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

被引:5
作者
Shelton, G. Diane [1 ]
Minor, Katie M. [2 ]
Guo, Ling T. [1 ]
Thomas-Hollands, Alison [3 ]
Walsh, Koranda A. [4 ]
Friedenberg, Steven G. [5 ]
Cullen, Jonah N. [5 ]
Mickelson, James R. [2 ]
机构
[1] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA
[2] Univ Minnesota, Coll Vet Med, Dept Vet & BioMed Sci, St Paul, MN 55108 USA
[3] Univ Penn, Sch Vet Med, Dept Clin Sci & Adv Med, Philadelphia, PA 19104 USA
[4] Univ Penn, Dept Clin Pathobiol, Sch Vet Med, Philadelphia, PA 19104 USA
[5] Univ Minnesota, Coll Vet Med, Dept Vet Clin Sci, St Paul, MN 55108 USA
关键词
dog; muscle; anemia; myopathy; whole genome sequencing; animal model; LINKED MYOTUBULAR MYOPATHY;
D O I
10.3390/genes13081427
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
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页数:7
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