Functional insight into a neurodevelopmental disorder caused by missense variants in an RNA-binding protein, RBM10.
J Hum Genet
; 68(9): 643-648, 2023 Sep.
Article
en En
| MEDLINE
| ID: mdl-37268768
ABSTRACT
The RNA-binding motif protein 10, RBM10, is an RNA splicing regulator essential for development. Loss-of-function RBM10 variants are associated with TARP syndrome, a severe X-linked recessive condition in males. We report a 3-year-old male with a mild phenotype, consisting of cleft palate, hypotonia, developmental delay, and minor dysmorphisms, associated with a missense RBM10 variant, c.943T>C, p.Ser315Pro, affecting the RRM2 RNA-binding domain. His clinical features were similar to a previously reported case associated with a missense variant. The p.Ser315Pro mutant protein was expressed normally in the nucleus, but its expression level and protein stability were slightly reduced. Nuclear magnetic resonance spectroscopy showed that the structure and the RNA-binding ability of the RRM2 domain with the p.Ser315Pro were unaffected. However, it affects the alternative splicing regulations of downstream genes, NUMB and TNRC6A, and its splicing alteration patterns were variable depending on target transcripts. In summary, a novel germline missense RBM10 p.Ser315Pro variant that causes functional changes in the expression of its downstream genes results in a non-lethal phenotype associated with developmental delays. The functional alteration effects depend on the residues affected by missense variants. Our findings are expected to bring broader insights into the RBM10-associated genotype-phenotype relationships by delineating the molecular mechanism of RBM10 functions.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Empalme Alternativo
/
Trastornos del Neurodesarrollo
Límite:
Humans
/
Male
Idioma:
En
Revista:
J Hum Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
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UK
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UNITED KINGDOM