Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.
Nat Genet
; 49(10): 1529-1538, 2017 Oct.
Article
en En
| MEDLINE
| ID: mdl-28805828
ABSTRACT
Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Complejos Multiproteicos
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Hernia Hiatal
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Microcefalia
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Mutación
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Nefrosis
Límite:
Animals
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Humans
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos