The Challenges of Autosomal Recessive and Other New Forms of OI

描述（由申请人提供）：全世界约有1/12，500人患有骨生成障碍（OI）。这意味着在美国大约有25，000人患有这种疾病，其中大多数人的病情相对较轻，一生中会经历几到几十次骨折。其余残疾人的残疾情况从行走时需要帮助到终生使用机动轮椅或手推车，再到因发育明显不足和胸部骨折导致肺功能不全而在围产期死亡。超过90%的OI患者在编码I型胶原蛋白链的两个基因（COL 1A 1和COL 1A 2）中的一个基因中存在突变，这些突变要么以显性方式遗传几代人，要么在家族中第一个受影响的婴儿中重新出现。隐性遗传的OI已被假定为在严重的形式与复发的同胞与未受影响的父母。最初，其中一些被证明是由I型胶原基因显性突变的亲本嵌合体引起的。然而，在过去的三年中，已经确定了三个基因（CRTAP，LEPRE 1和Smpd 3），其中突变可导致复发性遗传形式的OI。其中两个基因（CRTAP和LEPRE 1）的突变已被发现在人类中产生OI表型。Smpd 3中的突变导致隐性OI的来回小鼠模型。这些研究提供了一个新的背景，试图了解突变如何导致脆骨，生长迟缓和骨骼畸形，并应提供基板上设想和测试新形式的治疗OI，动物模型已经存在。这次会议，预计将汇集约70名基础科学家，临床研究人员，临床医生和学员，提供了第一次机会，综合我们对复发性遗传形式的OI的理解，检查临床表现的范围，了解所涉及的酶系统的作用，并研究从动物和人类研究中获得的见解如何可能导致对隐性形式的OI和更常见的显性遗传形式的更有效的治疗。常染色体隐性遗传和其他新形式的OI的挑战将导致研究人员之间加强合作，并增加临床研究中心主任的参与，所有这些人都受益于定期会议，以分享信息并更新其临床和研究策略。它还将促进识别新的OI基因，确定新的研究路径以使患者受益，并增加相关临床研究中心的进展。

DESCRIPTION (provided by applicant): Osteogenesis imperfecta (OI) affects about 1/12,500 individuals throughout the world. This means that there are about 25,000 individuals with this disorder in the United States, the majority of whom have a relatively mild form of the condition and endure a few to dozens of fractures throughout their lifetimes. For the remainder, disability ranges from the need for assists while walking, to the use of motorized wheelchairs or carts throughout their lifetimes, to death in the perinatal period from pulmonary insufficiency as a result of marked underdevelopment and fracture of bones of the chest. More than 90% of individuals with OI have mutations in one of the two genes (COL1A1 and COL1A2) that encode the chains of type I collagen, and these mutations are either inherited in a dominant fashion through several generations or arise de novo in the first affected infant in a family. Recessive inheritance of OI has been postulated in severe forms with recurrence in sibships with unaffected parents. Initially some of these were shown to result from parental mosaicism for dominant mutations in type I collagen genes. In the last three years, however, three genes have been identified (CRTAP, LEPRE1, and Smpd3) in which mutations can lead to recessively inherited forms of OI. Mutations in two of these genes (CRTAP and LEPRE1) have been found to produce OI phenotypes in people. Mutations in Smpd3 result in the fro/fro mouse model of recessive OI. These studies have provided a new background on which to try to understand how mutations result in brittle bones, growth retardation, and skeletal deformity, and should provide the substrate on which to envision and test new forms of treatment for OI, as animal models already exist. This meeting, which is expected to bring some 70 basic scientists, clinical investigators, clinicians, and trainees together, provides the first opportunity to synthesize our understanding of recessively inherited forms of OI, to examine the range of clinical presentation, to understand the roles of the enzymatic systems involved, and to examine how insights gained from both animal and human studies might lead to more effective treatments of recessive forms of OI and of the more common dominantly inherited forms. The Challenges of Autosomal Recessive and Other New Forms of OI will lead to enhanced collaboration among researchers, and to the growing involvement of directors of clinical research centers, all of whom benefit from regular meetings to share information and update their clinical and research strategies. It also will facilitate identification of new OI genes, identify new paths of research to benefit patients, and increase progress of the Linked Clinical Research Centers.