Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia

Gannagé-Yared, M.-H.; Chouery, Éliane; Sobacchi, Cristina; Mehawej, Cybel; Santoni, Federico; Guipponi, Michel; Antonarakis, Stylianos E.; Hamamy, Hanan; Mégarbané, André

doi:10.1016/j.bone.2014.08.014

Cited by 14 publications

(8 citation statements)

References 19 publications

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“…The QTL on SSC8 was indicated by both single- and multi-locus GWAS and pointed to Fraser Extracellular Matrix Complex Subunit 1 ( FRAS1 ) as positional candidate. Observations that patients with FRAS1 mutations could have more frequent skull ossification defects (van Haelst et al, 2008) tie in with evidence of an involvement of this gene in familial sclerosing bone dysplasia revealed by exome sequencing (Gannagé-Yared et al, 2014).…”

Section: Discussionmentioning

confidence: 95%

Genetic Contribution to Variation in Blood Calcium, Phosphorus, and Alkaline Phosphatase Activity in Pigs

et al. 2019

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Blood values of calcium (Ca), inorganic phosphorus (IP), and alkaline phosphatase activity (ALP) are valuable indicators for mineral status and bone mineralization. The mineral homeostasis is maintained by absorption, retention, and excretion processes employing a number of known and unknown sensing and regulating factors with implications on immunity. Due to the high inter-individual variation of Ca and P levels in the blood of pigs and to clarify molecular contributions to this variation, the genetics of hematological traits related to the Ca and P balance were investigated in a German Landrace population, integrating both single-locus and multi-locus genome-wide association study (GWAS) approaches. Genomic heritability estimates suggest a moderate genetic contribution to the variation of hematological Ca ( N = 456), IP ( N = 1049), ALP ( N = 439), and the Ca/P ratio ( N = 455), with values ranging from 0.27 to 0.54. The genome-wide analysis of markers adds a number of genomic regions to the list of quantitative trait loci, some of which overlap with previous results. Despite the gaps in knowledge of genes involved in Ca and P metabolism, genes like THBS2 , SHH , PTPRT , PTGS1 , and FRAS1 with reported connections to bone metabolism were derived from the significantly associated genomic regions. Additionally, genomic regions included TRAFD1 and genes coding for phosphate transporters ( SLC17A1 – SLC17A4 ), which are linked to Ca and P homeostasis. The study calls for improved functional annotation of the proposed candidate genes to derive features involved in maintaining Ca and P balance. This gene information can be exploited to diagnose and predict characteristics of micronutrient utilization, bone development, and a well-functioning musculoskeletal system in pig husbandry and breeding.

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Section: Discussionmentioning

confidence: 95%

Genetic Contribution to Variation in Blood Calcium, Phosphorus, and Alkaline Phosphatase Activity in Pigs

et al. 2019

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“…Another autosomal dominant form of the disease is mutations in FGF23 [11]. Recently we and others have identified mutations in DMP1 [6, 12–18], which are extremely rare due to their autosomal recessive nature. Regardless, clinical, biochemical, and histomorphometric parameters are essentially identical in both the dominant and recessive form of hypophosphatemic rickets.…”

Section: Introductionmentioning

confidence: 99%

Sclerostin antibody (Scl-Ab) improves osteomalacia phenotype in dentin matrix protein 1(Dmp1) knockout mice with little impact on serum levels of phosphorus and FGF23

et al. 2016

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Unlike treatments for most rickets, the treatment using 1,25-(OH)2 vitamin D3 has little efficacy on patients with hypophosphatemic rickets, a set of rare genetic diseases. Thus, understanding the local cause for osteomalacia in hypophosphatemic rickets and developing an effective treatment to restore mineralization in this rare disease has been a longstanding goal in medicine. Here, we used Dmp1 knockout (KO) mice (whose mutations led to the same type of autosomal recessive hypophosphatemic rickets in humans) as the model in which the monoclonal antibody of sclerostin (Scl-Ab) was tested in two age groups for 8 weeks: the prevention group (starting at age 4 weeks) and the treatment group (starting at age 12 weeks). Applications of Scl-Ab greatly improved the osteomalacia phenotype (>15%) and the biomechanical properties (3-point bending, ~60%) in the treated long-bone group. Our studies not only showed improvement of the osteomalacia in the alveolar bone, which has the highest bone metabolism rate, as well as the long bone phenotypes in treated mice. All these improvements attributed to the use of Scl-Ab are independent of the change in serum levels of phosphorus and FGF23, since Scl-Ab had little efficacy on those parameters. Finally, we propose a model to explain how Scl-Ab can improve the Dmp1 KO osteomalacia phenotype, in which the sclerostin level is already low.

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“…DMP1 has a tripeptide of leucine‐proline‐valine (LPV) similar to that of DSPP after the ER‐entry signal peptide cleavage site. Although several mutations in DMP1 causing Autosomal Recessive Hypophosphatemic Rickets/osteomalacia (ARHR) have been identified in humans (Feng et al, ; Farrow et al, ; Koshida et al, ; Gannage‐Yared et al, ), none of these mutations affects the LPV motif of DMP1. In addition, we previously showed that the phosphorylated acidic 57 kDa C‐terminal fragment lacking the intact LPV motif was secreted in vitro and in vivo and rescued the skeletal and serum biochemical abnormalities of Dmp1 ‐null mice (Lu et al, , ).…”

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confidence: 99%

The LPV Motif Is Essential for the Efficient Export of Secretory DMP1 From the Endoplasmic Reticulum

et al. 2015

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Dentin matrix protein 1 (DMP1) is found abundantly in the extracellular matrices of bone and dentin. Secretory DMP1 begins with a tripeptide of leucine-proline-valine (LPV) after the endoplasmic reticulum (ER)-entry signal peptide is cleaved. The goal of this study was to determine the role of the LPV motif in the secretion of DMP1. A series of DNA constructs was generated to express various forms of DMP1 with or without the LPV motif. These constructs were transfected into a preosteoblast cell line, the MC3T3-E1 cells, and the subcellular localization and secretion of various forms of DMP1 were examined by immunofluorescent staining and Western-blotting analyses. Immunofluorescent staining showed that the LPV-containing DMP1 variants were primarily localized in the Golgi complex, whereas the LPV-lacking DMP1 variants were found abundantly within the ER. Western-blotting analyses demonstrated that the LPV-containing DMP1 variants were rapidly secreted from the transfected cells, as they did not accumulate within the cells, and the amounts increased in the conditioned media over time. In contrast, the LPV-lacking DMP1 variants were predominantly retained within the cells, and only small amounts were secreted out of the cells over time. These results suggest that the LPV motif is essential for the efficient export of secretory DMP1 from the ER to the Golgi complex.

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Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia

Cited by 14 publications

References 19 publications

Genetic Contribution to Variation in Blood Calcium, Phosphorus, and Alkaline Phosphatase Activity in Pigs

Genetic Contribution to Variation in Blood Calcium, Phosphorus, and Alkaline Phosphatase Activity in Pigs

Sclerostin antibody (Scl-Ab) improves osteomalacia phenotype in dentin matrix protein 1(Dmp1) knockout mice with little impact on serum levels of phosphorus and FGF23

The LPV Motif Is Essential for the Efficient Export of Secretory DMP1 From the Endoplasmic Reticulum

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