Genetics and molecular biology of melorheostosis

骨髓变性的遗传学和分子生物学

• 批准号: 10001303
• 负责人: Joan C Marini
• 金额: $ 43.17万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10001303
• 关键词: Affect; BMP2 gene; Biopsy; Cell Proliferation; Clinical Trials; Collaborations; Contracture; Contralateral; Data; Disease; Etiology; Flow Cytometry; Genes; Genetic; Goals; Histology; Human; Immunohistochemistry; Impairment; In Vitro; Institutes; Joints; Lesion; MAP2K1 gene; MAPK3 gene; Mediating; Melorheostosis; Metabolism; Molecular Biology; Mosaicism; Mutation; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Child Health and Human Development; Oncogenes; Osteoblasts; Osteogenesis; Osteoid; Pain; Patients; Pattern; Physiologic calcification; Population; Research Personnel; Role; Skeleton; Skin; Surface; Testing; Time; Transcript; bone; causal variant; cortical bone; exome sequencing; functional disability; inhibitor/antagonist; mineralization; mouse model; mutant; skeletal; soft tissue

Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. A collaboration of investigators in NICHD, NIAMS and the Institute of Osteology in Vienna came together to investigate the genetics of melorheostosis. To increase the ability of sequencing to detect causative mutations, 15 melorheostosis patients unwent biopsies of both affected and contralateral unaffected bone. Using whole exome sequencing, we identified somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2- mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.

骨质疏松症是一种散发性疾病的病因不明的特点是不对称的骨 过度生长和功能障碍。NICHD、NIAMS和维也纳骨学研究所的研究人员合作，共同研究了骨质疏松症的遗传学。为了提高测序检测致病突变的能力，15名骨质疏松症患者对受累骨和对侧未受累骨进行了活检。使用全外显子组测序，我们确定了体细胞嵌合体MAP 2K 1突变，在受影响的，但不是未受影响的，8个无关的melorheostosis患者的骨。激活突变（Q56 P、K57 E和K57 N）紧密聚集在MEK 1负调控结构域中。受影响的骨骼显示出增加的马赛克图案 成骨细胞免疫组化中p-ERK 1/2。从受影响的骨中培养成骨细胞 包括两个具有不同p-ERK 1/2水平的群体，通过流式细胞术，增强的ERK 1/2 活化和增加的细胞增殖。然而，这些MAP 2K 1突变抑制BMP 2 - 2。 体外介导的成骨细胞矿化和分化，明显支持 在受影响的骨组织学中检测到类骨质增加。在皮肤中也检测到镶嵌现象 在五个测试的患者中的四个中覆盖骨病变。我们的数据显示，MAP 2K 1 癌基因在人骨形成中是重要的，并暗示MEK 1抑制是一种潜在的 骨质疏松症的治疗途径。