New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis.
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New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis. / Sabrautzki, Sibylle; Rubio-Aliaga, Isabel; Hans, Wolfgang; Fuchs, Helmut; Rathkolb, Birgit; Calzada-Wack, Julia; Cohrs, Christian M; Klaften, Matthias; Seedorf, Hartwig; Eck, Sebastian; Benet-Pagès, Ana; Favor, Jack; Esposito, Irene; Strom, Tim M; Wolf, Eckhard; Lorenz-Depiereux, Bettina; Martin, Hrabě de Angelis.
In: MAMM GENOME, Vol. 23, No. 7-8, 7-8, 2012, p. 416-430.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis.
AU - Sabrautzki, Sibylle
AU - Rubio-Aliaga, Isabel
AU - Hans, Wolfgang
AU - Fuchs, Helmut
AU - Rathkolb, Birgit
AU - Calzada-Wack, Julia
AU - Cohrs, Christian M
AU - Klaften, Matthias
AU - Seedorf, Hartwig
AU - Eck, Sebastian
AU - Benet-Pagès, Ana
AU - Favor, Jack
AU - Esposito, Irene
AU - Strom, Tim M
AU - Wolf, Eckhard
AU - Lorenz-Depiereux, Bettina
AU - Martin, Hrabě de Angelis
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Female
KW - Mice, Inbred C57BL
KW - DNA Mutational Analysis
KW - Mutation
KW - Phenotype
KW - Amino Acid Sequence
KW - Base Sequence
KW - Mutagenesis
KW - Polymorphism, Single Nucleotide
KW - Statistics, Nonparametric
KW - Disease Models, Animal
KW - Mice, Inbred C3H
KW - Alkaline Phosphatase/genetics
KW - Bone Diseases, Metabolic/blood/enzymology/genetics
KW - Calcium/blood
KW - Chromosomes, Mammalian
KW - Ethylnitrosourea/pharmacology
KW - Mice/genetics
KW - Mutagens/pharmacology
KW - PHEX Phosphate Regulating Neutral Endopeptidase/genetics
KW - Phosphates/blood
KW - Receptors, Calcium-Sensing/genetics
KW - X Chromosome
KW - Animals
KW - Male
KW - Female
KW - Mice, Inbred C57BL
KW - DNA Mutational Analysis
KW - Mutation
KW - Phenotype
KW - Amino Acid Sequence
KW - Base Sequence
KW - Mutagenesis
KW - Polymorphism, Single Nucleotide
KW - Statistics, Nonparametric
KW - Disease Models, Animal
KW - Mice, Inbred C3H
KW - Alkaline Phosphatase/genetics
KW - Bone Diseases, Metabolic/blood/enzymology/genetics
KW - Calcium/blood
KW - Chromosomes, Mammalian
KW - Ethylnitrosourea/pharmacology
KW - Mice/genetics
KW - Mutagens/pharmacology
KW - PHEX Phosphate Regulating Neutral Endopeptidase/genetics
KW - Phosphates/blood
KW - Receptors, Calcium-Sensing/genetics
KW - X Chromosome
M3 - SCORING: Journal article
VL - 23
SP - 416
EP - 430
JO - MAMM GENOME
JF - MAMM GENOME
SN - 0938-8990
IS - 7-8
M1 - 7-8
ER -