面肩肱型肌营养不良症发病机制的研究进展

Molecular genetics of facioscapulohumeral muscular dystrophy.

面肩肱型肌营养不良症,是一种常染色体显性遗传疾病,至今尚未找到其致病基因。大部分面肩肱型肌营养不良症患者和4q35区域3.3-kb的串联重复序列Z4D4的整倍缺失紧密连锁,几乎所有面肩肱型肌营养不良症患者,Southern杂交片段小于35 kb(少于11个D4Z4重复序列),而正常人群该片段为350 kb(11-150个D4Z4重复序列)。通过分子生物学研究与生物信息学分析,在4q35区域内,排除了FRG1、FRG2、ALP、ANT1、DUX4、YY I、HMGB2及Nu-c lolin等几个可能的候选基因;有关肩肱型肌营养不良症发病机制的位置变异效应假说,需要更多的证据支持;另一假说认为,面肩肱型肌营养不良症患者,D4Z4区域内类似沉默子的序列与转录抑制复合物相结合,由于D4Z4的缺失,该复合物不能形成并导致D4Z4上游基因的过表达,有关基因的过表达通过某种不明机制导致FSHD疾病的发生;D4Z4的缺失使4qter在细胞核内的定位异常,使许多基因的表达不正常,从而引起一系列的病理变化,并最终导致FSHD疾病的发生,也是FSHD发病的可能性机制之一。FSHD的发病相关基因和发病机制的研究有待深入。

Facioscapulohumeral muscular dystrophy （FSHD） is an autosomal dominant neuromuscular disorder involving deletion of an array of tandem 3.3 kb repeats （D4Z4） on chromosome 4q35. This copy - number polymorphic repeat, D4Z4, is present in arrays at both 4q35 and 10q26, linkage studies and Southern blot analyses based on EcoRI and EcoRI/BlnI digestion indicated only 4q35 arrays with one to 10 copies of the repeat are linked to FSHD. The most popular model for how the 4q35 array - shortening causes FSHD is that it results in a loss of postulated D4Z4 heterochromatinization, which spreads proximally, leading to overexpression of several FSHD genes in cis, but two recent studies dispute this, finding neither significant changes in the transcriptional level of any of the 4q35 genes, nor the causative variations of the related regions such as the DBE （D4Z4 binding element）. Current studies up to now suggested that FGR1, FGR2, HMBG2, YY1, ALP, ANT1, DUX4 and YYI are unlikely to represent the genes responsible for FSHD, the molecular mechanism of FSHD remains to be resolved.