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Abstract
GNE myopathy, or Hereditary Inclusion Body Myopathy (HIBM), is an autosomal recessive adult-onset muscle wasting disorder caused by hypomorphic GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase), the rate-limiting enzyme of sialic acid (Sia) biosynthesis. Unlike human patients, mice bearing the GneM712T/M712T genotype in C57BL/6 background strain suffer severe glomerular hematuria, show incomplete podocyte development, and do not survive beyond the first few days of life. We crossed heterozygous mice (GneM712T/+) of B6 strain with FVB strain mice. In mixed inbred FVB; B6 background, the homozygous mice showed attenuated glomerular disease and survived longer (mean survival 23.48 ± 13.99 weeks, n=73). Within the first 2 generations, 26% of the homozygous mice survived past the age of 40 weeks, and within the subsequent 3 generations the frequency of homozygous mice surviving past age of 40 weeks had increased to 44%. Additionally, the homozygous mice (GneM712tM712t) living past the age of 42 weeks began to show muscle pathology. These findings suggest that the mouse background strain affects the disease phenotype, and that natural selection may have an influence on the long-term maintenance of mouse models of human disease.
Highlights
Inclusion Body Myositis and Myopathies (IBMs) comprise a group of adult-onset slowly progressive muscle disorders that typically result in severe disability [1]
Two mouse models have been generated for preclinical studies on Hereditary Inclusion Body Myopathy (HIBM): 1) the GneM712T knock-in mouse model expressing the mutation p.M712T, the most common founder genotype of patients with HIBM; and 2) transgenic mice bearing the human GNE with the p.D176V mutation in GNE-null background [7,8]-Transgenic mice expressing the human GNE with p.D176V mutation show myopathy after the age of 40 weeks that resembles HIBM in human patients [8]
Since there are no reports of either renal pathology or overt kidney disease in human patients genotyped for GneM712T/M712T, the reason for renal disorders in the homozygous mice suggests that the efficiency of the sialic biosynthetic pathway in different organs is influenced by other background genes
Summary
Inclusion Body Myositis and Myopathies (IBMs) comprise a group of adult-onset slowly progressive muscle disorders that typically result in severe disability [1]. Hereditary Inclusion Body Myopathy (HIBM), called Inclusion Body Myopathy Type 2 (IBM2, MIM: 600737), is the most common inherited form of IBMs. HIBM is an autosomal recessive adult-onset muscle wasting disorder caused by mutations in the GNE gene (MIM: 603824) [2,3,4]. GNE mutations encoding for hypomorphic GNE/MNK enzyme have been associated with the pathophysiology of skeletal muscle in several clinical studies in patients with HIBM [5,6]. The GneM712T murine model is produced by homologous recombination, but the phenotype varies depending on the mouse strain [7]. In the C57BL/6 mouse strain, GneM712T/M712T mice develop severe kidney disease, glomerular hematuria, hyposialylation of podocalyxin, and partial formation of podocyte foot processes in the glomerular filtration barrier.
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