Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans.
Hum Genet
; 135(10): 1191-7, 2016 10.
Article
em En
| MEDLINE
| ID: mdl-27503289
ABSTRACT
Primary microcephaly is a clinical phenotype in which the head circumference is significantly reduced at birth due to abnormal brain development, primarily at the cortical level. Despite the marked genetic heterogeneity, most primary microcephaly-linked genes converge on mitosis regulation. Two consanguineous families segregating the phenotype of severe primary microcephaly, spasticity and failure to thrive had overlapping autozygomes in which exome sequencing identified homozygous splicing variants in CIT that segregate with the phenotype within each family. CIT encodes citron, an effector of the Rho signaling that is required for cytokinesis specifically in proliferating neuroprogenitors, as well as for postnatal brain development. In agreement with the critical role assigned to the kinase domain in effecting these biological roles, we show that both splicing variants predict variable disruption of this domain. The striking phenotypic overlap between CIT-mutated individuals and the knockout mice and rats that are specifically deficient in the kinase domain supports the proposed causal link between CIT mutation and primary microcephaly in humans.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
/
Predisposição Genética para Doença
/
Peptídeos e Proteínas de Sinalização Intracelular
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Microcefalia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Child
/
Female
/
Humans
/
Newborn
País/Região como assunto:
Asia
Idioma:
En
Revista:
Hum Genet
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Arábia Saudita