Variants in Nebulin (NEB) Are Linked to the Development of Familial Primary Angle Closure Glaucoma in Basset Hounds.
Several dog breeds are susceptible to developing primary angle closure glaucoma (PACG), which suggests a genetic basis for the disease. We have identified a four-generation Basset Hound pedigree with characteristic autosomal recessive PACG that closely recapitulates PACG in humans. Our aim is to utilize gene mapping and whole exome sequencing approaches to identify PACG-causing sequence variants in the Basset. Extensive clinical phenotyping of all pedigree members was conducted. SNP-chip genotyping was carried out in 9 affected and 15 unaffected pedigree members. Two-point and multipoint linkage analyses of genome-wide SNP data were performed using Superlink-Online SNP-1.1 and a locus was mapped to chromosome 19q with a maximum LOD score of 3.24. The locus contains 12 Ensemble predicted canine genes and is syntenic to a region on chromosome 2 in the human genome. Using exome-sequencing analysis, a possibly damaging, non-synonymous variant in the gene Nebulin (NEB) was found to segregate with PACG which alters a phylogenetically conserved Lysine residue. The association of this variants with PACG was confirmed in a secondary cohort of unrelated Basset Hounds (p = 3.4 × 10-4, OR = 15.3 for homozygosity). Nebulin, a protein that promotes the contractile function of sarcomeres, was found to be prominently expressed in the ciliary muscles of the anterior segment. Our findings may provide insight into the molecular mechanisms that underlie PACG. The phenotypic similarities of disease presentation in dogs and humans may enable the translation of findings made in this study to patients with PACG.
Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, United States of America.
Dina F
DF
Ahram
Animal Eye Consultants of Iowa, North Liberty, IA, United States of America.
Sinisa D
SD
Grozdanic
Animal Eye Consultants of Iowa, North Liberty, IA, United States of America.
Helga
H
Kecova
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Arjen
A
Henkes
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Rob W J
RW
Collin
Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, United States of America.
Markus H
MH
Kuehn
D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D019295:Computational Biology / Q000379:methods; D004283:Dog Diseases / Q000175:diagnosis / Q000235:genetics*; D004285:Dogs; D059472:Exome; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D015812:Glaucoma, Angle-Closure / Q000662:veterinary*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008126:Lod Score; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment
D009124:Muscle Proteins; C035620:nebulin