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

• 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
• 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

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（由申请方提供）：低磷酸酶症（HPP）是一种遗传性代谢性骨病，由组织非特异性碱性磷酸酶（TNSALP）基因的功能缺失突变引起，因此具有血清碱性磷酸酶水平低的特征。HPP的临床表现是由于骨骼基质的矿化受损（引起佝偻病或骨软化症），因为过量的焦磷酸盐（TNSALP的底物）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股骨干骨折（ASFF）与长期使用双膦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酶症中所见的假性骨折，并且双膦酸盐是焦磷酸盐的化学衍生物，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，以确定他们是否是TNSALP突变或多态性的携带者，这些突变或多态性可能使他们易患这些不寻常和衰弱的骨折。我们已经记录了这样一个案例。一位55岁的女性，在口服和静脉注射双膦酸盐治疗骨质疏松症4年后，同时发生了非创伤性双侧ASFF。在对她的TNSALP基因进行测序后，我们确定了一个单一的突变（c.212 G>A，p.Arg71His）。这种缺陷可以作为一个单一的显性轻度突变遗传，也可以在严重的隐性HPP中与第二个突变相结合。该患者从未被诊断患有HPP，尽管她的血清ALP较低（26 U/L，NI 32 - 116 U/L）。我们假设，无论是隐性TNSALP突变的携带者或有一个轻微的显性形式（诊断或未诊断）的HPP由于一个单一的TNSALP突变的“骨质疏松症”患者易患ASFF。二膦酸盐治疗会进一步加重骨骼疾病，导致明显骨折。我们假设大量使用双膦酸盐并患有ASFF的“骨质疏松症”患者将携带TNSALP突变。因此，我们将测试使用双膦酸盐治疗并经历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。如果我们的假设是有效的，骨质疏松症患者应筛查血清TNSALP活性，然后进一步测试TNSALP底物水平，也许TNSALP突变。携带者或显性HPP的患者不应接受双膦酸盐治疗。这将减少骨质疏松症患者ASFF的发生率。