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Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

ABSTRACT: The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

SUBMITTER: Swan AL

PROVIDER: S-EPMC7822523 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

Swan Anna L AL Schütt Christine C Rozman Jan J Del Mar Muñiz Moreno Maria M Brandmaier Stefan S Simon Michelle M Leuchtenberger Stefanie S Griffiths Mark M Brommage Robert R Keskivali-Bond Piia P Grallert Harald H Werner Thomas T Teperino Raffaele R Becker Lore L Miller Gregor G Moshiri Ala A Seavitt John R JR Cissell Derek D DD Meehan Terrence F TF Acar Elif F EF Lelliott Christopher J CJ Flenniken Ann M AM Champy Marie-France MF Sorg Tania T Ayadi Abdel A Braun Robert E RE Cater Heather H Dickinson Mary E ME Flicek Paul P Gallegos Juan J Ghirardello Elena J EJ Heaney Jason D JD Jacquot Sylvie S Lally Connor C Logan John G JG Teboul Lydia L Mason Jeremy J Spielmann Nadine N McKerlie Colin C Murray Stephen A SA Nutter Lauryl M J LMJ Odfalk Kristian F KF Parkinson Helen H Prochazka Jan J Reynolds Corey L CL Selloum Mohammed M Spoutil Frantisek F Svenson Karen L KL Vales Taylor S TS Wells Sara E SE White Jacqueline K JK Sedlacek Radislav R Wurst Wolfgang W Lloyd K C Kent KCK Croucher Peter I PI Fuchs Helmut H Williams Graham R GR Bassett J H Duncan JHD Gailus-Durner Valerie V Herault Yann Y Mallon Ann-Marie AM Brown Steve D M SDM Mayer-Kuckuk Philipp P Hrabe de Angelis Martin M

PLoS genetics 20201228 12

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from rece ...[more]

PMID: 33370286

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Project description:PurposeFamilial exudative vitreoretinopathy (FEVR) is caused by mutations in the genes encoding low-density lipoprotein receptor-related protein (LRP5) or its interacting partners, namely frizzled class receptor 4 (FZD4) and norrin cystine knot growth factor (NDP). Mouse models for Lrp5, Fzd4, and Ndp have proven to be important for understanding the retinal pathophysiology underlying FEVR and systemic abnormalities related to defective Wnt signaling. Here, we report a new mouse mutant, tvrm111B, which was identified by electroretinogram (ERG) screening of mice generated in the Jackson Laboratory Translational Vision Research Models (TVRM) mutagenesis program.MethodsERGs were used to examine outer retinal physiology. The retinal vasculature was examined by in vivo retinal imaging, as well as by histology and immunohistochemistry. The tvrm111B locus was identified by genetic mapping of mice generated in a cross to DBA/2J, and subsequent sequencing analysis. Gene expression was examined by real-time PCR of retinal RNA. Bone mineral density (BMD) was examined by peripheral dual-energy X-ray absorptiometry.ResultsThe tvrm111B allele is inherited as an autosomal recessive trait. Genetic mapping of the decreased ERG b-wave phenotype of tvrm111B mice localized the mutation to a region on chromosome 19 that included Lrp5. Sequencing of Lrp5 identified the insertion of a cytosine (c.4724_4725insC), which is predicted to cause a frameshift that disrupts the last three of five conserved PPPSPxS motifs in the cytoplasmic domain of LRP5, culminating in a premature termination. In addition to a reduced ERG b-wave, Lrp5tvrm111B homozygotes have low BMD and abnormal features of the retinal vasculature that have been reported previously in Lrp5 mutant mice, including persistent hyaloid vessels, leakage on fluorescein angiography, and an absence of the deep retinal capillary bed.ConclusionsThe phenotype of the Lrp5tvrm111B mutant includes abnormalities of the retinal vasculature and of BMD. This model may be a useful resource to further our understanding of the biological role of LRP5 and to evaluate experimental therapies for FEVR or other conditions associated with LRP5 dysfunction.

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Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

Publications

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

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