Very low penetrance in 85 Japanese families with facioscapulohumeral muscular dystrophy 1A
Very low penetrance in 85 Japanese families with facioscapulohumeral muscular dystrophy 1A
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DOI：
10.1136/jmg.2003.008755
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发表时间：
2004-01-01
影响因子：
4
通讯作者：
Hayashi, YK
中科院分区：
文献类型：
--
作者：
Goto, K;Nishino, I;Hayashi, YK
面肩肱型肌营养不良症（FSHD）是第三常见的肌肉疾病，具有常染色体显性遗传特征，其发生率约为2万分之一。其特征是面部、肩带和上肢肌肉的虚弱和萎缩。骨盆带和下肢也随之受累，最终，20%的患者在40岁时不得不使用轮椅。1大多数患者在儿童晚期或青春期出现临床症状，尽管疾病的发作及其临床严重程度是异质性的。通过遗传连锁分析将FSHD定位于第4号染色体长臂的亚端粒区。2-4用探针p13 E-11（FSHD 1A; MIM 158900）进行Southern印迹分析，超过95%的FSHD患者在染色体4 q35上有一个小的（35 kb）EcoRI片段。5-8该EcoRI片段含有3.3kb Kpn I单元（D4 Z4）的串联重复。在健康人中，D4 Z4重复的数量从11到150不等，尽管FSHD 1A患者的数量少于11。虽然在FSHD区域内没有分离出相关基因，但D4 Z4重复序列的数量是疾病发病年龄和临床严重程度的关键决定因素。一般来说，1-3个D4 Z4重复与儿童期出现的严重形式的疾病相关，4-7个重复与最常见形式的FSHD相关，8-10个重复与较轻的疾病和降低的发病率相关。8-12探针p13 E-11与染色体10 q26交叉杂交，该染色体含有高度同源的3.3kb Kpn I重复单位。由于BlnI限制性酶切位点仅存在于源自10 q26的每个单元中，而不存在于D4 Z4（源自4 q35的单元）中，因此用EcoRI和BlnI的双酶消化可以区分4 q35（BlnI抗性）片段和10 q26（BlnI敏感）片段。[13]高度同源的结构意味着4号和10号染色体之间的亚端粒染色体间易位经常发生（约20-30%的人），并被认为有助于染色体4 q35上Kpn I重复序列的缺失。[14-16]然而，健康人和FSHD患者之间的易位频率没有显著差异。17
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular disorder with an autosomal dominant trait, and its frequency is about one in 20 000. It is characterised by weakness and atrophy of the facial, shoulder girdle, and upper limb muscles. The pelvic girdle and lower limbs subsequently also become involved, and, eventually, 20% of patients have to use wheelchairs by the age of 40 years. 1 Most patients develop clinical symptoms in late childhood or adolescence, although the onset of the disease and its clinical severity are heterogeneous. The FSHD locus was mapped to the subtelomeric region of the long arm of chromosome 4 by genetic linkage analysis. 2–4 More than 95% of patients with FSHD had a small (, 35 kb) EcoRI fragment on chromosome 4q35 on southern blotting analysis with the probe p13E-11 (FSHD1A; MIM 158900). 5–8 This EcoRI fragment contains tandem repeats of the 3.3 kb KpnI unit (D4Z4). The number of D4Z4 repeats varies from 11 to 150 in healthy people, although the number is fewer than 11 in patients with FSHD1A. 6 8 Although no responsible gene has been isolated within the FSHD region, the number of D4Z4 repeats is a critical determinant of the age of onset and clinical severity of the disease. In general, 1–3 D4Z4 repeats are associated with a severe form of the disease that presents in childhood, 4–7 repeats with the most common form of FSHD, and 8–10 repeats with a milder disease and reduced penetrance. 8–12Probe p13E-11 crosshybridises with chromosome 10q26, which contains highly homologous 3.3 kb KpnI repeated units. As the BlnI restriction enzyme site exists exclusively within each unit derived from 10q26, but not in D4Z4 (a unit from 4q35), double enzyme digestion with EcoRI and BlnI can discriminate between the 4q35 (BlnI resistant) fragments and 10q26 (BlnI sensitive) fragments. 13 The highly homologous structure means that the subtelomeric interchromosomal translocation between chromosomes 4 and 10 occurs often (in about 20–30% of people) and has been suggested to contribute to deletion of KpnI repeats on chromosome 4q35. 14–16 The frequency of translocation, however, was not significantly different between healthy people and those with FSHD. 17