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: