Epigenetic Modifiers of D4Z4 in Facioscapulohumeral Muscular Dystrophy (FSHD)

描述（由申请人提供）：面肩肱骨肌营养不良症（FSHD）是一种成人发病的肌病，伴有表观遗传改变，最常见的是由于4号染色体上排列的3.3 kb D4Z4单位数量减少到少于11个单位。收缩诱导的表观遗传图谱导致正常情况下被抑制的DUX4逆转录基因的转录，并产生肌病变化，当允许的D4Z4单倍型阵列发生收缩时表现为肌肉无力。尽管D4Z4序列长度大于10个单位阈值，但仍有5%的FSHD患者会发展为FSHD，因此这种机制发生的FSHD被称为FSHD2或非收缩性FSHD。FSHD2个体的D4Z4序列表现出与更常见的机制相似的表观遗传去抑制，但染色质变化延伸到10号染色体上的类似阵列，以及4号染色体上的另一个等位基因，这表明可能通过参与大卫星重复序列表观遗传修饰的基因的活性发生收缩非依赖性阵列去抑制。我们对受fshd2影响的个体及其未受影响的家庭成员进行了外显子组测序，以确定其中一个位点。在受fshd2影响的个体中，61%的罕见变异与4号染色体上的受纳单倍型独立分离，只有当受纳单倍型和基因变异同时存在于同一个体时才会导致FSHD。与我们的假设一致，该基因蛋白水平的降低导致未受影响个体的正常人成肌细胞中D4Z4阵列去抑制和DUX4表达。在这里，我们建议确定D4Z4大卫星重复序列中这些表观遗传变化的背景和时间，并评估具有相似活性的基因对FSHD1或FSHD2个体DUX4转录的影响。通过这种方法，我们希望能够解释诸如非外显性、可变表达性和肌肉无力的不对称分布等疾病现象，并确定可能的药物干预的基因靶点。

DESCRIPTION (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) is an adult onset myopathy with epigenetic changes that most commonly occur as a consequence of reduction in the number of 3.3 kb D4Z4 units arrayed on chromosome 4 to less than 11 units. The contraction-induced epigenetic profile results in transcription of the normally repressed DUX4 retrogene and produces myopathic changes that manifest as muscle weakness when contractions occur on arrays with permissive D4Z4 haplotypes. Five percent of FSHD-affected individuals develop FHSD despite having D4Z4 array lengths greater than the 10 unit threshold so FSHD occurring by this mechanism has been called FSHD2 or contraction-independent FSHD. D4Z4 arrays of individuals with FSHD2 show epigenetic de-repression similar to that seen by the more common mechanism but chromatin changes extend to similar arrays on chromosome 10, and the other chromosome 4 allele suggesting that contraction-independent array-derepression may occur through the activity of genes involved in epigenetic modification of macrosatellite repeats. We performed exome sequencing of FSHD2-affected individuals and their unaffected family members to identify one of these loci. Rare variants present in 61% of FSHD2-affected individuals segregated independently of permissive haplotypes on chromosome 4 and only resulted in FSHD when a permissive haplotype and gene variant were present in the same individual. Consistent with our hypothesis, reduction of protein levels from this gene results in D4Z4 array de-repression and DUX4 expression in normal human myoblasts from unaffected individuals. Here we propose to determine the context and timing of these epigenetic changes at D4Z4 macrosatellite repeats, and assess the effect of genes with similar activities on DUX4 transcription in individuals with either FSHD1 or FSHD2. Using this approach we hope to explain disease phenomena such as non-penetrance, variable expressivity, and asymmetric distributions of muscle weakness as well as identify gene targets for possible pharmacological intervention.