Novel Homozygous ADAMTS2 Variants and Associated Disease Phenotypes in Dogs with Dermatosparactic Ehlers–Danlos Syndrome

Abstract

Tissue fragility, skin hyperextensibility and joint hypermobility are defining characteristics of Ehlers–Danlos syndrome (EDS). Human EDS is subclassified into fourteen types including dermatosparactic EDS, characterized by extreme skin fragility and caused by biallelic ADAMTS2 mutations. We report two novel, ADAMTS2 variants in DNA from EDS-affected dogs. Separate whole-genome sequences from a Pit Bull Terrier and an Alapaha Blue Blood Bulldog each contained a rare, homozygous variant (11:2280117delC, CanFam3.1), predicted to produce a frameshift in the transcript from the first coding ADAMTS2 exon (c.10delC) and a severely truncated protein product, p.(Pro4ArgfsTer175). The clinical features of these dogs and 4 others with the same homozygous deletion included multifocal wounds, atrophic scars, joint hypermobility, narrowed palpebral fissures, skin hyperextensibility, and joint-associated swellings. Due to severe skin fragility, the owners of all 6 dogs elected euthanasia before the dogs reached 13 weeks of age. Cross sections of collagen fibrils in post-mortem dermal tissues from 2 of these dogs showed hieroglyphic-like figures similar to those from cases of severe dermatosparaxis in other species. The whole-genome sequence from an adult Catahoula Leopard Dog contained a homozygous ADAMTS2 missense mutation, [11:2491238G>A; p.(Arg966His)]. This dog exhibited multifocal wounds, atrophic scars, and joint hypermobility, but has survived for at least 9 years. This report expands the spectrum of clinical features of the canine dermatosparactic subtype of EDS and illustrates the potential utility of subclassifying canine EDS by the identity of gene harboring the causal variant.

Identification of an ADAMTS2 frameshift variant in a cat family with Ehlers–Danlos syndrome

“…For example, in hereditary equine regional dermal asthenia, body sites exposed to stress or pressure are most prone to similar lesions ( Rashmir-Raven 2013 ). Comparable dermatological phenotypes can also be observed when caused by variants in ADAMTS2, such as in dogs ( Jaffey et al . 2022 ).…”

“…1999 ), and dogs ( Jaffey et al . 2019 , 2022 ). The human ClinVar database lists NM_014244.4( ADAMTS2 ):c.691del as a pathogenic variant.…”

The Role of the ADAMTS18 Gene-Induced Immune Microenvironment in Mouse Kidney Development

“…Biomedicines 2024, 12, 396 2 of 14 Mutations in ADAMTS2, which encodes a procollagen peptidase, lead to Ehlers-Danlos syndrome, which is characterized by tissue fragility and skin hyperextension [5], while mutations in ADAMTS5, 9, and 20 are involved in limb morphogenesis, cardiovascular development, skin pigmentation, and palatal development [6]. The main causes of this syndrome are tissue fragility and hyperextension of the skin.…”

Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers‐Danlos syndrome

“…In the 1980s, 2 case reports used transmission electron microscopy (TEM) and Western blotting to describe aberrant processing of the N-terminal propeptide of type I procollagen, as seen in humans, cattle, sheep, and dogs with dermatosparaxis EDS caused by a mutation in a disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS2). 1,2,[8][9][10]14 Recently, several collagen type V alpha 1 chain (COL5A1) mutations have been described in cats, a finding that is associated with classical EDS (cEDS) in humans. A heterozygous deletion, c.3420del in COL5A1 exon 43 leading to a frameshift mutation and premature stop codon was first described in a domestic shorthair cat in 2018.…”

“…To date, information on the genetics of EDS in cats is increasing but limited. In the 1980s, 2 case reports used transmission electron microscopy (TEM) and Western blotting to describe aberrant processing of the N‐terminal propeptide of type I procollagen, as seen in humans, cattle, sheep, and dogs with dermatosparaxis EDS caused by a mutation in a disintegrin and metalloproteinase with thrombospondin motifs 2 ( ADAMTS2 ) 1,2,8‐10,14 . Recently, several collagen type V alpha 1 chain ( COL5A1 ) mutations have been described in cats, a finding that is associated with classical EDS (cEDS) in humans.…”