title: Genome-wide association mapping in dogs enables identification of the homeobox gene, NKX2-8, as a genetic component of neural tube defects in humans.
abstract: Neural tube defects (NTDs) is a general term for central nervous system malformations secondary to a failure of closure or development of the neural tube. The resulting pathologies may involve the brain, spinal cord and/or vertebral column, in addition to associated structures such as soft tissue or skin. The condition is reported among the more common birth defects in humans, leading to significant infant morbidity and mortality. The etiology remains poorly understood but genetic, nutritional, environmental factors, or a combination of these, are known to play a role in the development of NTDs. The variable conditions associated with NTDs occur naturally in dogs, and have been previously reported in the Weimaraner breed. Taking advantage of the strong linkage-disequilibrium within dog breeds we performed genome-wide association analysis and mapped a genomic region for spinal dysraphism, a presumed NTD, using 4 affected and 96 unaffected Weimaraners. The associated region on canine chromosome 8 (pgenome  =3.0 × 10(-5)), after 100,000 permutations, encodes 18 genes, including NKX2-8, a homeobox gene which is expressed in the developing neural tube. Sequencing NKX2-8 in affected Weimaraners revealed a G to AA frameshift mutation within exon 2 of the gene, resulting in a premature stop codon that is predicted to produce a truncated protein. The exons of NKX2-8 were sequenced in human patients with spina bifida and rare variants (rs61755040 and rs10135525) were found to be significantly over-represented (p=0.036). This is the first documentation of a potential role for NKX2-8 in the etiology of NTDs, made possible by investigating the molecular basis of naturally occurring mutations in dogs.
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California Davis, Davis, California, USA. nsafra@ucdavis.edu
authors.forename: Noa
authors.initials: N
authors.lastname: Safra
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Ferguson
authors.forename: Miriam
authors.initials: M
authors.lastname: Aguilar
authors.forename: Rochelle L
authors.initials: RL
authors.lastname: Coulson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Thomas
authors.forename: Peta L
authors.initials: PL
authors.lastname: Hitchens
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dickinson
authors.forename: Karen M
authors.initials: KM
authors.lastname: Vernau
authors.forename: Zena T
authors.initials: ZT
authors.lastname: Wolf
authors.forename: Danika L
authors.initials: DL
authors.lastname: Bannasch
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D004285:Dogs; D005091:Exons / Q000235:genetics; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D009154:Mutation; D009436:Neural Tube Defects / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C108070:NKX2-8 protein, human; D014157:Transcription Factors; D005492:Folic Acid