Osteogenesis imperfecta (OI) is a hereditary disease occurring in humans and dogs. It is characterized by extremely fragile bones and teeth. Most human and some canine OI cases are caused by mutations in the COL1A1 and COL1A2 genes encoding the subunits of collagen I. Recently, mutations in the CRTAP and LEPRE1 genes were found to cause some rare forms of human OI. Many OI cases exist where the causative mutation has not yet been found. We investigated Dachshunds with an autosomal recessive form of OI. Genotyping only five affected dogs on the 50 k canine SNP chip allowed us to localize the causative mutation to a 5.82 Mb interval on chromosome 21 by homozygosity mapping. Haplotype analysis of five additional carriers narrowed the interval further down to 4.74 Mb. The SERPINH1 gene is located within this interval and encodes an essential chaperone involved in the correct folding of the collagen triple helix. Therefore, we considered SERPINH1 a positional and functional candidate gene and performed mutation analysis in affected and control Dachshunds. A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype. We thus have identified a candidate causative mutation for OI in Dachshunds and identified a fifth OI gene.

Microphthalmia in sheep is an autosomal recessive inherited congenital anomaly found within the Texel breed. It is characterized by extremely small or absent eyes and affected lambs are absolutely blind. For the first time, we use a genome-wide ovine SNP array for positional cloning of a Mendelian trait in sheep. Genotyping 23 cases and 23 controls using Illumina's OvineSNP50 BeadChip allowed us to localize the causative mutation for microphthalmia to a 2.4 Mb interval on sheep chromosome 22 by association and homozygosity mapping. The PITX3 gene is located within this interval and encodes a homeodomain-containing transcription factor involved in vertebrate lens formation. An abnormal development of the lens vesicle was shown to be the primary event in ovine microphthalmia. Therefore, we considered PITX3 a positional and functional candidate gene. An ovine BAC clone was sequenced, and after full-length cDNA cloning the PITX3 gene was annotated. Here we show that the ovine microphthalmia phenotype is perfectly associated with a missense mutation (c.338G>C, p.R113P) in the evolutionary conserved homeodomain of PITX3. Selection against this candidate causative mutation can now be used to eliminate microphthalmia from Texel sheep in production systems. Furthermore, the identification of a naturally occurring PITX3 mutation offers the opportunity to use the Texel as a genetically characterized large animal model for human microphthalmia.

BackgroundGenetic and epidemiologic evidence suggests that in horses, as in other species, different manifestations of hypersensitivity may occur together.HypothesisHorses affected with insect bite hypersensitivity (IBH) show airway hyperreactivity (AH) to inhaled histamine, even in the absence of overt clinical signs of equine asthma (EA).AnimalsTwenty‐two healthy controls (group C), 24 horses suffering from IBH alone (group IBH), and 23 horses suffering from IBH and EA (group IBH/EA).MethodsThe clinical histories were assessed using 2 standardized questionnaires, the Horse Owner Assessed Respiratory Signs Index (HOARSI), and IBH scoring. Horses were classified as EA‐affected if their HOARSI was >1 and as IBH‐affected if IBH score was >0. Confounding disorders were excluded by clinical examination. The arterial partial pressure of oxygen (PaO2) was measured and flowmetric plethysmography used to assess airway reactivity to increasing doses of inhaled histamine.ResultsThe median histamine provocation concentration (PC) when ∆flow values increased by 35% (PC35) was significantly higher in group C (5.94 [1.11–26.33] mg/mL) compared to group IBH (2.95 [0.23–10.13] mg/mL) and group IBH/EA (2.03 [0.43–10.94] mg/mL; P < 0.01). The PC50 and PC75 showed very similar differences between groups. Furthermore, PaO2 was significantly lower in group IBH (84 ± 8 mmHg) and group IBH/EA (78 ± 11 mmHg) compared to group C (89 ± 6 mmHg; P < 0.01).Conclusions and Clinical Importance IBH is associated with AH and decreased PaO2, even in the absence of overt respiratory clinical signs.