OMIA 002314-9615 : Dwarfism, pituitary, LHX3-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 600577 (gene) , 221750 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2011

Species-specific description: see also OMIA 000307-9615; Dwarfism, pituitary, generic and OMIA 002315-9615 : Dwarfism, pituitary, POU1F1-related in Canis lupus familiaris

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 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."

Thaiwong et al. (2021) "report a similar manifestation of dwarfism in Tibetan Terriers with the same [7bp deletion] LHX3 mutation."

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."

Breeds: Czechoslovakian wolfdog, German Shepherd Dog, Saarloo, Tibetan Terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
LHX3 LIM homeobox 3 Canis lupus familiaris 9 NC_051813.1 (50125225..50131690) LHX3 Homologene, Ensembl, NCBI gene


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.

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
362 Czechoslovakian wolfdog German Shepherd Dog Saarloo Tibetan Terrier Pituitary dwarfism LHX3 splicing Naturally occurring variant 9 "a deletion of one of six 7 bp [GTGTTTT] repeats in intron 5 of LHX3" 2011 22132174
608 German Shepherd Dog Pituitary dwarfism LHX3 insertion, small (<=20) Naturally occurring variant CanFam3.1 9 g.49252491_49252493dup c.545_547dup p.(N182dup) NM_001197187.1; NP_001184116.1; published as c.545_547dupACA 2011 22132174 Genomic coordinates in CanFam3.1 provided by Zoe Shmidt and Robert Kuhn.


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 Thaiwong, T., Corner, S., Forge, S., Kiupel, M. :
Dwarfism in Tibetan Terrier dogs with an LHX3 mutation. J Vet Diagn Invest 33:740-3, 2021. Pubmed reference: 33890524. DOI: 10.1177/10406387211007526.
2015 Voorbij, A.M., Meij, B.P., van Bruggen, L.W., Grinwis, G.C., Stassen, Q.E., Kooistra, H.S. :
Atlanto-axial malformation and instability in dogs with pituitary dwarfism due to an LHX3 mutation. J Vet Intern Med 29:207-13, 2015. Pubmed reference: 25586673. DOI: 10.1111/jvim.12523.
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.

Edit History

  • Created by Imke Tammen2 on 05 Mar 2021
  • Changed by Imke Tammen2 on 05 Mar 2021
  • Changed by Imke Tammen2 on 17 Jun 2021