A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle

BMC Genetics

Research Article

Jørgen S. Agerholm¹  Fintan J. McEvoy¹  Steffen Heegaard²  Vidhya Jagannathan³  Cord Drögemüller³  Carole Charlier⁴ 

[1] Department of Clinical Veterinary Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlægevej 16, 1870, Frederiksberg C, DK, Denmark;Department of Pathology, Rigshospitalet, University of Copenhagen, Frederik V’s Vej 11, 2100, Copenhagen Ø, DK, Denmark;Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen Ø, DK, Denmark;Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, 3001, Bern, Switzerland;Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège, 4000, Liège, Belgium;

关键词: Bovine;    Congenital;    Malformation;    Rare disease;    Hereditary;    Fibroblast growth factor receptor 2;    Crouzon syndrome;    Pfeiffer syndrome;   

DOI  :  10.1186/s12863-017-0541-3

 received in 2017-03-10, accepted in 2017-07-27,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundSurveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause.ResultsSeven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS.High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire.ConclusionsFDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given the phenotypic similarities in FDS affected calves, the genetic mapping and absence of further high impact variants in the critical genome regions, it is highly likely that the missense mutation in the FGFR2 gene caused the FDS phenotype in a dominant mode of inheritance.

【 授权许可】

CC BY   
© The Author(s). 2017