Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome.
Hum Mol Genet
; 25(10): 1912-1922, 2016 05 15.
Article
em En
| MEDLINE
| ID: mdl-26931467
ABSTRACT
Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the nine FGFR1 mutations recently detected in our screen of over 200 HPE probands by next generation sequencing, only five distinct mutations in the kinase domain behave as dominant-negative mutations in zebrafish over-expression assays. Three FGFR1 mutations seen in HPE probands behave identical to wild-type FGFR1 in rescue assays, including one apparent de novo variation. Interestingly, in one HPE family, a deleterious FGFR1 allele was transmitted from one parent and a loss-of-function allele in FGF8 from the other parent to both affected daughters. This family is one of the clearest examples to date of genegene synergistic interactions causing HPE in humans.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Deformidades Congênitas da Mão
/
Holoprosencefalia
/
Fenda Labial
/
Fissura Palatina
/
Predisposição Genética para Doença
/
Receptor Tipo 1 de Fator de Crescimento de Fibroblastos
/
Dedos
/
Hipogonadismo
/
Deficiência Intelectual
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Child
/
Child, preschool
/
Female
/
Humans
/
Infant
/
Male
Idioma:
En
Revista:
Hum Mol Genet
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos