This report describes Galloway-Mowat syndrome 3 (GAMOS3), renal-neurologic disease with autosomal recessive inheritance. GAMOS3 exhibits autosomal recessive inheritance. The human gene implicated in this disease is OSGEP, which encodes O-sialoglycoprotein endopeptidase, a subunit of the KEOPS complex. There is one high-scoring fly ortholog, Dmel\Tcs3, for which multiple genetic reagents, including an amorphic allele, RNAi-targeting constructs, and alleles caused by insertional mutagenesis, have been generated.
UAS constructs of the human Hsap\OSGEP, gene, including wild-type and variants implicated in disease, have been introduced into flies; see the 'Disease-Implicated Variants' table below. Heterologous rescue (functional complementation) has been demonstrated: targeted overexpression of wild-type, but not mutant, Hsap\OSGEP rescues the slit diaphragm defects induced by nephrocyte-specific Dmel\Tcs3 knockdown.
RNAi-mediated knockdown of Dmel\Tcs3 in nephrocytes results in slit diaphragm defects and upregulation of Dmel\crc, recapitulating the human kidney phenotype. RNAi-mediated knockdown, or chemical inhibition, of Dmel\crc, the fly ortholog of human ATF4, ameliorates the effect of Dmel\Tcs3 knockdown.
[updated Mar. 2024 by FlyBase; FBrf0222196]
[GALLOWAY-MOWAT SYNDROME 3; GAMOS3](https://omim.org/entry/617729)
[O-SIALOGLYCOPROTEIN ENDOPEPTIDASE; OSGEP](https://omim.org/entry/610107)
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, pubmed:28805828). [from MIM:617729; 2023.05.19]
Galloway-Mowat syndrome 3 (GAMOS3) is caused by homozygous or compound heterozygous mutation in the OSGEP gene on chromosome 14q11. [from MIM:617729; 2023.05.19]
The OSGEP gene encodes O-sialoglycoprotein endopeptidase, a subunit of the highly conserved 'kinase, endopeptidase, and other proteins of small size' (KEOPS) complex that regulates the second biosynthetic step in the formation of N-6-threonylcarbamoyladenosine (t6A) in the cytosol. T6A is a conserved tRNA modification that occurs at position A37 next to the anticodon stem loop of tRNAs that recognize codons that start with adenosine (ANN codons) and is necessary for translational accuracy and efficiency (summary by Edvardson et al., 2017, pubmed:28272532 and Braun et al., 2017, pubmed:28805828). [from MIM:610107; 2023.05.19]
One to one (1 human to 1 Drosophila); OSGEP has one high-scoring Drosophila ortholog, Tcs3.
High-scoring ortholog of human OSGEP (1 Drosophila to 1 human).
