Dataset Information

Variable bone fragility associated with an Amish COL1A2 variant and a knock-in mouse model.

ABSTRACT: Osteogenesis imperfecta (OI) is a heritable form of bone fragility typically associated with a dominant COL1A1 or COL1A2 mutation. Variable phenotype for OI patients with identical collagen mutations is well established, but phenotype variability is described using the qualitative Sillence classification. Patterning a new OI mouse model on a specific collagen mutation therefore has been hindered by the absence of an appropriate kindred with extensive quantitative phenotype data. We benefited from the large sibships of the Old Order Amish (OOA) to define a wide range of OI phenotypes in 64 individuals with the identical COL1A2 mutation. Stratification of carrier spine (L1-4) areal bone mineral density (aBMD) Z-scores demonstrated that 73% had moderate to severe disease (less than -2), 23% had mild disease (-1 to -2), and 4% were in the unaffected range (greater than -1). A line of knock-in mice was patterned on the OOA mutation. Bone phenotype was evaluated in four F(1) lines of knock-in mice that each shared approximately 50% of their genetic background. Consistent with the human pedigree, these mice had reduced body mass, aBMD, and bone strength. Whole-bone fracture susceptibility was influenced by individual genomic factors that were reflected in size, shape, and possibly bone metabolic regulation. The results indicate that the G610C OI (Amish) knock-in mouse is a novel translational model to identify modifying genes that influence phenotype and for testing potential therapies for OI.

SUBMITTER: Daley E

PROVIDER: S-EPMC3153383 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Variable bone fragility associated with an Amish COL1A2 variant and a knock-in mouse model.

Daley Ethan E Streeten Elizabeth A EA Sorkin John D JD Kuznetsova Natalia N Shapses Sue A SA Carleton Stephanie M SM Shuldiner Alan R AR Marini Joan C JC Phillips Charlotte L CL Goldstein Steven A SA Leikin Sergey S McBride Daniel J DJ

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20100201 2

Osteogenesis imperfecta (OI) is a heritable form of bone fragility typically associated with a dominant COL1A1 or COL1A2 mutation. Variable phenotype for OI patients with identical collagen mutations is well established, but phenotype variability is described using the qualitative Sillence classification. Patterning a new OI mouse model on a specific collagen mutation therefore has been hindered by the absence of an appropriate kindred with extensive quantitative phenotype data. We benefited fro ...[more]

PMID: 19594296

Similar Datasets

Project description:PurposePathogenic variants in FAM161A are the most common cause of retinitis pigmentosa in Israel. Two founder pathogenic variants explain the vast majority of cases of Jewish origin, 1 being a nonsense variant (p.Arg523∗). The aim of this study was to generate a knock-in (KI) mouse model harboring the corresponding p.Arg512∗ pathogenic variant and characterize the course of retinal disease.DesignExperimental study of a mouse animal model.Subjects/participants/controlsA total of 106 Fam161a knock-in mice and 29 wild-type mice with C57BL/6J background particiapted in this study.MethodsHomozygous Fam161a p.Arg512∗ KI mice were generated by Cyagen Biosciences. Visual acuity (VA) was evaluated using optomotor tracking response and retinal function was assessed by electroretinography (ERG). Retinal structure was examined in vivo using OCT and fundus autofluorescence imaging. Retinal morphometry was evaluated by histologic and immunohistochemical (IHC) analyses.Main outcome measuresVisual and retinal function assessments, clinical imaging examinations, quantitative histology, and IHC studies of KI as compared with wild-type (WT) mice retinas.ResultsThe KI model was generated by replacing 3 bp, resulting in p.Arg512∗. Homozygous KI mice that had progressive loss of VA and ERG responses until the age of 18 months, with no detectable response at 21 months. OCT showed complete loss of the outer nuclear layer at 21 months. Fundus autofluorescence imaging revealed progressive narrowing of blood vessels and formation of patchy hyper-autofluorescent and hypo-autofluorescent spots. Histologic analysis showed progressive loss of photoreceptor nuclei. Immunohistochemistry staining showed Fam161a expression mainly in photoreceptors cilia and the outer plexiform layer (OPL) in WT mice retinas, whereas faint expression was evident mainly in the cilia and OPL of KI mice.ConclusionsThe Fam161a - p.Arg512∗ KI mouse model is characterized by widespread retinal degeneration with relatively slow progression. Surprisingly, disease onset is delayed and progression is slower compared with the previously reported knock-out model. The common human null mutation in the KI mouse model is potentially amenable for correction by translational read-through-inducing drugs and by gene augmentation therapy and RNA editing, and can serve to test these treatments as a first step toward possible application in patients.Financial disclosuresThe author(s) have no proprietary or commercial interest in any materials discussed in this article.

Dataset Information

Variable bone fragility associated with an Amish COL1A2 variant and a knock-in mouse model.

Publications

Variable bone fragility associated with an Amish COL1A2 variant and a knock-in mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets