the sublamellar actin network in human podocytes and decreased podocyte migration. Fibroblasts derived from 1 patient (patient CP) with an R325Q mutation (610107.0001) showed increased phosphorylated H2AX (601772), consistent with activation of the DDR response. Braun et al. (2017) concluded that OSGEP 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 GAMOS3 families were part of a cohort of 91 GAMOS families who underwent genetic studies: mutations in 3 other genes of the KEOPS complex (LAGE3, TP53RK, 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 osgep 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 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.