Molecular pathophysiology of facioscapulohumeral muscul*

描述（由申请人提供）：面肩肱型肌营养不良症 FSHD是继Duchenne病之后最常见的遗传性肌肉疾病之一 肌营养不良和肌强直性营养不良。这种疾病是常染色体显性遗传的 到20岁时几乎完全昏迷（95%）。肌肉受累的严重程度 在FSHD是非常可变的，从老年人与轻度 对坐轮椅的孩子们来说是一个很大的挑战。除了变量之间 在个别患者中，FSHD患者经常表现出神秘的肌肉不对称 参与。这种疾病特征允许一种新颖的实验设计，其中 疾病的进展可以在单个患者中在单个时间点进行研究。 时间点。先前的研究显示， 临床表现的严重程度与D4 Z4重复缺失之间的关系， FSHD患者的染色体4 q35。目前的假设集中在一个位置 然而，端粒序列对缺失位点内或附近基因的影响 这种疾病背后的分子机制还远不清楚。在我们 研究中，我们假设FSHD患者肌肉显示疾病特异性 表达谱，相对于其他肌肉疾病（Duchenne muscle 营养不良、α-肌聚糖缺乏症、青少年皮肌炎，以及 dysferlin缺乏）。此外，我们假设，一个人可以识别一个 FSHD特异性基因的子集将显示与进展相关 通过比较FSHD肌肉中的肌肉参与的表达变化， 单一营养不良中临床受累肌肉与未受累肌肉 患者在我们的初步数据中，我们已经定义了一个FSHD特定的29 作为主要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 扩大研究的基因数量，这样一组全基因组的基因， 与原发病因有关的疾病。具体来说，我们将扩大 我们真正有希望的初步数据超过60，000个基因和EST序列 包括在人类基因组U95 A、B、C、D、E储备芯片上，以及> 我们定制的肌肉芯片上有2,000个人类肌肉EST。另外还有按 由来自4 q35和10 q26的约200个基因和EST组成的定制载玻片阵列 将用于鉴定基因表达中的FSHD区域特异性改变。 将对所有鉴定的FHSD-specific EST进行详细表征。进一步 研究将可能包括描绘一个完整的图片， FSHD的病理生理学，以及FSHD中功能性SNP的鉴定。 与疾病严重程度相关的精确基因列表。

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.