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.
Citation
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. (2016) Dominant-negative Kinase Domain Mutations in FGFR1 Can Explain the Clinical Severity of Hartsfield Syndrome. Human molecular genetics. 25(10):1912-1922.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping