title: Exome sequencing identifies a nonsense mutation in Fam46a associated with bone abnormalities in a new mouse model for skeletal dysplasia.
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.
authors.affiliation: Institute of Human Genetics, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Diener
authors.affiliation: Institute of Experimental Genetics and German Mouse Clinic, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.|Technische Universität München, II. Medizinische Klinik, Klinikum rechts der Isar, 81675, Munich, Germany.
authors.forename: Sieglinde
authors.initials: S
authors.lastname: Bayer
authors.affiliation: Institute of Experimental Genetics and German Mouse Clinic, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.|Member of German Center for Diabetes Research (DZD), Neuherberg, Germany.|Research Unit Comparative Medicine, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Sabrautzki
authors.affiliation: Institute of Human Genetics, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Experimental Labs Stem Cell Group, Orthopedic Department, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Friedrich-Bergius-Ring 15, 97076, Würzburg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Mentrup
authors.affiliation: Institute of Experimental Genetics and German Mouse Clinic, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.|Member of German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Gerhard K H
authors.initials: GK
authors.lastname: Przemeck
authors.affiliation: Institute of Experimental Genetics and German Mouse Clinic, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.|Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str.25, 81377, Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: Institute of Human Genetics, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.affiliation: Institute of Experimental Genetics and German Mouse Clinic, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.|Member of German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.affiliation: Institute of Experimental Genetics and German Mouse Clinic, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.|Member of German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: Institute of Experimental Genetics and German Mouse Clinic, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.affiliation: Institute of Human Genetics, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzmayr
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str.25, 81377, Munich, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Institute of Human Genetics, Universität Würzburg, Biozentrum Am Hubland, 97074, Würzburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.affiliation: Experimental Labs Stem Cell Group, Orthopedic Department, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Friedrich-Bergius-Ring 15, 97076, Würzburg, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
authors.affiliation: Institute of Human Genetics, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Trogerstr. 32, 81675, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Experimental Genetics and German Mouse Clinic, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.|Member of German Center for Diabetes Research (DZD), Neuherberg, Germany.|Chair in Experimental Genetics, Technische Universität München, 85350, Freising-Weihenstephan, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Institute of Human Genetics, German Research Center for Environmental Health (GmbH), Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany. lorenz-depiereux@helmholtz-muenchen.de.
authors.forename: Bettina
authors.initials: B
authors.lastname: Lorenz-Depiereux
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001848:Bone Diseases, Developmental / Q000235:genetics* / Q000473:pathology*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004789:Enzyme Activation; D059472:Exome; D005260:Female; D015870:Gene Expression; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: D018389:Codon, Nonsense; D000469:Alkaline Phosphatase