Biología molecular: acceso abierto

Background Strain and Natural Selection Improves Survival of HIBM Murine Model

Abstract

Valles-Ayoub. Y, Khokher. Z , Sandoval. L , Haghighatgoo. A, No. D, Saechao. C, Garcia-Figueroa. J, Carbajo. R, Darvish. B and Darvish. D

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 Gne^M712T/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 (Gne^M712T/+) 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 (Gne^M712tM712t) 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.