Identification of the Identical Human Mutation in ACVR1 in 2 Cats With Fibrodysplasia Ossificans Progressiva

Abstract

Two domestic shorthair cats, 1 intact female and 1 intact male, presented with progressive limb lameness and digital deformities at 4 and 6 months of age. Stiffness and swelling of the distal thoracic and pelvic limb joints progressed to involve hip and shoulder joints, resulting in reduced mobility. Radiographs in both cats and computed tomography of the male cat revealed ankylosing, polyarticular deposits of extracortical heterotopic bone spanning multiple axial and appendicular joints, extending into adjacent musculotendinous tissues. All findings supported fibrodysplasia ossificans progressiva (FOP), a disorder characterized by toe malformations and progressive heterotopic ossification in humans. In both cats, molecular analyses revealed the same heterozygous mutation in the activin A receptor type I (ACVR1) gene that occurs in humans with FOP. Several reports of heterotopic ossification in cats exist, but this is the first one to identify clinical FOP in 2 cats with the identical mutation that occurs in >95% of humans with FOP.

Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish

“…A small subset of patients with variant presentation of the classical FOP phenotype have distinct activating mutations in the ACVR1 gene, including the substitution G328R ( Kaplan et al, 2009 ; Haupt et al, 2018 ). While the phenotypic consequences of increased ACVR1 signaling have been well characterized in both patients and animal models ( Casal et al, 2019 ; Pignolo et al, 2011 ; Chakkalakal and Shore, 2019 ), the mechanism by which ACVR1 mutations lead to over-active signaling is less well understood.…”

Fibrodysplasia ossificans progressiva in a cat

“…However, in certain cases of FOP, the initial presentation was due to dermatological signs (including alopecia, erythema, pigmentation and purpura), which were not present in this case 5 8. The median age for cats reported with FOP at time of diagnosis was 15 months, with the range from 4 months to 6 years 4–12. There has been one previous report of FOP in a Maine coon,8 but it is difficult to effectively note any breed predilection as the disease is rare.…”

“…15 In 2019, two cats diagnosed with FOP were found to have the same mutation in the ACVR1 protein. 12 Interestingly, both cats had stunted second digits, and in people, stunted first digits are a characteristic sign of FOP. 12 This finding has not been noted in previous feline FOP cases and was not a finding in our case.…”

“…There are animal models (specifically, fruit fly and murine) of FOP that indicate mutations affecting the ACVR1 protein can result in similar lesions, with these models being used for further research into FOP in humans 15. In 2019, two cats diagnosed with FOP were found to have the same mutation in the ACVR1 protein 12. Interestingly, both cats had stunted second digits, and in people, stunted first digits are a characteristic sign of FOP 12.…”

“…2 The disease is very rare in people, with an estimated one in two million people being affected. 3 There have been a few case reports in veterinary literature of occurrences in animals, with a number of reports in cats [4][5][6][7][8][9][10][11][12] and one in a dog. 13 This is the first case reported in the literature in a cat in the UK.…”