Glaucoma-causing ADAMTS17 mutations are also reproducibly associated with height in two domestic dog breeds: selection for short stature may have contributed to increased prevalence of glaucoma

Abstract

Background In humans, ADAMTS17 mutations are known to cause Weill-Marchesani-like syndrome, which is characterised by lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Breed-specific homozygous mutations in ADAMTS17 are associated with primary open angle glaucoma (POAG) in several dog breeds, including the Petit Basset Griffon Vendeen (PBGV) and Shar Pei (SP). We hypothesised that these mutations are associated with short stature in these breeds. Methods Two hundred thirty-three PBGV and 66 SP were genotyped for their breed-specific ADAMTS17 mutations. The height of each dog was measured at the withers. We used linear (per allele) regression to assess the association between ADAMTS17 mutations and height as a continuous variable, and linear regression and likelihood ratio tests to assess the shape of the association by comparing a general model with a linear (per allele) model. Results The adjusted mean heights of affected, carrier, and clear PBGV were 33.49 cm ( n = 21, 95% CI 32.78–34.19 cm), 34.88 cm ( n = 85, 95% CI 34.53–35.25 cm), and 34.92 cm ( n = 121, 95% CI 34.62–35.21 cm), respectively. The mean heights of affected, carrier, and clear SP were 43.96 cm ( n = 9, 95% CI 41.88–46.03 cm), 47.56 cm ( n = 28, 95% CI 45.50–48.63 cm), and 48.95 cm ( n = 23, 95% CI 47.80–50.11 cm), respectively. There was a significant difference between the height of affected and clear animals in the PBGV ( P = 0.001) and the SP ( P = < 0.0001). Conclusions ADAMTS17 POAG mutations are significantly associated with height in these breeds. Electronic supplementary material The online version of this article (10.1186/s40575-019-0071-6) contains supplementary material, which is available to authorized users.

Current Understanding of the Genetics of Intervertebral Disc Degeneration

“…However, overexpression of FGF4 associated with insertion of FGF4 retrogenes on CFA12 and CFA18 appear to have broader influences on limb length across many breeds and are the only genes to have been implicated in body size in across-breed association studies ( 3 , 13 – 16 ). While many breed specific mutations are considered undesirable ( 8 – 10 , 12 ) some of these genes have been under positive selection in specific breeds due to their effects on height, despite associated pathologies including glaucoma and IVDD ( 11 , 13 ).…”

Looking into the future: Gene and cell therapies for glaucoma

“…While proof still needs to be provided in dogs that tissue biomechanical properties are linked to IOP susceptibility, initial studies in ADAMTS10 ‐mutant Beagles with OAG showed that their posterior sclera is weaker with reduced fibrous collagen density, possibly explaining the slower optic nerve degeneration with chronic, severe IOP increases compared to dogs of other breeds 45,229‐231 . Similar findings can be expected in other ADAMTS10 ‐ and ADAMTS17 ‐mutant dogs with OAG, for example Norwegian Elkhound ( ADAMTS10 ), 36 Petit Basset Griffon Vendéen ( ADAMTS17 ), 38,232 Basset Fauve de Bretagne ( ADAMTS17 ), 40 and Chinese Shar‐Pei ( ADAMTS17 ) 41,232 . Some transgenic mice are also resistant to glaucomatous damage, while hardening of the sclera with cross‐linking agents worsens IOP‐related damage to the RGC axons 224 …”

Gene Panel Screening Across Canine Eye Disorders Highlights Genetic Heterogeneity and the Need for Molecular Discoveries

“…Since then, at least 15 genes have been observed to be altered in both PRA and RP (Online Mendelian Database, OMIA, https://omia.org/; RetNet, https://sph.uth.edu/RetNet/). A similar pattern can be further recognized for glaucoma and ectopia lentis (EL), a canine equivalent of lens luxation (LL): ADAM metallopeptidase with thrombospondin type 1 motif-proteins -ADAMTS10 and ADAMTS17 -genes have been observed to harbor variants causative for primary glaucoma and LL in dogs and syndromic diseases, with symptoms including glaucoma and EL, in humans (Weill-Marchessani syndrome) (Farias et al, 2010;Forman et al, 2015;Jeanes et al, 2019;Morales et al, 2009). Overall, this pattern of shared genes harboring eye disease-causing variants indicates a need for further research in both species.…”