A novel variant of FGFR3 causes proportionate short stature

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Authors	KANT Sarina G. ČERVENKOVÁ Iveta BÁLEK Lukáš TRANTÍREK Lukáš SANTEN Gijs W. E. VRIES Martine C. de DUYVENVOORDE Hermine A. van WIELEN Michiel J. R. van der VERKERK Annemieke J. M. H. UITTERLINDEN André G. HANNEMA Sabine E. WIT Jan M. OOSTDIJK Wilma KREJČÍ Pavel LOSEKOOT Monique
Year of publication	2015
Type	Article in Periodical
Magazine / Source	European Journal od Endocrinology
MU Faculty or unit	Faculty of Medicine
Citation
Web	http://www.eje-online.org/content/172/6/763
Doi	http://dx.doi.org/10.1530/EJE-14-0945
Field	Endocrinology, diabetology, metabolism, nutrition
Keywords	FACTOR RECEPTOR-3 GENE; ASN540SER MUTATION; DUTCH CHILDREN; HYPOCHONDROPLASIA; ACTIVATION; PHENOTYPE; HEIGHT; FAMILY; LENGTH
Attached files	EL_1306875.pdf
Description	Objective: Mutations of the fibroblast growth factor receptor 3 (FGFR3) cause various forms of short stature, of which the least severe phenotype is hypochondroplasia, mainly characterized by disproportionate short stature. Testing for an FGFR3 mutation is currently not part of routine diagnostic testing in children with short stature without disproportion. Design: A three-generation family A with dominantly transmitted proportionate short stature was studied by whole-exome sequencing to identify the causal gene mutation. Functional studies and protein modeling studies were performed to confirm the pathogenicity of the mutation found in FGFR3. We performed Sanger sequencing in a second family B with dominant proportionate short stature and identified a rare variant in FGFR3. Methods: Exome sequencing and/or Sanger sequencing was performed, followed by functional studies using transfection of the mutant FGFR3 into cultured cells; homology modeling was used to construct a three-dimensional model of the two FGFR3 variants. Results: A novel p. M528I mutation in FGFR3 was detected in family A, which segregates with short stature and proved to be activating in vitro. In family B, a rare variant (p.F384L) was found in FGFR3, which did not segregate with short stature and showed normal functionality in vitro compared with WT. Conclusions: Proportionate short stature can be caused by a mutation in FGFR3. Sequencing of this gene can be considered in patients with short stature, especially when there is an autosomal dominant pattern of inheritance. However, functional studies and segregation studies should be performed before concluding that a variant is pathogenic.
Related projects:	CEITEC - Central European Institute of Technology FGFR3-specifický adaptérom a jeho role v patologické FGFR3 signalizaci v nemoci High-throughput screening of compound libraries aimed on discovery of novel inhibitors of the FGFR/ERK MAP kinase signaling