Genetic modifiers of Duchenne Muscular Dystrophy

描述(申请人提供)：Duchenne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，影响大约1：3500至1：5200的活男婴。DMD基因突变导致肌纤维中肌营养不良蛋白的缺失，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，会导致12岁时失去行走能力，历史上会导致20岁时死亡。这对家庭的心理和社会经济影响是巨大的；这些影响包括但不限于医疗成本、事业和工作的机会成本，以及父母和兄弟姐妹的心理损失。我们的长期目标是了解哪些基因可以改变疾病的进展和DMD的严重程度。我们最近利用联合营养不良项目(UDP)中登记的患者的数据证实了一个假说，该假说来自小鼠肌肉营养不良的遗传修饰物，证明了LTBP4基因的多态影响行走能力丧失的年龄。我们在这个项目中的目标是确定骨骼肌、心脏和呼吸功能的其他遗传修饰物，我们的中心假设是这些修饰物可以通过使用UDP数据库来识别，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定位修饰基因的特征，3)对具有极端异常表型的个体进行外显子测序，4)验证新发现的可能的遗传修饰基因。这些目标将通过国家儿童医院、犹他大学和加州大学洛杉矶分校的研究人员联盟的专业知识和努力来实现。确认假定的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的小鼠模型中发现了修饰基因，以及美国和欧洲的两个合作研究网络，他们有更多的DMD患者的自然病史队列。在这些目标的总结下，我们将获得与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.