Unidad de Oncogenética Molecular, Instituto de Genética Médica y Molecular (INGEMM), Edificio Quirúrgico Planta-2, Hospital Universitario La Paz, 28046 Madrid, Spain.
Unidad de Oncogenética Molecular, Instituto de Genética Médica y Molecular (INGEMM), Edificio Quirúrgico Planta-2, Hospital Universitario La Paz, 28046 Madrid, Spain; Institute of Cardiovascular Science, Faculty of Population Health, University College London, London WC1E 6BT, UK.
Neuromuscul Disord. 2019 Mar;29(3):187-191. doi: 10.1016/j.nmd.2018.12.003. Epub 2018 Dec 15.
Glycogen storage disease type II, or Pompe disease, is an autosomal recessive disorder caused by deficiency of lysosomal acid alpha-glucosidase (GAA). We performed genetic analysis to confirm the diagnosis of Pompe disease in a 61-year-old patient with progressive weakness in extremities, severe Sleep Apnea-Hypopnea Syndrome, a significant reduction of alpha-glucosidase in liquid sample of peripheral blood and muscular biopsy diagnosis. GAA gene sequencing showed the patient is homozygous for the splice-site mutation c.1194+5G>A, considered as nonpathogenic in Pompe Center mutation database. Further molecular RNA characterization of GAA transcripts allowed us to identify abnormal processing of pre-mRNA, leading to aberrant transcripts and a significant reduction of GAA mRNA levels. Our results indicate that c.1194+5G>A is a pathogenic splice-site mutation and should be considered as such for diagnostic purposes. This study emphasizes the potential role of functional studies to determine the consequences of mutations with no evident pathogenicity.
糖原贮积病 II 型，又称庞贝病，是一种常染色体隐性遗传病，由溶酶体酸性α-葡萄糖苷酶（GAA）缺乏引起。我们对一位 61 岁的四肢进行性无力、严重睡眠呼吸暂停低通气综合征、外周血液体样本中α-葡萄糖苷酶显著降低和肌肉活检诊断的患者进行了基因分析，以确认庞贝病的诊断。GAA 基因测序显示患者为剪接位点突变 c.1194+5G>A 的纯合子，在庞贝病基因突变数据库中被认为是非致病性的。进一步对 GAA 转录物的分子 RNA 特征分析，我们发现前体 mRNA 的异常加工，导致异常转录本和 GAA mRNA 水平的显著降低。我们的结果表明，c.1194+5G>A 是一种致病性剪接位点突变，应将其视为诊断目的的致病性突变。本研究强调了功能研究在确定无明显致病性突变后果方面的潜在作用。
