OMIA 000307-9615 : Dwarfism, pituitary in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 221750

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2011

Mapping: Using a genome-wide homozygosity-mapping strategy with 256 microsatellite markers, followed by fine-mapping with another 49 microsatellites, Voorbij et al. (2011) mapped this disorder to a region on chromosome CFA9 flanked by "markers REN256F13 at position 49.5 Mb and REN177B24 at 54.1 Mb".

By conducting a GWAS on 4 affected and 193 control German Shepherd dogs, each genotyped with the Affymetrix v2 canine SNP chip (Yielding 48,415 SNPs for the analysis), Tsai et al. (2012) confirmed the region on chromosome CFA9, which (they noted) includes a potential candidate gene, LHX3 (the same as was identified by Voorbij et al. (2011): see Molecular section below.

Molecular basis: Of the 137 genes annotated in the candidate region on CFA9 (see Mapping section above), only one was a likely candidate, namely "LHX3, a transcription factor essential for pituitary gland formation" (Voorbij et al., 2011). Sequencing revealed a causative mutation as "a deletion of one of six 7 bp repeats in intron 5 of LHX3, reducing the intron size to 68 bp . . . An exon trapping assay indicated that the shortened intron is not spliced efficiently, probably because it is too small." (with thanks to Frank Coopman for alerting FN to this discovery in Sep 2012).

Voorbij et al. (2011) also mentioned briefly that one of their dwarfs was a compound heterozygote for the above deletion and "for an insertion of an ACA trinucleotide sequence . . . . The insertion occurred at a site of two ACA triplets that are normally present in exon 5 (NM_001197187, c.545_547dupACA). The result for the open reading frame was an insertion of an AAC codon for asparagine at position 182 of the LHX3b protein isoform (p.N182dup), which is located in the first α-helix of the homeodomain of LHX3. The triplet insertion and the heterozygosity of the dwarf were confirmed by sequence analysis of exon 5 from genomic DNA . . . . The insertion is situated close to intron 5 and can be amplified as part of the same fragment." Thanks to Frank Coopman and Jonas Donner for pointing out this second mutation to FN.

Voorbij et al. (2014) reported that the same causal 7bp deletion in two breeds resulting from crossing German Shepherd dogs with wolves: "Saarloos and Czechoslovakian wolfdog dwarfs have the same 7 bp deletion in intron 5 of LHX3 as do German Shepherd Dog dwarfs."

Prevalence: Voorbij et al. (2011) reported that "Seven dogs from a group of 37 unrelated GSD from the Dutch population with normal growth were carrier of the 7 bp deletion (allele frequency = 0.094)."

Voorbij et al. (2014) reported that "The frequency of carriers of this mutation among clinically healthy Saarloos and Czechoslovakian wolfdogs used for breeding was 31% and 21%, respectively."

Breed: German Shepherd Dog.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
LHX3 LIM homeobox 3 Canis lupus familiaris 9 NC_006591.3 (49248555..49254128) LHX3 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Czechoslovakian wolfdog German Shepherd Dog Saarloo Pituitary dwarfism LHX3 splicing "a deletion of one of six 7 bp repeats in intron 5 of LHX3" 2011 22132174
German Shepherd Dog Pituitary dwarfism LHX3 insertion, small (<=20) NM_001197187 c.545_547dupACA p.N182dup 2011 22132174

