Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 608236 (trait) , 608136 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Probably autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2014

Cross-species summary: An inherited polyneuropathy observed in Leonberger and Saint Bernard dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The Leonberger disorder is a severe, juvenile-onset, chronic, progressive, and mixed polyneuropathy, characterized by exercise intolerance, gait abnormalities and muscle atrophy of the pelvic limbs, as well as inspiratory stridor and dyspnea.

Species-specific name: polyneuropathy

Species-specific symbol: LPN1; also known as ILPN (Jäderlund et al., 2011)

Species-specific description: An inherited polyneuropathy (PN) observed in Leonberger and Saint Bernard dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The disorder is a severe, juvenile-onset, chronic, progressive, and mixed PN, characterized by exercise intolerance, gait abnormalities and muscle atrophy of the pelvic limbs, as well as inspiratory stridor and dyspnea.

History: Variants in other genes have been associated with other forms of polyneuropathy and/or laryngeal paralysis in various breeds: OMIA 002222-9615 (RAPGEF6), OMIA 002119-9615 (GJA9), OMIA 001970-9615 (RAB3GAP1), OMIA 002284-9615 (SBF2), OMIA 002301-9615 (CNTNAP1). References relating to polyneuropathies and laryngeal paralysis in dogs without known genetic associations are listed under OMIA 001292-9615 and OMIA 001206-9615, respectively.

Mapping: A GWAS on 52 affected and 41 control Leonbergers, each genotyped with the Illumina CanineHD BeadChip (yielding 101,284 informative SNPs) enabled Ekenstedt et al. (2014) to map this disorder to a region of chromosome CFA16, with the strongest association at 57,375,008 bp (CanFam2). Homozygosity mapping identified a 250kb region.

Molecular basis: Of the two genes in the candidate region (see mapping section), one (ARHGEF10) was a comparative candidate (see OMIM link above). Sequencing of this gene in affecteds and controls enabled Ekenstedt et al. 92014) to identify "a 10 bp deletion in affected dogs that removes four nucleotides from the 3′-end of exon 17 and six nucleotides from the 5′-end of intron 17 (c.1955_1958+6delCACGGTGAGC). This eliminates the 3′-splice junction of exon 17, creates an alternate splice site immediately downstream in which the processed mRNA contains a frame shift, and generates a premature stop codon predicted to truncate approximately 50% of the protein. Homozygosity for the deletion was highly associated with the severe juvenile-onset PN phenotype in both Leonberger and Saint Bernard dogs".

Clinical features: As summarised by Ekenstedt et al. (2014), this disorder in the Leonberger breed "is characterized by generalized weakness, hypotonia, and muscle atrophy secondary to denervation, particularly of the pelvic limbs . . . . Affected dogs frequently present with a high-stepping pelvic limb gait (pseudo-hypermetria of the hock) . . . , decreased or absent tendon reflexes, and changes associated with degeneration of the recurrent laryngeal nerve, including inspiratory stridor resulting from laryngeal paralysis. The age-of-onset of clinical signs can vary from <1 year up to 11 years of age; however, the juvenile-onset patients typically have a more severe and rapidly progressing course of disease. Peroneal nerve biopsies show decreased myelinated fiber density resulting from axonal degeneration and endoneurial fibrosis indicative of chronic nerve fiber loss. Cranial tibial muscle biopsies demonstrate neurogenic atrophy and fatty replacement of muscle fibers indicative of chronic denervation".

Breeds: Leonberger (Dog) (VBO_0200819), Saint Bernard (Dog) (VBO_0201160).
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: