Abnormality in SHOX gene behind bone disorder in Shetland ponies – study

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A young Shetland pony with skeletal atavism. See more details below.
CT scans of a young Shetland pony with skeletal atavism. See more details below.

Problems with the crucial SHOX gene in Shetland ponies appear to behind the abnormal bone development in a condition known as skeletal atavisim, which appears to hark back to the horse’s ancient ancestors.

SHOX – the short stature homeobox gene – is known to also be associated with short stature in humans.

Skeletal atavism in Shetland ponies is an inheritable disorder involving abnormal growth of the ulna and fibula leg bones that extend the carpal and tarsal joints, respectively. This causes an abnormal skeletal structure and impaired movement. Affected foals are usually euthanized.

Shetland ponies born with abnormal development of the ulna and fibula have been described since the 1950s, with the condition known as skeletal atavism reported in Britain, the Netherlands, and Sweden since the 1960s.

Fossil records show that around 15 million year ago, in the ancestors of modern equids, the ulna and fibula were reduced in size and were fused to the radius and tibia, respectively.

The reappearance of properties previously seen at an earlier evolutionary stage of a species is referred to as an atavism, and the disease in Shetland ponies has therefore been called skeletal atavism. Other examples of atavisms include excess hair in humans and polydactyly (extra feet) in horses.

“It is important to reveal the genetic basis of the disease and to develop a diagnostic test that can be used to avoid mating disease allele carriers,” the international study team reported in the journal G3: Genes, Genomes and Genetics.

In a first attempt to unravel the genetic basis of skeletal atavisim, Nima Rafati and his fellow researchers performed a genome-wide association study of 72 Shetlands – 36 controls, 22 carriers, and 14 with the condition. This analysis did not reveal any association between genetic markers and disease status.

They went on to perform whole genome resequencing of six Shetlands with the condition and a pool of control horses.

Analysis of the data showed that skeletal atavism was associated with two, partially overlapping, large deletions on sequence scaffolds not assigned to any chromosome in the EquCab2.0 horse genome assembly.

The genotyping array used for the earlier genome-wide association study had no markers near this associated region, they noted.

One of the identified deletions removed the entire coding region of the SHOX gene and both deletions remove parts of the cytokine receptor-like factor 2 (CRLF2) gene located downstream of SHOX.

Discussing their findings, the study team said SHOX expression was crucial during development, and problems with the gene have been associated with skeletal defects involving short stature and limb deformities in humans.

They said that although they could not exclude that the deletion of CRLF2 was involved in the expression of skeletal atavism in Shetlands, they believed that the similarity to human phenotypes caused by SHOX deficiency supported the interpretation that the condition in Shetlands was manifested by a reduction of SHOX expression.

“The deletion of CRLF2 may affect other hitherto unexplored phenotypes in affected horses and possibly also in carriers,” they wrote.

Rafati was joined in the research by Lisa Andersson, Sofia Mikko, Chungang Feng, Terje Raudsepp, Jessica Pettersson, Jan Janecka, Ove Wattle, Adam Ameur, Gunilla Thyreen, John Eberth, John Huddleston, Maika Malig, Ernest Bailey, Evan Eichler, Göran Dalin, Bhanu Chowdary, Leif Andersson, Gabriella Lindgren, and Carl-Johan Rubin.

The researchers were variously affiliated with Sweden’s Uppsala University, Texas A&M University, the University of Kentucky, the Seattle-based University of Washington, and Qatar University.

Large Deletions at the SHOX Locus in the Pseudoautosomal Region Are Associated with Skeletal Atavism in Shetland Ponies
Nima Rafati, Lisa Andersson, Sofia Mikko, Chungang Feng, Terje Raudsepp, Jessica Pettersson, Jan Janecka, Ove Wattle, Adam Ameur, Gunilla Thyreen, John Eberth, John Huddleston, Maika Malig, Ernest Bailey, Evan Eichler, Göran Dalin, Bhanu Chowdary, Leif Andersson, Gabriella Lindgren, and Carl-Johan Rubin.
The full study, published under a Creative Commons License, can be read here

Limbs of a 16-week-old Shetland pony with skeletal atavism. (A) View from the front when standing square, (B) caudal view when standing, and (C) caudal view at walk. Complete fibulas and ulnas cause instability in the tarsocrural and antebrachiocarpal joints, respectively; angular limb deformities become more severe at walk. (D–G) Computed tomography scans of the 16-wk-old Shetland pony’s gaskin and forearm. Dorsal views of tibia and complete fibula, right (D) and left (E) hind limbs. (F) Dorsal and (G) lateral views of left front limb radius and complete ulna. (H) Computed tomography scans showing dorsal and (I) lateral views of normally developed radius and ulna, with the ulna about to be fused to the radius, of a 16-wk-old nonatavistic Swedish Warmblood foal.
Limbs of a 16-week-old Shetland pony with skeletal atavism. (A) View from the front when standing square, (B) caudal view when standing, and (C) caudal view at walk. Complete fibulas and ulnas cause instability in the tarsocrural and antebrachiocarpal joints, respectively; angular limb deformities become more severe at walk. (D–G) Computed tomography scans of the 16-wk-old Shetland pony’s gaskin and forearm. Dorsal views of tibia and complete fibula, right (D) and left (E) hind limbs. (F) Dorsal and (G) lateral views of left front limb radius and complete ulna. (H) Computed tomography scans showing dorsal and (I) lateral views of normally developed radius and ulna, with the ulna about to be fused to the radius, of a 16-week-old nonatavistic Swedish Warmblood foal.  
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