Galloway-Mowat Syndrome 2, X-Linked

A number sign (#) is used with this entry because of evidence that X-linked Galloway-Mowat syndrome-2 (GAMOS2) is caused by hemizygous mutation in the LAGE3 gene (300060) on chromosome Xq28.

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

Braun et al. (2017) reported 4 male patients from 3 unrelated families with GAMOS4. The families were of European (B65), Japanese (B60), and Taiwanese descent (16M0417), respectively. Two Japanese brothers (B60 and his sib) had previously been reported by Shiihara et al. (2003). The patients presented with nephrotic syndrome with proteinuria between 3 months and 2 years of age. One had end-stage renal disease resulting in death at 8 months, whereas 2 sibs had a more protracted course and died at ages 8 and 25 years, respectively. The fourth patient was alive at age 5 months, although he had end-stage renal disease. Renal biopsy showed focal segmental glomerulosclerosis (FSGS) or minimal change disease. Neurologic features included primary microcephaly, developmental delay with intellectual disability, speech delay, seizures, hypotonia, dysmetria, nystagmus, and spasticity. Brain imaging showed variable abnormalities, such as polymicrogyria, poor myelination, cerebral atrophy, and cerebellar hypoplasia. Most patients had dysmorphic facial features, including narrow forehead, esotropia, micrognathia, and high-arched palate. Additional variable features included short stature, arachnodactyly, scoliosis, intrauterine growth retardation, and feeding difficulties.

Inheritance

The transmission pattern of GAMOS2 in the families reported by Braun et al. (2017) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 4 male patients from 3 unrelated families with GAMOS2, Braun et al. (2017) identified hemizygous mutations in the LAGE3 gene (300060.0001-300060.0003). The mutations were inherited from the unaffected mothers; cells derived from 2 of the mothers showed skewed X inactivation. The LAGE3 mutations did not abrogate intermolecular interactions among KEOPS complex proteins; however, additional functional studies of the LAGE3 variants were not performed. 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. Cellular knockdown studies of other KEOPS complex genes suggested that human mutations impair both the canonical and noncanonical functions of the KEOPS complex, resulting in several potential pathogenic mechanisms, including translational attenuation, activation of DNA damage response (DDR) signaling, increased apoptosis, and defects in actin regulation, which would have major effects on neurons and podocytes. The GAMOS2 families were part of a cohort of 91 GAMOS families who underwent genetic studies: mutations in 3 other genes of the KEOPS complex (OSGEP; TPRKB, 608680; and TP53RK, 608679) 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 Lage3 gene in mouse embryos resulted in a microcephaly phenotype, with significantly shorter cerebral cortex lengths, cortex-midbrain midline lengths, and cortex widths compared to wildtype embryos. Mutant mice did not have a renal phenotype, possibly a result of early lethality masking renal involvement that may have occurred in older animals.