TNSALP Mutations in Atypical Femoral Fractures with Long-Term Bisphosphonate Use

长期使用双膦酸盐导致非典型股骨骨折的 TNSALP 突变

基本信息

批准号：
8652438
负责人：
STEVEN R MUMM
金额：
$ 19.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8652438
关键词：
Accounting Adult Advisory Committees Affect Aftercare Age Alkaline Phosphatase American Amino Acids Bilateral Biological Assay Blood Bone Diseases Caring Cell Transplantation Chemicals Childhood Clinical Collaborations Control Groups DNA Sequence Analysis Databases Defect Dental Cementum Diagnosis Diphosphates Disease Dose Exons Femoral Fractures Fracture Frequencies Genes Genetic Genetic Polymorphism Genomic DNA Growth Hospitals Hydroxyapatites Hypophosphatasia Incidence Inherited Intravenous Length Marrow Medical Messenger RNA Metabolic Bone Diseases Minerals Mutation Mutation Analysis Oral Osteomalacia Osteoporosis Patients Pediatric Hospitals Perinatal Process Pyridoxal Phosphate RNA Splicing Recommendation Recruitment Activity Reporting Research Research Personnel Rickets Serum Severities Site Skeleton Societies Teriparatide Testing Therapeutic Tissues Tooth Loss Universities Untranslated Regions Urine Washington bisphosphonate bone carrier status deciduous tooth enzyme replacement therapy experience extracellular follower of religion Jewish in utero infancy inhibitor/antagonist interest loss of function mutation medical schools mineralization older women phosphoethanolamine premature prevent public health relevance sex skeletal skeletal disorder stillbirth

项目摘要

DESCRIPTION (provided by applicant): Hypophosphatasia (HPP), a heritable metabolic bone disease, is caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, and therefore features low serum levels of alkaline phosphatase. HPP manifests clinically due to impaired mineralization of skeletal matrix (causing rickets or osteomalacia) because the excess levels of pyrophosphate, the substrate for TNSALP, inhibits the mineralization process. Recently, a task force was established by the American Society for Bone and Mineral Research to investigate the association of atypical subtrochanteric and diaphyseal femoral fractures (ASFFs) with the long-term use of bisphosphonates for osteoporosis. Because these fractures resemble pseudofractures seen in adult hypophosphatasia, and that bisphosphonates are chemical derivatives of pyrophosphate, one of their recommendations was to sequence the TNSALP gene in these osteoporosis patients to see if they are carriers of TNSALP mutations or polymorphisms that may predispose them to these unusual and debilitating fractures. We have now documented such a case. A 55 year-old woman, after treatment for four years with oral and later intravenous bisphosphonates for presumed osteoporosis, suffered simultaneous atraumatic bilateral ASFFs. After sequencing her TNSALP gene, we identified a single mutation (c.212 G>A, p.Arg71His). This defect can be inherited as a single dominant mild mutation or combined with a second mutation in severe recessive HPP. The patient had never been diagnosed with HPP, although her serum ALP was low (26 U/L, Nl 32 - 116 U/L). We hypothesize that being either a carrier of a recessive TNSALP mutation or having a mild dominant form (diagnosed or undiagnosed) of HPP due to a single TNSALP mutation predisposes "osteoporosis" patients to ASFFs. Treatment with bisphosphonates then further exacerbates skeletal disease leading to overt fracture. We hypothesize that a significant number of "osteoporosis" patients using bisphosphonates and having ASFFs will carry TNSALP mutations. Therefore, we will test whether osteoporosis patients who are using bisphosphonate therapy and experience ASFFs have a higher frequency of TNSALP mutations or polymorphisms than control groups. If our hypothesis is validated, osteoporosis patients should be screened for serum TNSALP activity, and then further tested for TNSALP substrate levels and perhaps TNSALP mutations. Those with evidence of carrier status or dominant HPP should not be treated with bisphosphonates. This will reduce the incidence of ASFFs in osteoporosis patients.

描述（申请人提供）：低磷酸酯酶症（HPP）是一种遗传性代谢性骨病，是由组织非特异性碱性磷酸酶（TNSALP）基因功能丧失突变引起的，因此具有低血清碱性磷酸酶水平的特点。 HPP 的临床表现是由于骨骼基质矿化受损（导致佝偻病或骨软化症），因为过量的焦磷酸盐（TNSALP 的底物）会抑制矿化过程。最近，美国骨与矿物质研究学会成立了一个工作组，调查非典型转子下和骨干股骨骨折（ASFF）与长期使用双磷酸盐治疗骨质疏松症的关系。由于这些骨折类似于成人低磷酸酯酶症中出现的假性骨折，并且双磷酸盐是焦磷酸盐的化学衍生物，因此他们的建议之一是对这些骨质疏松症患者的 TNSALP 基因进行测序，看看他们是否是 TNSALP 突变或多态性的携带者，这些突变或多态性可能使他们容易患上这些骨折。不寻常且使人衰弱的骨折。我们现在已经记录了这样一个案例。一名 55 岁女性，因疑似骨质疏松症而口服双膦酸盐，随后静脉注射双膦酸盐治疗四年，随后同时出现非创伤性双侧 ASFF。对她的 TNSALP 基因进行测序后，我们发现了一个单一突变（c.212 G>A，p.Arg71His）。这种缺陷可以作为单一显性轻度突变遗传，也可以与严重隐性 HPP 中的第二个突变相结合。尽管患者的血清 ALP 较低（26 U/L，N1 32 - 116 U/L），但该患者从未被诊断出患有 HPP。我们假设，作为隐性 TNSALP 突变的携带者，或者由于单一 TNSALP 突变而患有轻度显性 HPP（诊断或未诊断），会使“骨质疏松症”患者容易患 ASFF。双磷酸盐治疗会进一步加剧骨骼疾病，导致明显骨折。我们假设大量使用双磷酸盐且患有 ASFF 的“骨质疏松症”患者将携带 TNSALP 突变。因此，我们将测试使用双磷酸盐治疗并经历 ASFF 的骨质疏松症患者是否比对照组具有更高的 TNSALP 突变或多态性频率。如果我们的假设得到验证，骨质疏松症患者应该筛查血清 TNSALP 活性，然后进一步测试 TNSALP 底物水平，或许还有 TNSALP 突变。那些有携带者状态或显性 HPP 证据的患者不应接受双磷酸盐治疗。这将减少骨质疏松症患者 ASFF 的发生率。