OMIA 002564-9615 : Dyserythropoietic anemia and myopathy syndrome in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 619583 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2022

Cross-species summary: Also called Congenital dyserythropoietic anemia and polymyopathy.

Species-specific symbol: DAMS

History: This canine disorder was first reported in English Springer Spaniels [ESSPs] in Australia by Holland et al. (1991), and recently cases with a less severe clinical presentation were reported in Labrador Retrievers in the USA by Thomas-Hollands et al. (2021). Two different likely causal variants in the EHPB1L1 gene were reported - one in each breed - at almost the same time in the same journal by Shelton et al. (2022; published 11 August) and by Østergård Jensen et al. (2022; published 26 August).

Inheritance: Østergård Jensen et al. (2022): "Pedigree analysis confirmed that the affected ESSPs were related. Variant genotyping showed appropriate complete segregation in the family, which was consistent with an autosomal recessive mode of inheritance".

Molecular basis: Shelton et al. (2022): "Using whole genome sequencing and mapping to the CanFam4 (Canis lupus familiaris reference assembly 4), a nonsense variant in the EHBP1L1 gene was identified in a homozygous form in the Labrador Retriever littermates. The mutation produces a premature stop codon that deletes approximately 90% of the protein."

Østergård Jensen et al. (2022): "genome sequencing of two affected [ESSP] dogs was compared to 782 genomes of different canine breeds. A homozygous frameshift single-base deletion in EHBP1L1 was identified; this gene was not previously associated with DAMS. ... All five ESSPs with DAMS and the two ESSP puppies from Sweden with neonatal death, as well as the two tested ESSPs with DAMS from Australia [Holland et al., 1991], were homozygous for the mutant EHBP1L1 allele."

Clinical features: Holland et al. (1991) "A polysystemic disorder was observed in three related English Springer Spaniel dogs that demonstrated regurgitation from an early age, slowly progressive temporal muscle atrophy with partial trismus, and less pronounced generalized skeletal muscle atrophy. All dogs exhibited moderate dyserythropoietic anemia, polymyopathy with megaesophagus, and varying degrees of cardiomegaly." Østergård Jensen et al. (2022) investigated five affected Swedish ESSPs, as well as tissue samples from two puppies who died within the first day: "all dogs affected with DAMS appeared slightly stunted, less well muscled, and less active compared to their littermates during the first few weeks of life. ... [The dogs presented later with] exercise intolerance, weakness, and regurgitation from puppyhood. In addition, difficulties opening and closing the mouth, dysphagia, and difficulty in lapping water ... , as well as aspiration pneumonia ... , seizures ... , and chronic diarrhea ... , were noted in the affected juvenile dogs. The affected dogs were 0.7 to 4 years of age at the initial examination and were followed over a period from two months to three years. ... Progressive weakness, muscle atrophy—particularly of the temporal and pelvic muscles—trismus, dysphagia, and regurgitation due to megaesophagus were observed at all ages. Affected dogs had a non-regenerative, microcytic hypochromic anemia with metarubricytosis, target cells, and acanthocytes. Marked erythroid hyperplasia and dyserythropoiesis with non-orderly maturation of erythrocytes and inappropriate microcytic metarubricytosis were present. ... The five affected dogs ... were euthanized at approximately 1, 1.5, 5, 7, and 7.5 years of age, respectively, due to failure to thrive, progressive clinical signs, and poor quality of life. ... [The] two puppies (in a litter of nine) that died shortly after birth were homozygous for the EHBP1L1 variant. ... These neonatal losses indicate that EHBP1L1 deficiency could also be a cause of neonatal death in dogs, but the specific cause of death was not determined."

Thomas-Hollands et al. (2021): "Two Labrador retriever littermates were identified based on incidentally noted marked microcytosis and inappropriate metarubricytosis. Muscle atrophy was noted and associated with distinctive pathological findings in biopsy samples from 1 dog studied. ... the dogs ... did not have apparent cardiac disease."

Pathology: Østergård Jensen et al. (2022): "Muscle biopsies [of affected ESSP] showed centralized nuclei, central pallor, lipocyte infiltrates, and fibrosis, which was consistent with centronuclear myopathy."

Thomas-Hollands et al. (2021): "Muscle biopsy samples [of an affected Labrador] were collected from the contralateral right biceps, triceps, and frontalis muscles. ... Prominent findings are variability in myofiber size, central nuclei ..., and central accumulations of reactivity that are basophilic with the H&E stain and red with the modified Gomori trichrome stain, and dark brown or dark blue with the cytochrome C oxidase and SDH reactions, respectively. ... These findings supported a noninflammatory, congenital myopathy with pathological changes consistent with the centronuclear/myotubular myopathy group of neuromuscular diseases."

Breeds: English Springer Spaniel, Labrador Retriever.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
EHBP1L1 EH domain binding protein 1-like 1 Canis lupus familiaris 18 NC_051822.1 (52667675..52649609) EHBP1L1 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
1483 Labrador Retriever Congenital dyserythropoietic anemia and polymyopathy EHBP1L1 nonsense (stop-gain) Naturally occurring variant CanFam4 18 g.52128140G>A c.388C>T p.(R130*) XM_038563927.1; 2022 36011338
1481 English Springer Spaniel Dyserythropoietic anemia and myopathy syndrome (DAMS) EHBP1L1 deletion, small (<=20) Naturally occurring variant UU_Cfam_GSD_1.0 18 g.52123541delG c.3120delC p.(F1041Sfs*30) XM_038563927.1; XP_038419855.1 2022 36140701

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.
2022 Shelton, G.D., Minor, K.M., Guo, L.T., Thomas-Hollands, A., Walsh, K.A., Friedenberg, S.G., Cullen, J.N., Mickelson, J.R. :
An EHPB1L1 nonsense mutation associated with congenital dyserythropoietic anemia and polymyopathy in Labrador Retriever littermates. Genes (Basel) 13:, 2022. Pubmed reference: 36011338. DOI: 10.3390/genes13081427.
Østergård Jensen, S., Christen, M., Rondahl, V., Holland, C.T., Jagannathan, V., Leeb, T., Giger, U. :
EHBP1L1 Frameshift Deletion in English Springer Spaniel Dogs with Dyserythropoietic Anemia and Myopathy Syndrome (DAMS) or Neonatal Losses. Genes (Basel) 13:1533, 2022. Pubmed reference: 36140701. DOI: 10.3390/genes13091533.
2021 Thomas-Hollands, A., Shelton, G.D., Guo, L.T., Loughran, K., Kaiman, G., A Hutton, T., Walsh, K.A. :
Congenital dyserythropoiesis and polymyopathy without cardiac disease in male Labrador retriever littermates. J Vet Intern Med 35:2409-2414, 2021. Pubmed reference: 34227150. DOI: 10.1111/jvim.16214.
1991 Holland, C.T., Canfield, P.J., Watson, A.D., Allan, G.S. :
Dyserythropoiesis, polymyopathy, and cardiac disease in three related English springer spaniels. J Vet Intern Med 5:151-9, 1991. Pubmed reference: 1920252. DOI: 10.1111/j.1939-1676.1991.tb00942.x.

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  • Created by Frank Nicholas on 29 Aug 2022
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