In other species: white-tufted-ear marmoset , dog , domestic cat , Asiatic elephant , horse , pig , red deer , Northern giraffe , taurine cattle , indicine cattle (zebu) , goat , sheep , callipterus cichlid , Angolan giraffe

Categories: Skeleton phene (incl. short stature & teeth) , Growth / size / body region phene

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2017

Species-specific symbol: dw

Species-specific description: Robinson (1958, pp. 343-346) provides an extensive summary of this form of proportionate dwarfism. The effect of the mutant dw allele on a wide range of traits was reported by Crary and Sawin (1949), Sawin and Dietz (1950), Sawin and Curran (1952), and in three 1955 papers by Latimer and Sawin. The results of Carneiro et al. (2017) "imply that small size in dwarf rabbits results from a large effect, loss-of-function (LOF) mutation in HMGA2 combined with polygenic selection."

History: A single-locus proportionate dwarfism that is autosomal recessive lethal was first reported by Greene et al. (1934) and subsequently by Kroning (1939). As summarised by Robinson (1958), "The growth rate of heterozygotes is comparable to that of normals but the size difference [approximately two-thirds of normal homozygotes] at birth persists into adult life. They are normal in other respects but for a greater tendency for the females to accumulate fat unless bred from regularly."

Inheritance: As reported by Carneiro et al. (2017), "The dwarf phenotype characterizes the smallest of rabbit breeds and is governed largely by the effects of a single dwarfing allele with an incompletely dominant effect on growth. Dwarf rabbits typically weigh under 1 kg and have altered craniofacial morphology. The dwarf allele is recessive lethal and dwarf homozygotes die within a few days of birth. The dwarf phenotype is expressed in heterozygous individuals and rabbits from dwarf breeds homozygous for the wild-type allele are normal, although smaller when compared to other breeds." The mode of inheritance has been changed from 'autosomal recessive lethal' to 'autosomal incompletely dominant' in May 2022 to reflect that animals with a single copy of the HMGA2 mutation present with a milder form of dwarfism.

Mapping: Castle and Sawin (1941) showed that the dw gene is linked to agouti (OMIA 000201-9986) in linkage group IV.

Molecular basis: Carneiro et al. (2017) showed "that the dwarf allele constitutes a ~12.1 kb deletion overlapping the promoter region and first three exons of the HMGA2 gene leading to inactivation of this gene." Very interestingly, mutation in this same gene is associated with body-size variation in dogs (OMIA 001968-9615) and horses (OMIA 001968-9796), and with beak size in Darwin's finches (OMIA 001992-48881); see the hyperlink to HMGA2 under the heading "OMIA gene details page" in the table below.

Clinical features: As reported by Green et al. (1934): "The [homozygous] dwarfs of this stock are born alive and occasionally they are capable of nursing, but so far, none of them has lived longer than a few days. They are delicately formed and to outward appearance are fully developed except for the bones of the calvarium, which, as a rule, are incompletely calcified."

Pathology: The pathology in individuals homozygous for the dwarf mutation leads to death. Although heterozygous individuals are viable and can live a healthy life, due to their craniofacial morphology they are particularly prone to dental disorders due to their proportionately smaller heads and longer jaw, which can cause issues with misalignment. This mandibular prognathism predisposes to abnormal dental wear, causing altered teeth positions or elongation due to abnormal grinding patterns (Mäkitaipale, Harcourt-Brown and Laitinen-Vapaavuori, 2015). [IT thanks DVM student Carmen Ip for contributions to this entry in April 2022].

Control: Breeding of two animals that are both heterozgyous for the dwarf mutation should be avoided. For the breeding of dwarf rabbits, each breeding pair should include an animal heterozygous for the dwarf mutation (dwarf rabbit) and an animal that does not have the dwarf mutation. This will avoid the birth of non viable homozygous dwarfs and result in the birth of 50% viable (heterozygous) dwarfs and 50% normal sized rabbits.

Breeds: Dwarf, long-haired, Holland Lop (Rabbit) (VBO_0001258), Netherland dwarf (Rabbit) (VBO_0001266).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: