Categories: Haematopoietic system phene

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

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

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 (Dog) (VBO_0200497), Labrador Retriever (Dog) (VBO_0200800).
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: