Categories: Skeleton phene (incl. short stature & teeth) , Endocrine / exocrine gland phene (incl mammary gland)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600577 (gene) , 221750 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2011

Cross-species summary: Renamed from 'Dwarfism, pituitary, LHX3-related' [05/09/2024]

Species-specific name: Dwarfism, pituitary, LHX3-related; pituitary dwarfism

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 variant (omia.variant:362) 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; omia.variant:608). 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."
Dang et al. (2024) sequenced the Lhx3 gene in three Japanese native dog breeds that have different body sizes (Akita, Shiba Inu, and Mame Shiba Inu dogs) and identified a SNP in codon 280 (p.(S280N), rs24576347 ) associated with body size in these breeds. "To validate the function of this SNP on body size, [the authors] introduced this change into the Lhx3 gene of mice. Homozygous mutant mice ... were found to have significantly increased body lengths and weights compared to heterozygous mutant ... and wild-type ... mice several weeks after weaning."

Clinical features: Dogs with homozygous LXH3 defects experience deficiency in pituitary hormone production, including GH, TSH and reproductive hormones (Voorbji et al., 2011). As a result of the primary insufficiency in GH, IGF levels are low in affected dogs compared to healthy dogs, leading to marked growth retardation with proportional dwarfism (Eigenmann et al., 1984; Voorbij and Kooistra, 2009). The affected puppies have normal growth during the first weeks, but the growth rate markedly slows down (Voorbij, Leegwater and Kooistra, 2014; Voorbij and Kooistra, 2009). Other characteristic clinical features include bilateral symmetrical alopecia mostly at the trunk, neck and proximal extremities, retention of secondary hair coat and lack of guard hairs (Voorbij and Kooistra, 2009). Concurrent problems such as hyperpigmentation, pyoderma, and scales may also occur (Voorbij and Kooistra, 2009). Some dogs develop neurological signs due to anatomical abnormalities in the atlanto-axial joint (Voorbij et al., 2015). IT thanks DVM student Riley Lin, who provided the basis of this contribution in May 2023.

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 [omia.variant:363] (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 (Dog) (VBO_0200402), German Shepherd Dog (Dog) (VBO_0200577), Saarloos Wolfhond (Dog) (VBO_0201158), Tibetan Terrier (Dog) (VBO_0201353).
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: