Chondrodysplasia, Munchkin phenotype (UGDH-related)

Gene: UGDH

Transmission: Autosomal dominant (homozygote embryo lethal)

An animal with one copy of the mutation (M/N) will develop the chondrodysplasia (Munchkin) phenotype. If only one parent is a carrier (M/N), the kittens have a 50% chance of having the chondrodysplasia phenotype. If both parents are carriers, the kittens have a 67% chance of having the chondrodysplasia phenotype. Embryos with two copies of the mutation (M/M, homozygous mutant) die in utero.

Mutation: Deletion, UGDH gene; 3303 bp deletion involving part of intron10-11, exon 11 and part of the 3’-UTR, Chr.B1

Medical system: Skeletal

Breed: Munchkin

Age of onset of symptoms: From birth (congenital)

The Munchkin cat displays disproportionate dwarfism (chondrodysplasia), involving shortened limbs but a normal body size.  Identified in the 1940s due to a naturally occurring mutation, the Munchkin cat was recognized as a breed in 1991.  The standard Munchkin cat has the chondrodysplasia (short-legged) phenotype while the non-standard Munchkin cat has legs of normal length, and both standard and non-standard kittens can occur in the same litter.  Breeding trials suggest an autosomal dominant pattern of heredity where the Munchkin phenotype is seen in the carrier (M/N) animal.  The double mutant animal (M/M) is not seen, suggesting that this is a case of early embryo lethality.  Evidence for this includes small litter sizes when two munchkin animals are mated.

The mutation responsible for the Munchkin phenotype has recently been described and involves a large deletion within the UGDH gene.  This gene codes for the protein enzyme UDP-glucose 6-dehydrogenase, which is involved in the synthesis of extracellular glucosaminoglycan (GAG) molecules, including chondroitin sulfate.  Chondroitin sulfate is an important structural component of cartilage, and proper cartilage formation is necessary for normal endochondral bone formation, as seen in the long bones of the limbs.  In addition, chondroitin sulfate is a component of proteoglycan molecules, which are themselves important regulators of Fibroblast Growth Factor (FGF) signalling during normal bone growth.  Deregulated FGF expression in the dog, due to mutations involving FGF retrogenes, are responsible for the canine chondrodysplasia phenotype (with or without associated intervertebral disk disease) as is seen in several dog breeds such as the Dachshund.    It is not clear whether Munchkin cats are more susceptible to intervertebral disk disease than are normal cats.  It is known that Munchkin cats are more susceptible to osteoarthritis than are normal cats.

Because of potential of health concerns, the Munchkin cat breed is not recognized by a number of cat associations, and breeding of Munchkin cats has been banned in some countries including the Netherlands.

References:

OMIA link: [2541-9685]

Lyons LA. (2024) Genetic testing: practical dos and don’ts for cats.  J Feline medicine and surgery 26:1-13.  [pm/39648935]

Anderson LM, Fox DB, Chesney KL, et al. (2021) Skeletal manifestations of heritable disproportionate dwarfism in cats as determined by radiography and magnetic resonance imaging. Vet Comp Orthop Traumatol 34:327-337.  [pm/34082456]

Buckley RM, Davis BW, Brashear WA, et al. (2020) A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism. PLoS Genet 16:e1008926.  [pm/33090996]

Struck AK, Braun M, Detering KA, et al. (2020) A structural UGDH variant associated with standard Munchkin cats. BMC Genet 21:67. [pm/32605545]

With contributions by: Sarah Goulet and Siba Moukarzel, Class of 2028, and update by Jody Zhao and Judy Zhong, Class of 2030, Faculty of Veterinary Medicine, University of Montreal.  (Translation: DWS).