The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1

L A Lansdon; H V Bernabe; N Nidey; J Standley; M J Schnieders; J C Murray

doi:10.1177/0022034517726496

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The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1

Journal article

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Peer reviewed

The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1

L A Lansdon, H V Bernabe, N Nidey, J Standley, M J Schnieders and J C Murray

Journal of dental research, Vol.96(11), pp.1339-1345

10/2017

DOI: 10.1177/0022034517726496

PMCID: PMC5613887

PMID: 28825856

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Abstract

Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies. The proband presented with bilateral cleft lip and palate, malformed auricles, and bilateral ectrodactyly of his hands and feet at birth. He was later diagnosed with diabetes insipidus, spastic quadriplegia, developmental delay, agenesis of the corpus callosum, and enlargement of the third cerebral ventricle. We noted the substantial phenotypic overlap with individuals with Hartsfield syndrome, the rare combination of holoprosencephaly and ectrodactyly. Sequencing of FGFR1 identified a previously unreported de novo variant in exon 11 (p.Gly487Cys), which we modeled to determine its predicted effect on the protein structure. Although it was not predicted to significantly alter protein folding stability, it is possible this variant leads to the formation of nonnative intra- or intermolecular disulfide bonds. We then mapped this and other disease-associated variants to a 3-dimensional model of FGFR1 to assess which protein domains harbored the highest number of pathogenic changes. We observed the greatest number of variants within the domains involved in FGF binding and FGFR activation. To further explore the contribution of each variant to disease, we recorded the phenotype resulting from each FGFR1 variant to generate a series of phenotype-specific protein maps and compared our results to benign variants appearing in control databases. It is our hope that the use of phenotypic maps such as these will further the understanding of genetic disease in general and diseases caused by variation in FGFR1 specifically.

Genetic Association Studies

Humans

Genotype

Male

Cleft Palate - genetics

Holoprosencephaly - genetics

Mutation, Missense

Receptor, Fibroblast Growth Factor, Type 1 - genetics

Intellectual Disability - genetics

Genetic Variation

Cleft Lip - genetics

Phenotype

Hand Deformities, Congenital - genetics

Adult

Fingers - abnormalities

Craniofacial Abnormalities - genetics

Details

Title: Subtitle: The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1
Creators: L A Lansdon - 3 Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, USA
H V Bernabe - 4 Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA
N Nidey - 1 Department of Pediatrics, University of Iowa, Iowa City, IA, USA
J Standley - 1 Department of Pediatrics, University of Iowa, Iowa City, IA, USA
M J Schnieders - 4 Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA
J C Murray - 3 Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Journal of dental research, Vol.96(11), pp.1339-1345
DOI: 10.1177/0022034517726496
PMID: 28825856
PMCID: PMC5613887
NLM abbreviation: J Dent Res
ISSN: 0022-0345
eISSN: 1544-0591
Publisher: United States
Grant note: R37 DE008559 / NIDCR NIH HHS T32 GM008629 / NIGMS NIH HHS R01 DC002842 / NIDCD NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 10/2017
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Addiction Medicine; Biology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Biochemistry and Molecular Biology; Dental Research
Record Identifier: 9984024535402771

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