Ginjaar I B, Kneppers A L, v d Meulen J D, Anderson L V, Bremmer-Bout M, van Deutekom J C, Weegenaar J, den Dunnen J T, Bakker E
Department of Human and Clinical Genetics, Leiden University Medical Center, The Netherlands.
Eur J Hum Genet. 2000 Oct;8(10):793-6. doi: 10.1038/sj.ejhg.5200535.
Within one X-linked muscular dystrophy family, different phenotypes for three males occurred: (1) a severely affected Becker patient with cardiomyopathy, (2) a mildly affected Becker patient, and (3) an apparently healthy male with elevated serum CK levels. In the muscle biopsy specimen of patient2 one out of four antibodies (NCL-DYS1) showed absence of dystrophin. The protein truncation test detected a truncated dystrophin for both muscle tissue and lymphocytes of this patient next to an additional near normal size fragment in muscle. Genomic sequence analysis revealed a nonsense mutation in exon 29 (4148C > T) of the dystrophin gene. Sequence analysis of the mRNA fragment of the larger peptide showed skipping of exon 29, restoring an open reading frame. Consequently, the epitope of the antibody NCL-DYS1 is mapped to exon 29. The variable clinical features of the three relatives from healthy to severely affected therefore seems to be related to the level of skipping of exon 29. This finding underscores the future potential of gene therapeutic strategies aimed at inducing exon skipping in Duchenne muscular dystrophy, to generate a much milder disease.
在一个X连锁肌营养不良家族中，三名男性出现了不同的表型：（1）一名患有心肌病的严重受累的贝克型患者；（2）一名轻度受累的贝克型患者；（3）一名血清肌酸激酶（CK）水平升高但表面健康的男性。在患者2的肌肉活检标本中，四种抗体中的一种（NCL-DYS1）显示肌营养不良蛋白缺失。蛋白质截短试验在该患者的肌肉组织和淋巴细胞中均检测到截短的肌营养不良蛋白，同时在肌肉中还检测到一个接近正常大小的额外片段。基因组序列分析显示肌营养不良蛋白基因第29外显子存在无义突变（4148C>T）。对较大肽段的mRNA片段进行序列分析发现第29外显子跳跃，恢复了开放阅读框。因此，抗体NCL-DYS1的表位定位于第29外显子。这三名亲属从健康到严重受累的不同临床特征似乎与第29外显子的跳跃水平有关。这一发现强调了旨在诱导杜氏肌营养不良症中外显子跳跃以产生症状轻得多的疾病的基因治疗策略的未来潜力。
