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麦克尔病患者肌肉糖原磷酸化酶基因的表达:无义介导的mRNA降解的作用

Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay.

作者信息

Nogales-Gadea Gisela, Rubio Juan Carlos, Fernandez-Cadenas Israel, Garcia-Consuegra Ines, Lucia Alejandro, Cabello Ana, Garcia-Arumi Elena, Arenas Joaquin, Andreu Antoni L, Martín Miguel A

机构信息

Departament de Patologia Mitocondrial i Neuromuscular, Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

出版信息

Hum Mutat. 2008 Feb;29(2):277-83. doi: 10.1002/humu.20649.

Abstract

Nearly 35% of all mutations identified in the muscle glycogen phosphorylase gene (PYGM) in patients with McArdle disease result in premature termination codons (PTCs), particularly the p.R50X mutation. The latter accounts for more than 50% of the mutated alleles in most Caucasian patient populations. Mutations resulting in PTC could trigger the degradation of mRNA through a mechanism known as nonsense mediated decay (NMD). To investigate if NMD affects the levels of transcripts containing PYGM mutations, 28 Spanish patients with McArdle disease, harboring 17 different mutations with PTCs in 77% of their alleles, were studied. Transcripts levels of PYGM were measured and sequenced. We assessed that 92% of patients showed NMD. The most frequent mutation (p.R50X) elicited decay in all the genotypes tested. Other PTC producing mutations resulting in NMD were: p.L5VfsX22, p.Q73HfsX7, p.E125X, p.N134KfsX161, p.W388SfsX34, p.R491AfsX7, and p.D534VfsX5. Located in the last exon, the mutation p.E797VfsX19 was not affected by NMD. Missense mutations did not appear to be affected by NMD. In the cDNA sequences they appeared as homozygous, despite being heterozygous in the genomic DNA sequences. Exceptions to the rules governing NMD were found in the mutations p.A704 V and p.K754NfsX49.

摘要

在麦克尔病患者的肌肉糖原磷酸化酶基因(PYGM)中鉴定出的所有突变中,近35%会导致过早终止密码子(PTC),尤其是p.R50X突变。在大多数白种人患者群体中,后者占突变等位基因的比例超过50%。导致PTC的突变可通过一种称为无义介导衰变(NMD)的机制触发mRNA的降解。为了研究NMD是否影响含有PYGM突变的转录本水平,我们对28名西班牙麦克尔病患者进行了研究,这些患者携带17种不同的突变,其等位基因中有77%带有PTC。对PYGM的转录本水平进行了测量和测序。我们评估发现92%的患者表现出NMD。最常见的突变(p.R50X)在所有测试的基因型中均引发衰变。导致NMD的其他产生PTC的突变有:p.L5VfsX22、p.Q73HfsX7、p.E125X、p.N134KfsX161、p.W388SfsX34、p.R491AfsX7和p.D534VfsX5。位于最后一个外显子的p.E797VfsX19突变不受NMD影响。错义突变似乎不受NMD影响。在cDNA序列中,它们表现为纯合子,尽管在基因组DNA序列中是杂合子。在p.A704 V和p.K754NfsX49突变中发现了NMD规则的例外情况。

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