Genetic modifiers of Duchenne Muscular Dystrophy

描述（由申请人提供）：杜氏肌营养不良症 (DMD) 是一种退行性肌肉疾病，由 X 连锁 DMD 基因突变引起，影响约 1:3500 至 1:5200 的活产男性。 DMD 基因突变导致肌纤维中抗肌营养不良蛋白缺失，从而导致肌纤维坏死、肌内膜纤维化和脂肪替代。这是一种毁灭性的疾病，导致 12 岁时丧失行走能力，历史上导致 20 岁时死亡。对家庭的心理和社会经济影响是巨大的；这些包括但不限于医疗费用、职业和工作的机会成本以及对父母和兄弟姐妹造成的心理损失。我们的长期目标是了解哪些基因可以改变 DMD 的疾病进展和严重程度。为了证实源自小鼠肌营养不良基因修饰剂的假设，我们最近使用参加联合肌营养不良项目 (UDP) 的患者的数据来证明 LTBP4 基因的多态性影响丧失行走能力的年龄。我们在这个项目中的目标是确定骨骼肌、心脏和通气功能的其他遗传修饰因子，我们的中心假设是可以通过使用 UDP 数据库来识别此类修饰因子，UDP 数据库是一个独特的资源，包含来自 900 多名 DMD 患者的详细表型数据和存档 DNA 样本。我们的具体目标是 1) 更新和分析 UDP 队列中的表型数据，2) 通过高密度单核苷酸多态性阵列绘制修饰性状，3) 对具有极端异常表型的个体进行外显子组测序，4) 验证新识别的假定遗传修饰。这些目标将通过全国儿童医院、犹他大学和加州大学洛杉矶分校的研究人员联盟的综合专业知识和努力来实现。验证假定修饰基因的合作者包括芝加哥大学的研究人员，他们率先在营养不良小鼠模型中发现了修饰基因，以及美国和欧洲的两个研究人员合作网络，他们拥有更多的 DMD 患者自然史队列。在完成这些目标时，我们将获得有关与 DMD 严重程度和进展相关的修饰基因的新信息。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder that affects approximately 1:3500 to 1:5200 live male births caused by mutations in the X-linked DMD gene. DMD gene mutations result in absence of the dystrophin protein in muscle fibers, leading to myofiber necrosis, endomysial fibrosis, and fat replacement. It is a devastating disorder, leading to loss of ambulation by age 12, and historically to death by age 20. The psychological and socioeconomic effects on families are enormous; these include but are not limited to the costs of medical care, opportunity costs for career and work, and the psychological toll taken on parents and siblings. Our long-term goal is to understand which genes modify disease progression and severity of DMD. Confirming a hypothesis derived from a genetic modifier of muscular dystrophies in mice, we have recently used data from patients enrolled in the United Dystrophinopathy Project (UDP) to demonstrate that polymorphisms in the LTBP4 gene influence age at loss of ambulation. Our objective in this project is to identify additional genetic modifiers of skeletal muscle, cardiac, and ventilatory function, and our central hypothesis is that such modifiers can be identified by use of the UDP database, a unique resource that contains detailed phenotypic data and archived DNA samples from over 900 DMD patients. Our specific aims are to 1) update and analyze phenotypic data within the UDP cohort, 2) map modifier traits by high-density single nucleotide polymorphism arrays, 3) perform exome sequencing of individuals with extreme outlier phenotypes, and 4) validate newly identified putative genetic modifiers. These aims will be achieved by the combined expertise and efforts from a consortium of researchers at Nationwide Children's Hospital, the University of Utah and UCLA. Collaborators for validating putative modifier genes include investigators at the University of Chicago who have pioneered modifier gene discovery in dystrophic mouse models, and two collaborating networks of investigators in the US and Europe, who have additional natural history cohorts of DMD patients. At the conclusion of these Aims, we will have gained new information about modifier genes associated with the severity and progression of DMD.