PUBLICATION

Dominant-negative Kinase Domain Mutations in FGFR1 Can Explain the Clinical Severity of Hartsfield Syndrome

Authors
Hong, S., Hu, P., Marino, J., Hufnagel, S.B., Hopkin, R.J., Toromanović, A., Richieri-Costa, A., Ribeiro-Bicudo, L.A., Kruszka, P., Roessler, E., Muenke, M.
ID
ZDB-PUB-160305-28
Date
2016
Source
Human molecular genetics   25(10): 1912-1922 (Journal)
Registered Authors
Hong, Sung-Kook, Hu, Ping
Keywords
none
MeSH Terms
  • Alleles
  • Animals
  • Child
  • Child, Preschool
  • Cleft Lip/genetics*
  • Cleft Lip/physiopathology
  • Cleft Palate/genetics*
  • Cleft Palate/physiopathology
  • Disease Models, Animal
  • Female
  • Fingers/abnormalities*
  • Fingers/physiopathology
  • Gene Expression Regulation
  • Genetic Predisposition to Disease*
  • Genotype
  • Hand Deformities, Congenital/genetics*
  • Hand Deformities, Congenital/physiopathology
  • High-Throughput Nucleotide Sequencing
  • Holoprosencephaly/genetics*
  • Holoprosencephaly/physiopathology
  • Humans
  • Hypogonadism/genetics*
  • Hypogonadism/pathology
  • Infant
  • Intellectual Disability/genetics*
  • Intellectual Disability/physiopathology
  • Kallmann Syndrome/genetics
  • Kallmann Syndrome/pathology
  • Male
  • Mutation
  • Pedigree
  • Receptor, Fibroblast Growth Factor, Type 1/genetics*
  • Severity of Illness Index
  • Zebrafish/genetics
PubMed
26931467 Full text @ Hum. Mol. Genet.
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. Un-related clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism (IHH). FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the 9 FGFR1 mutations recently detected in our screen of over two hundred 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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping