机构：[1]Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China[2]Huashan Rare Disease Center, Shanghai Medical College, Huashan Hospital, Fudan University, Shanghai, China[3]National Center for Neurological Disorders (NCND), Shanghai, China[4]State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China[5]Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China[6]The First People's Hospital of Yunnan Province, Kunming, China云南省第一人民医院[7]Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China[8]Jinshan Hospital Center for Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China[9]The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, The Institutes of Brain Science, Shanghai, China[10]Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China[11]Department of Anesthesiology, Zhongshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China[12]Department of Neurology, Jing'an District Center Hospital of Shanghai, Shanghai, China
Introduction/Aims: GNE myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway. Although over 300 GNE variants have been reported, some patients remain undiagnosed with monoallelic pathogenic variants. This study aims to analyze the entire GNE genomic region to identify novel pathogenic variants. Methods: Patients with clinically compatible GNE myopathy and monoallelic pathogenic variants in the GNE gene were enrolled. The other GNE pathogenic variant was verified using comprehensive methods including exon 2 quantitative polymerase chain reaction and nanopore long-read single-molecule sequencing (LRS). Results: A deep intronic GNE variant, c.862+870C>T, was identified in nine patients from eight unrelated families. This variant generates a cryptic splice site, resulting in the activation of a novel pseudoexon between exons 5 and 6. It results in the insertion of an extra 146 nucleotides into the messenger RNA (mRNA), which is predicted to result in a truncated human GNE1 (hGNE1) protein. Peanut agglutinin (PNA) lectin staining of muscle tissues showed reduced sialylation of mucin O-glycans on sarcolemmal glycoproteins. Notably, a third of patients with the c.862+870C>T variant exhibited thrombocytopenia. A common core haplotype harboring the deep intronic GNE variant was found in all these patients. Discussion: The transcript with pseudoexon activation potentially affects sialic acid biosynthesis via nonsense-mediated mRNA decay, or resulting in a truncated hGNE1 protein, which interferes with normal enzyme function. LRS is expected to be more frequently incorporated in genetic analysis given its efficacy in detecting hard-to-find pathogenic variants.
基金：
National Natural Science Foundation of China,
Grant/Award Numbers: 82171398, 82271437;
Science and Technology Commission of
Shanghai Municipality, Grant/Award Number:
20S31904200; Fudan University Brain Science
Interdisciplinary Integration Exploration
Project
第一作者机构：[1]Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China[2]Huashan Rare Disease Center, Shanghai Medical College, Huashan Hospital, Fudan University, Shanghai, China[3]National Center for Neurological Disorders (NCND), Shanghai, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China[2]Huashan Rare Disease Center, Shanghai Medical College, Huashan Hospital, Fudan University, Shanghai, China[3]National Center for Neurological Disorders (NCND), Shanghai, China[12]Department of Neurology, Jing'an District Center Hospital of Shanghai, Shanghai, China[*1]Department of Neurology,Huashan Hospital, Fudan University,12 Middle Wulumuqi Road, Shanghai 200040,China[*2]Department of Neurology,Jing'an District Center Hospital of Shanghai,Shanghai, China
推荐引用方式(GB/T 7714)：
Jiao Kexin,Cheng Nachuan,Huan Xiao,et al.Pseudoexon activation by deep intronic variation in GNE myopathy with thrombocytopenia[J].MUSCLE & NERVE.2024,69(6):708-718.doi:10.1002/mus.28092.
APA：
Jiao, Kexin,Cheng, Nachuan,Huan, Xiao,Zhang, Jialong,Ding, Yu...&Zhu, Wenhua.(2024).Pseudoexon activation by deep intronic variation in GNE myopathy with thrombocytopenia.MUSCLE & NERVE,69,(6)
MLA：
Jiao, Kexin,et al."Pseudoexon activation by deep intronic variation in GNE myopathy with thrombocytopenia".MUSCLE & NERVE 69..6(2024):708-718
