Exome sequencing identifies a nonsense mutation in <Emphasis Type="Italic">Fam46a</Emphasis> associated with bone abnormalities in a new mouse model for skeletal dysplasia |
| |
| Authors: | Susanne Diener Sieglinde Bayer Sibylle Sabrautzki Thomas Wieland Birgit Mentrup Gerhard K H Przemeck Birgit Rathkolb Elisabeth Graf Wolfgang Hans Helmut Fuchs Marion Horsch Thomas Schwarzmayr Eckhard Wolf Eva Klopocki Franz Jakob Tim M Strom Martin Hrabě de Angelis Bettina Lorenz-Depiereux |
| |
| Institution: | 1.Institute of Human Genetics, German Research Center for Environmental Health (GmbH),Helmholtz Zentrum München,Neuherberg,Germany;2.Institute of Experimental Genetics and German Mouse Clinic, German Research Center for Environmental Health,Helmholtz Zentrum München,Neuherberg,Germany;3.Member of German Center for Diabetes Research (DZD),Neuherberg,Germany;4.Experimental Labs Stem Cell Group, Orthopedic Department, Orthopedic Center for Musculoskeletal Research,University of Würzburg,Würzburg,Germany;5.Chair for Molecular Animal Breeding and Biotechnology, Gene Center,Ludwig-Maximilians-Universit?t München,Munich,Germany;6.Institute of Human Genetics,Universit?t Würzburg,Würzburg,Germany;7.Institute of Human Genetics,Technische Universit?t München,Munich,Germany;8.Chair in Experimental Genetics,Technische Universit?t München,Freising-Weihenstephan,Germany;9.Technische Universit?t München,Munich,Germany;10.Research Unit Comparative Medicine, German Research Center for Environmental Health,Helmholtz Zentrum München,Neuherberg,Germany |
| |
| Abstract: | We performed exome sequencing for mutation discovery of an ENU (N-ethyl-N-nitrosourea)-derived mouse model characterized by significant elevated plasma alkaline phosphatase (ALP) activities in female and male mutant mice, originally named BAP014 (bone screen alkaline phosphatase #14). We identified a novel loss-of-function mutation within the Fam46a (family with sequence similarity 46, member A) gene (NM_001160378.1:c.469G>T, NP_001153850.1:p.Glu157*). Heterozygous mice of this mouse line (renamed Fam46a E157*Mhda) had significantly high ALP activities and apparently no other differences in morphology compared to wild-type mice. In contrast, homozygous Fam46a E157*Mhda mice showed severe morphological and skeletal abnormalities including short stature along with limb, rib, pelvis, and skull deformities with minimal trabecular bone and reduced cortical bone thickness in long bones. ALP activities of homozygous mutants were almost two-fold higher than in heterozygous mice. Fam46a is weakly expressed in most adult and embryonic tissues with a strong expression in mineralized tissues as calvaria and femur. The FAM46A protein is computationally predicted as a new member of the superfamily of nucleotidyltransferase fold proteins, but little is known about its function. Fam46a E157*Mhda mice are the first mouse model for a mutation within the Fam46a gene. |
| |
| Keywords: | |
| 本文献已被 SpringerLink 等数据库收录！ |
|