References


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.
2014 Voorbij, A.M., Leegwater, P.A., Kooistra, H.S. :
Pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs is associated with a mutation in LHX3. J Vet Intern Med 28:1770-4, 2014. Pubmed reference: 25273400. DOI: 10.1111/jvim.12448.
2012 Tsai, K.L., Noorai, R.E., Starr-Moss, A.N., Quignon, P., Rinz, C.J., Ostrander, E.A., Steiner, J.M., Murphy, K.E., Clark, L.A. :
Genome-wide association studies for multiple diseases of the German Shepherd Dog. Mamm Genome 23:203-11, 2012. Pubmed reference: 22105877. DOI: 10.1007/s00335-011-9376-9.
2011 Voorbij, A.M., van Steenbeek, F.G., Vos-Loohuis, M., Martens, E.E., Hanson-Nilsson, J.M., van Oost, B.A., Kooistra, H.S., Leegwater, P.A. :
A contracted DNA repeat in LHX3 intron 5 is associated with aberrant splicing and pituitary dwarfism in German shepherd dogs. PLoS One 6:e27940, 2011. Pubmed reference: 22132174. DOI: 10.1371/journal.pone.0027940.
2010 Voorbij, A.M., Leegwater, P.A., Kooistra, H.S. :
[Hypopituitarism associated dwarfism in German Shepherds, saarloos wolf dogs and Czechoslovakian wolf dogs. Access to genetic testing]. Tijdschr Diergeneeskd 135:950-4, 2010. Pubmed reference: 21287722.
2009 Voorbij, A.M.W.Y., Kooistra, H.S. :
Pituitary Dwarfism in German Shepherd Dogs JCVS 2:4-11, 2009.
2006 Bhatti, SF., De Vliegher, SP., Mol, JA., Van Ham, LM., Kooistra, HS. :
Ghrelin-stimulation test in the diagnosis of canine pituitary dwarfism. Res Vet Sci 81:24-30, 2006. Pubmed reference: 16271735. DOI: 10.1016/j.rvsc.2005.09.009.
Hanson, JM., Mol, JA., Leegwater, PA., Kooistra, HS., Meij, BP. :
The leukemia inhibitory factor receptor gene is not involved in the etiology of pituitary dwarfism in German shepherd dogs. Res Vet Sci 81:316-20, 2006. Pubmed reference: 16624355. DOI: 10.1016/j.rvsc.2006.03.001.
2002 Knottenbelt, C.M., Herrtage, M.E. :
Use of proligestone in the management of three German shepherd dogs with pituitary dwarfism Journal of Small Animal Practice 43:164-170, 2002. Pubmed reference: 11996393.
van Oost, B.A., Versteeg, S.A., Imholz, S., Kooistra, H.S. :
Exclusion of the lim homeodomain gene LHX4 as a candidate gene for pituitary dwarfism in German shepherd dogs Molecular &amp; Cellular Endocrinology 197:57-62, 2002. Pubmed reference: 12431796.
2000 Everts, R.E., Hazewinkel, H.A.W., Rothuizen, J., van, Oost, B.A. :
Bone disorders in the dog: A review of modern genetic strategies to find the underlying causes [Review] Veterinary Quarterly 22:63-70, 2000. Pubmed reference: 10789512.
Kooistra, H.S., Voorhout, G., Mol, J.A., Rijnberk, A. :
Combined pituitary hormone deficiency in german shepherd dogs with dwarfism. Domest Anim Endocrinol 19:177-90, 2000. Pubmed reference: 11064220.
Lantinga-van, Leeuwen, I.S., Kooistra, H.S., Mol, J.A., Renier, C., Breen, M., van, Oost, B.A. :
Cloning, characterization, and physical mapping of the canine Prop-1 gene (PROP1): exclusion as a candidate for combined pituitary hormone deficiency in German shepherd dogs Cytogenetics & Cell Genetics 88:140-144, 2000.
Leeuwen, I.S.L., Mol, J.A., Kooistra, H.S., Rijnberk, A., Breen, M., Renier, C., van, Oost, B.A. :
Cloning of the canine gene encoding transcription factor Pit-1 and its exclusion as candidate gene in a canine model of pituitary dwarfism Mammalian Genome 11:31-36, 2000. Pubmed reference: 10602989.
1999 Hamann, F., Kooistra, H.S., Mol, J.A., Gottschalk, S., Bartels, T., Rijnberk, A. :
Pituitary function and morphology in two German shepherd dogs with congenital dwarfism Veterinary Record 144:644-646, 1999. Pubmed reference: 10399248.
1998 Kooistra, H.S., Voorhout, G., Selman, P.J., Rijnberk, A. :
