Molecular pathophysiology of facioscapulohumeral muscul*

描述(申请人提供)：面部肩周型肌营养不良症 (FSHD)是继Duchenne之后最常见的遗传性肌肉疾病之一 肌营养不良和强直性肌营养不良。这种疾病是常染色体显性遗传的 到20岁时几乎完全外显(95%)。肌肉受累的严重程度 在FSHD中的变化极大，从患有轻度FSHD的老年人 坐轮椅的孩子脸部虚弱。除了可变性之外， 个别患者，FSHD患者通常表现为神秘的肌肉不对称 参与其中。这种疾病特征允许一种新的实验设计，其中 疾病的进展可以在单个患者体内进行研究。 时间点。以前的研究表明，在统计上有显著的相关性 临床表现的严重性与D4Z4重复序列缺失之间的关系 FSHD患者的4q35号染色体。当前的假设集中在一个位置上 然而，端粒序列对缺失位点上或附近基因的影响 这种疾病背后的分子机制还远不清楚。在我们的 研究中，我们假设FSHD患者的肌肉表现出一种疾病特异性 相对于其他肌肉疾病的表达情况(Duchenne肌肉疾病 营养不良、α-肌聚糖缺乏、幼年性皮肌炎和 脱铁蛋白缺乏)。此外，我们假设一个人可以识别出一个 FSHD特异性基因的子集将被证明与疾病进展相关 比较FSHD肌肉相关表达变化对肌肉受累的影响 在单个营养不良中，临床上受影响的肌肉与未受影响的肌肉 病人。在我们的初步数据中，我们定义了29个特定于FSHD的集合 参与疾病发病机制的候选基因 使用HuGeneFL阵列(-6,000个全长基因)。在这份提案中，我们计划 为了扩大研究的基因数量，以便全基因组的一组基因 与原发病因学有关的可以定义。具体来说，我们将延长 我们真正有希望的60,000多个基因和EST序列的初步数据 包括在人类基因组U95A、B、C、D、E股票芯片上，以及&gt； 我们定制的肌肉芯片上有2000条人类肌肉EST。此外，a 由来自4q35和10q26的-200个基因和EST组成的定制玻片阵列 将用于识别基因表达中FSHD区域的特异性变化。 所有确定的FHSD特定EST将被详细描述。进一步 研究可能包括描绘一幅完整的 FSHD的病理生理机制以及功能性SNPs的鉴定 与疾病严重程度相关的精炼基因列表。

DESCRIPTION (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited muscle diseases following Duchenne muscular dystrophy and myotonic dystrophy. The disorder is autosomal dominant with nearly complete penetrance (95%) by age 20. Severity of muscle involvement in FSHD is extremely variable, ranging from elderly individuals with mild facial weakness to wheelchair bound children. Besides variability between individual patients, FSHD patients often show enigmatic asymmetry of muscle involvement. This disease feature permits a novel experimental design, where progression of the disease can be studied within a single patient at a single time point. Previous studies showed a statistically significant correlation between severity of clinical presentation and the deletion of D4Z4 repeats on chromosome 4q35 in patients with FSHD. Current hypotheses center on a position effect of telomeric sequences on genes in or near the deletion site, however the molecular mechanisms underlying this disease are far from clear. In our study, we hypothesize that FSHD patient muscle shows a disease-specific expression profile, relative to other muscle disease (Duchenne muscular dystrophy, alpha-sarcoglycan deficiency, juvenile dermatomyositis, and dysferlin deficiency). In addition, we hypothesize that one can identify a subset of the FSHD-specific genes will be shown to correlate with progression of-muscle involvement in FSHD muscle by comparing expression changes correlated with clinically-affected vs. unaffected muscles within single dystrophy patients. In our preliminary data, we have defined an FSHD-specific set of 29 genes that are candidates for primary involvement of disease pathogenesis by using the HuGeneFL array (-6,000 full length genes). In this proposal, we plan to broaden the number of genes studied, so that a genome-wide set of genes implicated in the primary etiology can be defined. Specifically, we will extend our truly promising preliminary data to over 60,000 genes and EST sequences included on the Human genome U95A, B, C, D, E stock chips, as well as the > 2,000 human muscle ESTs on our custom-produced MuscleChip. In addition, a custom glass slide array consisting of - 200 genes and ESTs from 4q35 and lOq26 will be used to identify FSHD region specific alterations in gene expression. All FHSD-specific ESTs identified will be characterized in detail. Further studies will likely include the delineation of a complete picture of the pathophysiology of FSHD, as well as identification of functional SNPs in the refined gene list that correlate with disease severity.