Dwarfism, chondrodysplasia

 

Gene: ACAN

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease. Both parents of an affected animal must be carriers of at least one copy of the mutation. Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutations:

Mutation D1 (Miniature) : Deletion, ACAN gene; c.245 del, p.(K82R fs STOP 54), exon2, chr.1.

Mutation D2 (Miniature) : Substitution, ACAN gene; c.1270 C>T, p.(V424M), exon6, chr.1.

Mutation D3* (Miniature, Shetland) : Substitution, ACAN gene; c.1513 G>C, p.(A505P), exon7, chr.1.

Mutation D4 (Miniature) : Deletion, ACAN gene; c.7633_7653 del, p.(F2545_D2551 dél), exon15, chr.1.

Medical system: Skeletal

Breeds: Miniature Horse, Shetland Poney

Age of onset of symptoms: At birth.

The Miniature Horse has a phenotype of a small, proportionate body size but can also have a phenotype of chondrodysplastic dwarfism.  This dwarfism is characterized by skeletal dysplasia with disproportionate shortening of the long bones, bowed legs, shortened neck, mandibular prognathism, a disproportionately large and possibly domed head, and possibly a cleft palate, an abdominal hernia and embryonic lethality.  Molecular studies of dwarf Miniature horses revealed 4 distinct mutations within the ACAN gene as being responsible for the dwarf phenotype, either with homozygous recessive or with double heterozygote recessive heredity.  The ACAN gene codes for the Aggrecan protein, which is a core protein for chondroitin sulfate proteoglycans.  Chondroitin sulfate proteoglycans are extracellular matrix components found in cartilage tissue and are important for the ability of articular cartilage to withstand compression.  In addition, healthy cartilage is important for endochondral (indirect) bone formation in long bones.  Histology of the joints of dwarf Miniature horses showed irregular chondrocyte organization.  The combined carrier frequency rate of the described ACAN gene mutations was estimated to be 26.2% in the Miniature horse population.  It was noted that the D1 mutation, when homozygous or when double heterozygous with another ACAN mutation, is embryo lethal.  Furthermore, there may be additional uncharacterized mutations within the ACAN gene that can contribute to the dwarf phenotype.  DNA tests for these known mutations will now allow breeders of Miniature horses to avoid the dwarf phenotype in their animals through selective breeding.

 

References:

OMIA link: [1271-9796]

Andrade DGA, Basso RM, Castiglioni MC, et al. (2020) Description of the D4/D4 genotype in Miniature horses with dwarfism. J Vet Diagn Invest 32(1):99-102.  [pm/31906815]

Andrade DGA, Basso RM, Magro AJ, et al. (2020) Evaluation of a new variant in the aggrecan gene potentially associated with chondrodysplastic dwarfism in Miniature horses. Sci Rep 10(1):15238. [pm/32943661]

Graves KT, Eberth JE, Bailey E. (2020) Heterozygotes for ACAN dwarfism alleles in horses have reduced stature. Anim Genet 51(3):420-422.  [pm/32065671]

Eberth JE, Graves KT, MacLeod JN, Bailey E. (2018) Multiple alleles of ACAN associated with chondrodysplastic dwarfism in Miniature horses. Anim Genet 49(5) :413-420.  [pubmed/30058072]

Metzger J, Gast AC, Schrimpf R, et al. (2017) Whole-genome sequencing reveals a potential causal mutation for dwarfism in the Miniature Shetland pony. Mamm Genome 28:143-151.  [pm/27942904]

 

Contributions by: Laurie-Ann Laflamme and Mégane Malouin, Class of 2027, and Heidi Figueroa-Gosselin and Sandrine Martineau, Class of 2028, Faculty of Veterinary Medicine, University of Montreal.