OMIA:000299-9986 : Dwarfism, generic in Oryctolagus cuniculus
In other species: domestic cat , taurine cattle , dog , goat , pig , sheep , horse , Northern giraffe , Angolan giraffe , white-tufted-ear marmoset , red deer , Asiatic elephant , callipterus cichlid , indicine cattle (zebu)
Categories: Skeleton phene (incl. short stature & teeth)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal incomplete dominant
Considered a defect: 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."
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].
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.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|HMGA2||high mobility group AT-hook 2||Oryctolagus cuniculus||4||NC_067377.1 (52276651..52407628)||HMGA2||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|689||Dwarf, long-haired Holland Lop (Rabbit) Netherland dwarf (Rabbit)||Dwarfism||HMGA2||dw||deletion, gross (>20)||Naturally occurring variant||4||"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."||2017||27986804|
Cite this entry
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2021||Derks, M.F.L., Steensma, M. :|
|Review: Balancing selection for deleterious alleles in livestock. Front Genet 12:761728, 2021. Pubmed reference: 34925454 . DOI: 10.3389/fgene.2021.761728.|
|2017||Carneiro, M., Hu, D., Archer, J., Feng, C., Afonso, S., Chen, C., Blanco-Aguiar, J.A., Garreau, H., Boucher, S., Ferreira, P.G., Ferrand, N., Rubin, C.J., Andersson, L. :|
|Dwarfism and altered craniofacial development in rabbits is caused by a 12.1 kb deletion at the HMGA2 locus. Genetics 205:955-965, 2017. Pubmed reference: 27986804 . DOI: 10.1534/genetics.116.196667.|
|2015||Mäkitaipale, J., Harcourt-Brown, F.M., Laitinen-Vapaavuori, O. :|
|Health survey of 167 pet rabbits (Oryctolagus cuniculus) in Finland. Vet Rec 177:418, 2015. Pubmed reference: 26475828 . DOI: 10.1136/vr.103213.|
|1997||Wegner, W. :|
|Problematic aspects of breeding dwarf rabbits [German] Deutsche Tierarztliche Wochenschrift 104:181-183, 1997. Pubmed reference: 9289403 .|
|1990||Komatsu, M., Imaoka, K., Satoh, M., Mikami, H. :|
|Hereditary C8-alpha-gamma deficiency associated with dwarfism in the rabbit. Journal of Heredity 81:413-417, 1990.|
|1981||Webber, R.J., Fox, R.R., Sokoloff, L. :|
|In vitro culture of rabbit growth plate chondrocytes. 2. Chondrodystrophic mutants. Growth 45:269-78, 1981. Pubmed reference: 6458543 .|
|1958||Robinson, R. :|
|Genetic studies of the rabbit. Bibliographia Genetica 17:229–558, 1958.|
|1957||Latimer, H.B., Sawin, P.B. :|
|Morphogenetic studies of the rabbit. XV. Measurements of the digestive tube and of its parts in normal and dwarf rabbits of race X. Anat Rec 129:1-16, 1957. Pubmed reference: 13509179 .|
|1955||Latimer, H.B., Sawin, P.B. :|
|The weight of the brain, of its parts and the weight and length of the spinal cord in the rabbit (race X). J Comp Neurol 103:513-39, 1955. Pubmed reference: 13286369 .|
|Latimer, H.B., Sawin, P.B. :|
|Morphogenetic studies of the rabbit. XII. Organ size in relation to body weights in adults of small sized race X. Anat Rec 123:81-102, 1955. Pubmed reference: 13268896 .|
|Latimer, H.B., Sawin, P.B. :|
|Morphogenetic studies of the rabbit. XIII. The influence of the dwarf gene upon organ size and variability in race X. Anat Rec 123:447-66, 1955. Pubmed reference: 13292775 .|
|1952||Sawin, P.B., Curran, R.H. :|
|Genetic and physiological background of reproduction in the rabbit. 1. The problem and its biological significance. Journal of Experimental Zoology 128:165-201, 1952.|
|1950||Sawin, P.B., Dietz, D.B. :|
|Morphogenetic studies of the rabbit. IX. Masking of prenatal growth gradients in adults. Moderne Biologie (eds Griineberg, H. and Ulrich, W.) :215-229, 1950.|
|1949||Crary, D.D., Sawin, P.B. :|
|Morphogenetic studies in the rabbit. VI. Genetic factors influencing the ossification pattern of the limbs. Genetics 34:508-23, 1949. Pubmed reference: 17247330 .|
|1941||Castle, W.E., Sawin, P.B. :|
|Genetic linkage in the rabbit. Proc Natl Acad Sci U S A 27:519-23, 1941. Pubmed reference: 16588495 .|
|1940||Greene, H.S. :|
|A dwarf mutation in the rabbit: the constitutional influence on homozygous and heterozygous individuals J Exp Med 71:839-56, 1940. Pubmed reference: 19871001 .|
|1939||Kroning, F. :|
|Ein neuer Fall erblichen Zwergwuchs beim Kaninchen Biologisches Zentralblatt 59:268-272, 1939.|
|1937||Nachtsheim, H. :|
|Erbpathologische Untersuchungen am Kaninchen [Investigation of inherited defects in rabbits] Z. indo Abst. u. Vererbgs 73:463-466, 1937. DOI: 10.1007/BF01847500.|
|1934||Greene, H.S., Hu, C.K., Brown, W.H. :|
|A lethal dwarf mutation in the rabbit with stigmata of endocrine abnormality Science 79:487-8, 1934. Pubmed reference: 17840734 . DOI: 10.1126/science.79.2056.487.|
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