title: New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis.
abstract: Metabolic bone disorders arise as primary diseases or may be secondary due to a multitude of organ malfunctions. Animal models are required to understand the molecular mechanisms responsible for the imbalances of bone metabolism in disturbed bone mineralization diseases. Here we present the isolation of mutant mouse models for metabolic bone diseases by phenotyping blood parameters that target bone turnover within the large-scale genome-wide Munich ENU Mutagenesis Project. A screening panel of three clinical parameters, also commonly used as biochemical markers in patients with metabolic bone diseases, was chosen. Total alkaline phosphatase activity and total calcium and inorganic phosphate levels in plasma samples of F1 offspring produced from ENU-mutagenized C3HeB/FeJ male mice were measured. Screening of 9,540 mice led to the identification of 257 phenodeviants of which 190 were tested by genetic confirmation crosses. Seventy-one new dominant mutant lines showing alterations of at least one of the biochemical parameters of interest were confirmed. Fifteen mutations among three genes (Phex, Casr, and Alpl) have been identified by positional-candidate gene approaches and one mutation of the Asgr1 gene, which was identified by next-generation sequencing. All new mutant mouse lines are offered as a resource for the scientific community.
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Sabrautzki
authors.forename: Isabel
authors.initials: I
authors.lastname: Rubio-Aliaga
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.forename: Christian M
authors.initials: CM
authors.lastname: Cohrs
authors.forename: Matthias
authors.initials: M
authors.lastname: Klaften
authors.forename: Hartwig
authors.initials: H
authors.lastname: Seedorf
authors.forename: Sebastian
authors.initials: S
authors.lastname: Eck
authors.forename: Ana
authors.initials: A
authors.lastname: Benet-Pagès
authors.forename: Jack
authors.initials: J
authors.lastname: Favor
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Bettina
authors.initials: B
authors.lastname: Lorenz-Depiereux
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D002118:Calcium / Q000097:blood; D033481:Chromosomes, Mammalian; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice / Q000235:genetics*; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics; D010641:Phenotype; D010710:Phosphates / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D018709:Statistics, Nonparametric; D014960:X Chromosome
chemical_list: D009153:Mutagens; D010710:Phosphates; D044169:Receptors, Calcium-Sensing; D000469:Alkaline Phosphatase; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse; D005038:Ethylnitrosourea; D002118:Calcium