title: Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome.
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 gene:gene synergistic interactions causing HPE in humans.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sungkook
authors.initials: S
authors.lastname: Hong
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.affiliation: São Paulo University, Bauru, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Marino
authors.affiliation: Department of Medical Genetics, Cincinnati Children's Medical Center, Cincinnati, OH, USA and.
authors.forename: Sophia B
authors.initials: SB
authors.lastname: Hufnagel
authors.affiliation: Department of Medical Genetics, Cincinnati Children's Medical Center, Cincinnati, OH, USA and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hopkin
authors.affiliation: Department of Pediatrics, University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina.
authors.forename: Alma
authors.initials: A
authors.lastname: Toromanović
authors.affiliation: São Paulo University, Bauru, Brazil.
authors.forename: Antonio
authors.initials: A
authors.lastname: Richieri-Costa
authors.affiliation: São Paulo University, Bauru, Brazil.
authors.forename: Lucilene A
authors.initials: LA
authors.lastname: Ribeiro-Bicudo
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Kruszka
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA, mmuenke@nhgri.nih.gov.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000483:Alleles; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002971:Cleft Lip / Q000235:genetics* / Q000503:physiopathology; D002972:Cleft Palate / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005385:Fingers / Q000002:abnormalities* / Q000503:physiopathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D016142:Holoprosencephaly / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000473:pathology; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D017436:Kallmann Syndrome / Q000235:genetics / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D012720:Severity of Illness Index; D015027:Zebrafish / Q000235:genetics
chemical_list: C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1