An EHPB1L1 Nonsense Mutation Associated with Congenital Dyserythropoietic Anemia and Polymyopathy in Labrador Retriever Littermates

Abstract

In this report, we describe a novel genetic basis for congenital dyserythropoietic anemia and polymyopathy in Labrador Retriever littermates characterized by incidental detection of marked microcytosis, inappropriate metarubricytosis, pelvic limb weakness and muscle atrophy. A similar syndrome has been described in English Springer Spaniel littermates with an early onset of anemia, megaesophagus, generalized muscle atrophy and cardiomyopathy. Muscle histopathology in both breeds showed distinctive pathological changes consistent with congenital polymyopathy. 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. This variant was not present in the English Springer Spaniels. Currently, EHPB1L1 is described as critical to actin cytoskeletal organization and apical-directed transport in polarized epithelial cells, and through connections with Rab8 and a BIN1-dynamin complex generates membrane vesicles in the endocytic recycling compartment. Furthermore, EHBP1L1 knockout mice die early and develop severe anemia. The connection of EHBP1L1 to BIN1 and DMN2 functions is particularly interesting due to BIN1 and DMN2 mutations being causative in forms of centronuclear myopathy. This report, along with an independent study conducted by another group, are the first reports of an association of EHBP1L1 mutations with congenital dyserythropoietic anemia and polymyopathy.

Whole Animal Genome Sequencing: user-friendly, rapid, containerized pipelines for processing, variant discovery, and annotation of short-read whole genome sequencing data

“…For example, we have cataloged genetic variants from WGS data of nearly 700 dogs across more than 50 breeds, using 2 canine reference genomes ( Lindblad-Toh et al 2005 ; Hoeppner et al 2014 ; Wang et al 2021 ). Ongoing analyses have demonstrated the usefulness of this catalog in identifying genetic variants associated with various Mendelian diseases and traits in our canine companions ( Olby et al 2020 ; Shelton et al 2021 ; Shelton, Minor, Guo, et al 2022 ; Shelton, Minor, Vieira, et al 2022 ). However, unlike humans with the Genome in a Bottle Consortium ( Zook et al 2016 ), we do not have an extensively curated truth set of genetic variants in animal species for validating the accuracy of WAGS.…”

EHBP1L1 Frameshift Deletion in English Springer Spaniel Dogs with Dyserythropoietic Anemia and Myopathy Syndrome (DAMS) or Neonatal Losses

“…During this study, we became aware of an independent effort to investigate the genetic defect in Labrador retrievers with a similar syndrome [ 18 ]. Shelton et al reported the identification of an EHBP1L1 nonsense variant as a likely cause for dyserythropoietic anemia and polymyopathy in this breed [ 58 ]. The fact that two independent truncating variants in the same gene lead to virtually identical and highly characteristic clinical phenotypes in ESSPs and Labrador retrievers provides a further proof for the causality of these variants.…”