A unifying genetic model for facioscapulohumeral muscular dystrophy.
A unifying genetic model for facioscapulohumeral muscular dystrophy.
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DOI：
10.1126/science.1189044
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发表时间：
2010-09-24
期刊：
影响因子：
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通讯作者：
van der Maarel SM
中科院分区：
文献类型：
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作者：
Lemmers RJ;van der Vliet PJ;Klooster R;Sacconi S;Camaño P;Dauwerse JG;Snider L;Straasheijm KR;van Ommen GJ;Padberg GW;Miller DG;Tapscott SJ;Tawil R;Frants RR;van der Maarel SM
面肩肱型肌营养不良症（FSHD）是成人肌营养不良症的一种常见形式，其主要特征是上半身肌肉的进行性消耗。FSHD与染色体4q35上的D4Z4大卫星重复的收缩相关，但这种收缩仅在某些“允许的”染色体背景中是致病的。在这里，我们表明，FSHD患者携带特定的单核苷酸多态性（SNP）的染色体区域远端的最后D4Z4重复。这种FSHD易感配置创建了一个典型的多聚腺苷酸化信号的转录衍生自DUX4，一个双同源框基因的未知功能，跨越最后的重复单元和相邻的序列。转染研究表明，DUX4转录本是有效的聚腺苷酸化，更稳定时，从允许的染色体表达。这些发现表明FSHD是通过归因于稳定的远端DUX4转录物的毒性功能获得而产生的。
Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35 but this contraction is pathogenic only in certain “permissive” chromosomal backgrounds. Here we show that FSHD patients carry specific single nucleotide polymorphisms (SNPs) in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.