Evaluation of ADAMTS17 in Chinese Shar-Pei with primary open-angle glaucoma, primary lens luxation, or both

Abstract

OBJECTIVE To evaluate the coding regions of ADAMTS17 for potential mutations in Chinese Shar-Pei with a diagnosis of primary open-angle glaucoma (POAG), primary lens luxation (PLL), or both. ANIMALS 63 Shar-Pei and 96 dogs of other breeds. PROCEDURES ADAMTS17 exon resequencing was performed on buccal mucosal DNA from 10 Shar-Pei with a diagnosis of POAG, PLL, or both (affected dogs). A candidate causal variant sequence was identified, and additional dogs (53 Shar-Pei [11 affected and 42 unaffected] and 95 dogs of other breeds) were genotyped for the variant sequence by amplified fragment length polymorphism analysis. Total RNA was extracted from ocular tissues of 1 affected Shar-Pei and 1 ophthalmologically normal Golden Retriever; ADAMTS17 cDNA was reverse transcribed and sequenced, and ADAMTS17 expression was evaluated by quantitative reverse-transcription PCR assay. RESULTS All affected Shar-Pei were homozygous for a 6-bp deletion in exon 22 of ADAMTS17 predicted to affect the resultant protein. All unaffected Shar-Pei were heterozygous or homozygous for the wild-type allele. The variant sequence was significantly associated with affected status (diagnosis of POAG, PLL, or both). All dogs of other breeds were homozygous for the wild-type allele. The cDNA sequencing confirmed presence of the expected variant mRNA sequence in ocular tissue from the affected dog only. Gene expression analysis revealed a 4.24-fold decrease in the expression of ADAMTS17 in ocular tissue from the affected dog. CONCLUSIONS AND CLINICAL RELEVANCE Results supported that the phenotype (diagnosis of POAG, PLL, or both) is an autosomal recessive trait in Shar-Pei significantly associated with the identified mutation in ADAMTS17.

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

“…Indeed, the word “basset” comes from the medieval French for “of low stature” [22]. It could therefore be speculated, given that five different ADAMTS17 mutations have now been identified in breeds of small stature [3–5, 13], that this locus could be under positive selection.…”

“…A different mutation in ADAMTS17 (a deletion of six base pairs on canine chromosome 3 at co-ordinates 40,935,387 – 40,935,393 (CanFam 3.1) has more recently been identified in the Shar Pei (SP) [5]. As in the PBGV, this mutation causes an autosomal recessive form of POAG, and primary lens luxation (PLL) is also associated with this mutation [5, 11]. An independent ADAMTS17 mutation has been shown to cause PLL in several breeds [12, 13].…”

The future of canine glaucoma therapy

“…As veterinary ophthalmologists we have a unique opportunity to study how the biomechanical properties of the ocular tissues affect susceptibility to IOP. For example, we observe that ADAMTS10 ‐mutant beagles and ADAMTS17 ‐mutant Chinese shar‐peis with POAG maintain eye sight longer with slower progression of ONH atrophy than many other glaucomatous dog breeds with comparable pressures . While proof still needs to be provided that tissue properties are linked to IOP susceptibility in dogs, initial biomechanical studies in ADAMTS10 ‐mutant beagles showed that their posterior sclera is weaker with reduced fibrous collagen density .…”

The ADAMTS/Fibrillin Connection: Insights into the Biological Functions of ADAMTS10 and ADAMTS17 and Their Respective Sister Proteases

“…However, most mutations are located in the domains comprising the catalytic domain and there is a notable paucity of mutations located in the ancillary domains. Mutations in ADAMTS17 are also associated with short stature, lens dislocation, and glaucoma in several dog breeds, suggesting a fundamental role for ADAMTS17 in bone growth and in the formation and/or homeostasis of the ciliary zonule which is comprised of fibrillin microfibrils and holds the lens in place [43][44][45][46][47]. ADAMTS10 and ADAMTS17 were identified in a genome-wide association study (GWAS) of more than 12,000 cases versus 390,000 controls as susceptibility loci likely to cause carpal tunnel syndrome [48].…”