OMIA 002284-9615 : Polyneuropathy, SBF2-related in Canis lupus familiaris

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

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"

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.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
SBF2 SET binding factor 2 Canis lupus familiaris 21 NC_051825.1 (34339237..33884844) SBF2 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
1233 Miniature Schnauzer Polyneuropathy, SBF2-related SBF2 splicing Naturally occurring variant CanFam3.1 21 g.33080022C>A c.2363+1G>T p.(G775Vfs*5) 2019 31772832

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2020 Farré Mariné, A., Granger, N., Bertolani, C., Mascort Boixeda, J., Shelton, G.D., Luján Feliu-Pascual, A. :
Long-term outcome of Miniature Schnauzers with genetically confirmed demyelinating polyneuropathy: 12 cases. J Vet Intern Med 34:2005-11, 2020. Pubmed reference: 32738000. DOI: 10.1111/jvim.15861.
2019 Granger, N., Luján Feliu-Pascual, A., Spicer, C., Ricketts, S., Hitti, R., Forman, O., Hersheson, J., Houlden, H. :
Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicing <i>SBF2 (MTMR13)</i> genetic variant: a new spontaneous clinical model. PeerJ 7:e7983, 2019. Pubmed reference: 31772832. DOI: 10.7717/peerj.7983.
2008 Vanhaesebrouck, AE., Couturier, J., Cauzinille, L., Mizisin, AP., Shelton, GD., Granger, N. :
Demyelinating polyneuropathy with focally folded myelin sheaths in a family of Miniature Schnauzer dogs. J Neurol Sci 275:100-5, 2008. Pubmed reference: 18809183. DOI: 10.1016/j.jns.2008.07.031.

Edit History


  • Created by Frank Nicholas on 04 Aug 2020
  • Changed by Frank Nicholas on 04 Aug 2020
  • Changed by Imke Tammen2 on 11 Dec 2020