Dominant-negative kinase domain mutations inFGFR1can explain the clinical severity of Hartsfield syndrome
| Autor: | Sophia B. Hufnagel, Antonio Richieri-Costa, Robert J. Hopkin, Erich Roessler, Maximilian Muenke, Alma Toromanović, Juliana Marino, Ping Hu, Sung-Kook Hong, Lucilene Arilho Ribeiro-Bicudo, Paul Kruszka |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Proband Kallmann syndrome Dominant-Negative Mutation Bioinformatics medicine.disease_cause Severity of Illness Index Holoprosencephaly Genotype Child Zebrafish Genetics (clinical) Genetics Mutation FENÓTIPOS High-Throughput Nucleotide Sequencing Articles General Medicine Pedigree Cleft Palate Child Preschool Female Hand Deformities Congenital musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Cleft Lip Biology Fingers 03 medical and health sciences Hypogonadotropic hypogonadism Intellectual Disability medicine Animals Humans Genetic Predisposition to Disease Receptor Fibroblast Growth Factor Type 1 Allele Molecular Biology Alleles Hypogonadism Infant Kallmann Syndrome medicine.disease Disease Models Animal stomatognathic diseases 030104 developmental biology Gene Expression Regulation |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddw064 |
| Popis: | 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 gene:gene synergistic interactions causing HPE in humans. |
| Databáze: | OpenAIRE |
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