Morisaki H, Morisaki T, Newby L K, Holmes E W
Seymour Gray Molecular Medicine Laboratory, Department of Medicine, University of Pennsylvania, Philadelphia 19104-4283.
J Clin Invest. 1993 May;91(5):2275-80. doi: 10.1172/JCI116455.
Approximately 2% of Caucasians and African-Americans are homozygous for a nonsense mutation in exon 2 of the AMPD1 (AMP deaminase) gene. These individuals have a high grade deficiency of AMPD activity in their skeletal muscle. More than 100 patients with AMPD1 deficiency have been reported to have symptoms of a metabolic myopathy, but it is apparent many individuals with this inherited defect are asymptomatic given the prevalence of this mutant. Results of the present study provide a potential molecular explanation for "correction" of this genetic defect. Alternative splicing eliminates exon 2 in 0.6-2% of AMPD1 mRNA transcripts in adult skeletal muscle. Expression studies document that AMPD1 mRNA, which has exon 2 deleted, encodes a functional AMPD peptide. A much higher percentage of alternatively spliced transcripts are found during differentiation of human myocytes in vitro. Transfection studies with human minigene constructs demonstrate that alternative splicing of the primary transcript of human AMPD1 is controlled by tissue-specific and stage-specific signals. Alternative splicing of exon 2 in individuals who have inherited this defect provides a mechanism for phenotypic rescue and variations in splicing patterns may contribute to the variability in clinical symptoms.
大约2%的白种人和非裔美国人在AMPD1（AMP脱氨酶）基因的第2外显子上存在无义突变的纯合子。这些个体的骨骼肌中AMPD活性严重缺乏。据报道，100多名患有AMPD1缺乏症的患者有代谢性肌病的症状，但鉴于这种突变的普遍性，显然许多有这种遗传缺陷的个体没有症状。本研究结果为这种遗传缺陷的“纠正”提供了一种潜在的分子解释。可变剪接在成年骨骼肌中0.6%-2%的AMPD1 mRNA转录本中消除了第2外显子。表达研究表明，缺失第2外显子的AMPD1 mRNA编码一种功能性的AMPD肽。在人肌细胞体外分化过程中发现可变剪接转录本的比例要高得多。用人微小基因构建体进行的转染研究表明，人AMPD1初级转录本的可变剪接受组织特异性和阶段特异性信号控制。在继承了这种缺陷的个体中，第2外显子的可变剪接为表型挽救提供了一种机制，剪接模式的变化可能导致临床症状的变异性。
