A neurodevelopmental disorder associated with a loss-of-function missense mutation in RAB35.
J Biol Chem
; 300(4): 107124, 2024 Apr.
Article
em En
| MEDLINE
| ID: mdl-38432637
ABSTRACT
Rab35 (Ras-associated binding protein) is a small GTPase that regulates endosomal membrane trafficking and functions in cell polarity, cytokinesis, and growth factor signaling. Altered Rab35 function contributes to progression of glioblastoma, defects in primary cilia formation, and altered cytokinesis. Here, we report a pediatric patient with global developmental delay, hydrocephalus, a Dandy-Walker malformation, axial hypotonia with peripheral hypertonia, visual problems, and conductive hearing impairment. Exome sequencing identified a homozygous missense variant in the GTPase fold of RAB35 (c.80G>A; p.R27H) as the most likely candidate. Functional analysis of the R27H-Rab35 variant protein revealed enhanced interaction with its guanine-nucleotide exchange factor, DENND1A and decreased interaction with a known effector, MICAL1, indicating that the protein is in an inactive conformation. Cellular expression of the variant drives the activation of Arf6, a small GTPase under negative regulatory control of Rab35. Importantly, variant expression leads to delayed cytokinesis and altered length, number, and Arl13b composition of primary cilia, known factors in neurodevelopmental disease. Our findings provide evidence of altered Rab35 function as a causative factor of a neurodevelopmental disorder.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Mutação de Sentido Incorreto
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Proteínas rab de Ligação ao GTP
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Transtornos do Neurodesenvolvimento
Limite:
Female
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Humans
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Male
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Canadá