Categories: Skeleton phene (incl. short stature & teeth) , Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 147267 (gene) , 620111 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0859311: Charcot-Marie-Tooth disease, demyelinating, type 1J

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2025

Species-specific name: Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta

Species-specific description: Hytönen et al. (2025) "report the identification of a homozygous nonsense variant in the ITPR3 gene in Lancashire Heeler dogs, presenting with a severe developmental enamel defect and reduced nerve conduction velocity." 

Mapping: Hytönen et al. (2025): Genome-wide genotyping with a canine high density SNP array followed by "homozygosity mapping revealed only one case-specific region of allelic homozygosity (ROH) on chromosome 12 (g.156,577–5,127,877). 

Molecular basis: Hytönen et al. (2025) "performed whole-exome sequencing (WES) on two affected dogs ...  and whole-genome sequencing (WGS) on one affected dog" and idendified a likely causal variant: g.12:3214076C>T; XM_038553756.1:5002C>T; XP_038409684:p.Q1668X.

Clinical features: Hytönen et al. (2025): "affected Lancashire Heeler dogs ... were originally identified by abnormal enamel in the permanent teeth, including severe yellow to brown discoloration, enamel hypoplasia and abrasion leading to exposure of dentin ... . The enamel defects were already apparent upon tooth eruption. ... Two out of three dogs had deformity detected in their front limbs, i.e. outward rotation of front limbs from the elbow joint. ... Abnormal electromyographic findings consistent with demyelinating neuropathy were detected in all three examined dogs and consisted of fibrillation potentials and positive sharp waves occurring predominantly in distal appendicular limb muscles ... . Fibrillation potentials were also detected in paraspinal musculature." Reduced motor nerve conduction velocities and decreased compound muscle action potential (CMAP) amplitudes and increased CMAP duration were observed in two out of three affected dogs."

Breed: Lancashire Heeler (Dog) (VBO_0200808).
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: