A Missense Variant in the Bardet-Biedl Syndrome 2 Gene (BBS2) Leads to a Novel Syndromic Retinal Degeneration in the Shetland Sheepdog

Abstract

Canine progressive retinal atrophy (PRA) describes a group of hereditary diseases characterized by photoreceptor cell death in the retina, leading to visual impairment. Despite the identification of multiple PRA-causing variants, extensive heterogeneity of PRA is observed across and within dog breeds, with many still genetically unsolved. This study sought to elucidate the causal variant for a distinct form of PRA in the Shetland sheepdog, using a whole-genome sequencing approach. Filtering variants from a single PRA-affected Shetland sheepdog genome compared to 176 genomes of other breeds identified a single nucleotide variant in exon 11 of the Bardet–Biedl syndrome-2 gene (BBS2) (c.1222G>C; p.Ala408Pro). Genotyping 1386 canids of 155 dog breeds, 15 cross breeds and 8 wolves indicated the c.1222G>C variant was only segregated within Shetland sheepdogs. Out of 505 Shetland sheepdogs, seven were homozygous for the variant. Clinical history and photographs for three homozygotes indicated the presence of a novel phenotype. In addition to PRA, additional clinical features in homozygous dogs support the discovery of a novel syndromic PRA in the breed. The development and utilization of a diagnostic DNA test aim to prevent the mutation from becoming more prevalent in the breed.

Special Issue: “Canine Genetics 2”

“…A MYO5A variant is reported in a single Miniature Dachshund with coat color dilution and a lethal neurological defect resembling the human Griscelli syndrome type I [16]. A new late-onset progressive retinal atrophy (PRA) in Shetland Sheepdogs that is associated with an upturned nose and coat and tooth defects was phenotypically characterized and a variant in BBS2 unraveled as the likely sole causal variant [17]. Another syndrome in Cane Corso dogs, termed the dental-skeletal-retinal anomaly, was phenotypically characterized and a causal variant in MIA3 was identified that is hypothesized to cause a defect in cellular export in the post-translational maturation of various collagens [18].…”

Manifestations of systemic disease in the retina and fundus of cats and dogs

“…A close inspection of affected dogs showed that they suffered from clinical and morphological signs similar to those seen in human BBS patients such as obesity, renal abnormalities, sperm defects and anosmia ( 5 ). A missense variant in BBS2 is reported to cause syndromic PRA in Shetland sheepdogs ( 6 ). Systemic signs in the affected dogs included uncharacteristic wavy haircoat, upturned nose, dental defects, renal changes and occasional obesity ( 6 ).…”

“…A missense variant in BBS2 is reported to cause syndromic PRA in Shetland sheepdogs ( 6 ). Systemic signs in the affected dogs included uncharacteristic wavy haircoat, upturned nose, dental defects, renal changes and occasional obesity ( 6 ). A mutation in BBS4 was also described in the Hungarian puli resulting in PRA and severe reduction in sperm motility ( 7 ).…”