Progestin-induced growth hormone (gh) production in the treatment of dogs with congenital gh deficiency Domestic Animal Endocrinology 15:93-102, 1998. Pubmed reference: 9532423.
1997 Ramsey, I.K., Evans, H., Herrtage, M.E. :
Thyroid-stimulating hormone and total thyroxine concentrations in euthyroid, sick euthyroid and hypothyroid dogs Journal of Small Animal Practice 38:540-545, 1997. Pubmed reference: 9444634.
1993 Rijnberk, A., Vanherpen, H., Mol, J.A., Rutteman, G.R. :
Disturbed Release of Growth Hormone in Mature Dogs - A Comparison with Congenital Growth Hormone Deficiency Veterinary Record 133:542-545, 1993. Pubmed reference: 8116157.
1991 Greco, D.S., Feldman, E.C., Peterson, M.E., Turner, J.L., Hodges, C.M., Shipman, L.W. :
Congenital Hypothyroid Dwarfism in a Family of Giant Schnauzers Journal of Veterinary Internal Medicine 5:57-65, 1991. Pubmed reference: 2061865.
1990 Randolph, J.F., Miller, C.L., Cummings, J.F., Lothrop, C.D. :
Delayed Growth in 2 German Shepherd Dog Littermates with Normal Serum Concentrations of Growth Hormone, Thyroxine, and Cortisol Journal of the American Veterinary Medical Association 196:77-83, 1990. Pubmed reference: 2295557.
1985 Greco, D.S., Peterson, M.E., Cho, D.Y., Markovits, J.E. :
Juvenile-onset hypothyroidism in a dog. J Am Vet Med Assoc 187:948-50, 1985. Pubmed reference: 4055523.
1981 Eigenmann, J.E. :
Diagnosis and treatment of dwarfism in a German Shepherd dog Journal of the American Animal Hospital Association 17:798-804, 1981.
1980 Müller-Peddinghaus, R., El Etreby, M.F., Siefert, J., Ranke, M. :
[Pituitary dwarfism in a German shepherd dog (author's transl)]. Vet Pathol 17:406-21, 1980. Pubmed reference: 6247812.
1979 Muller, GH. :
Pituitary dwarfism. Vet Clin North Am Small Anim Pract 9:41-8, 1979. Pubmed reference: 462708.
1978 Allan, G.S., Huxtable, C.R.R., Howlett, C.R., Baxter, R.C., Duff, B., Farrow, B.R.H. :
Pituitary dwarfism in German Shepherd dogs Journal of Small Animal Practice 19:711-727, 1978. Pubmed reference: 723236.
Andresen, E. :
Origin and distribution of pituitary dwarfism in the dog and a basis for detecting carriers of various genetic diseases using biochemical methods Kleintierpraxis 23:65-74, 1978.
Cassel, S.E. :
Ovarian imbalance in a German Shepherd dwarf. Vet Med Small Anim Clin 73:162-3, 1978. Pubmed reference: 245902.
Nicholas, F.W. :
Pituitary dwarfism in German Shepherd dogs: a genetic analysis of some Australian data Journal of Small Animal Practice 19:167-174, 1978. Pubmed reference: 642476.
1977 Andresen, E., Willeberg, P. :
Pituitary dwarfism in Carelian bear-dogs: evidence of simple, autosomal recessive inheritance. Hereditas 84:232-4, 1977. Pubmed reference: 838602.
1976 Andresen, E., Willeberg, P. :
Pituitary dwarfism in German Shepherd dogs : additional evidence of simple, autosomal recessive inheritance Nordisk Veterinaermedicin 28:481-486, 1976. Pubmed reference: 980693.
Andresen, E., Willeberg, P., Riis, P.M. :
Somatomedin levels in dogs with pituitary dwarfism Hereditas 84:239 only, 1976.
1975 Andresen, E., Willeberg, P., Rasmussen, P.G. :
Hereditary pituitary dwarfism in German Shepherd dogs Hunden. Medlemsblad Dansk Kennel Klub 85:112-114, 1975.
Willeberg, P., Kastrup, K.W., Anderson, E. :
Pituitary dwarfism in German Shepherd dogs: studies on somatomedin activity Nordisk Veterinaermedicin 27:448-454, 1975. Pubmed reference: 1178442.
1974 Andresen, E., Willeberg, P., Rusmussen, P.G. :
Pituitary dwarfism in German Shepherd dogs : genetic investigations Nordisk Veterinaermedicin 26:692-701, 1974. Pubmed reference: 4449724.

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