Categories: Nervous system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 604563 (trait) , 607697 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2019

Cross-species summary: This is an animal model of the human disorder Charcot-Marie-Tooth type 4B2 (see OMIM link)

History: Variants in other genes have been associated with other forms of polyneuropathy and/or laryngeal paralysis in various breeds: OMIA 001917-9615 (ARHGEF10), OMIA 002119-9615 (GJA9), OMIA 001970-9615 (RAB3GAP1), OMIA 002222-9615 (RAPGEF6), 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.

Inheritance: Granger et al. (2019): "[Vanhaesebrouck et al. (2008)] described the clinical, electrophysiological and pathological findings of a demyelinating motor and sensory neuropathy in Miniature Schnauzer dogs, with a suspected autosomal recessive mode of inheritance based on pedigree analysis."

Mapping: Granger et al. (2019): a "genome-wide association study [of affected and normal Miniature Schnauzers] gave an indicative signal on canine chromosome 21. Although the signal was not of genome-wide significance due to the small number of cases, the SBF2 (also known as MTMR13) gene within the region of shared case homozygosity was a strong [functional] positional candidate, as 22 genetic variants in the gene have been associated with demyelinating forms of Charcot-Marie-Tooth disease in humans."

Molecular basis: Granger et al. (2019): "Sequencing of SBF2 in cases revealed a splice donor site genetic variant, resulting in cryptic splicing and predicted early termination of the protein based on RNA sequencing results. . . . his revealed a homozygous +1 splice genetic variant in exon 19 (c.2363+1 G>T; chr21:33,080,022 C>A CanFam3.1) in the affected case in comparison to the control (Fig. 3). No further variants were found in the entire coding sequence. This putative disease-causing c.2363+1 G>T variant was assessed in the initial GWAS set (2 affected and 39 controls) plus six additional affected cases and a further 192 Miniature Schnauzers with no report of the disorder"

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Granger et al. (2019): "at a young age (<2 years), affected Miniature Schnauzers presented regurgitations caused by mega-esophagus and inspiratory dyspnea caused by laryngeal paralysis. Electrophysiological studies revealed marked slowing of motor and sensory nerve conduction velocities (∼20 m/s), although some nerves had preserved conduction velocities."

Farré Mariné et al. (2020): "Twelve Miniature Schnauzers presented between March 2013 and June 2019. Only dogs presented with consistent clinical signs and homozygous for the MTRM13/SBF2 genetic variant were included. Clinical signs, age of onset and presentation, time from onset to presentation, treatment, outcome, and time from diagnosis to final follow-up were retrospectively reviewed. The hallmark clinical signs at the time of presentation were regurgitation with radiologically confirmed megaesophagus (11/12) and aphonic bark (11/12) with or without obvious neuromuscular weakness despite electrodiagnostic evidence of appendicular demyelinating polyneuropathy. Age of onset and clinical presentation were 3-18 and 4-96 months, respectively. Treatment was mostly symptomatic and consisted of head elevation during meals, antacids, prokinetics, bethanechol, sildenafil, mirtazapine, or some combination of these. During the follow-up period (7-73 months), clinical signs were unchanged in (11/12) cases with aspiration pneumonia developing occasionally (6/12) and being the cause of death in 1 dog. Demyelinating polyneuropathy of Miniature Schnauzers tends to remain stable over the long term leading to a good prognosis with preventive feeding measures and symptomatic treatment to control aspiration pneumonia."

Prevalence: Granger et al. (2019): "Screening for the variant in a dataset of 802 whole genome sequences from 162 purebred dogs/mixed breed dogs/wolves identified two Miniature Schnauzers that were heterozygous for the variant and one mutant homozygote; the remaining 799 dogs were clear (File S3). On follow-up investigation the mutant homozygous dog was affected with neonatal lethal spondylocostal dysostosis, hence no clinical data relevant to the demyelinating neuropathy phenotype was available".

Breed: Miniature Schnauzer.
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: