英国纽卡斯尔大学Volker Straub研究组在研究中取得进展。他们发现肌肉特异性蛋白激酶和肌联蛋白双基因突变可导致骨骼肌肌病。2024年3月1日出版的《自然-遗传学》发表了这项成果。

研究人员发现SRPK3（编码X连锁丝氨酸/精氨酸蛋白激酶3）中的预测致病变体，只有在与TTN基因中的杂合变体结合时才会导致进行性早发骨骼肌肌病。在76,702名健康男性个体中，未发现SRPK3/TTN有害突变的同时出现，统计建模也支持双基因遗传为最佳拟合模型。

此外，斑马鱼双突变个体（srpk3^-/-; ttn.1^+/-）重新了肌病表型，并表现出肌纤维紊乱。转录组数据表明，斑马鱼体内srpk3和ttn.1的相互作用发生在转录后水平。该研究认为，同时影响蛋白激酶SRPK3和肌联蛋白titin的二基因遗传突变会导致骨骼肌病，其可作为其他遗传疾病的模型。

研究人员表示，在双基因遗传中，两个基因中的致病变体必须同时遗传才会致病。在神经肌肉疾病领域，只发现了极少数双基因遗传病。

附：英文原文

Title: Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Author: Tpf, Ana, Cox, Dan, Zaharieva, Irina T., Di Leo, Valeria, Sarparanta, Jaakko, Jonson, Per Harald, Sealy, Ian M., Smolnikov, Andrei, White, Richard J., Vihola, Anna, Savarese, Marco, Merteroglu, Munise, Wali, Neha, Laricchia, Kristen M., Venturini, Cristina, Vroling, Bas, Stenton, Sarah L., Cummings, Beryl B., Harris, Elizabeth, Marini-Bettolo, Chiara, Diaz-Manera, Jordi, Henderson, Matt, Barresi, Rita, Duff, Jennifer, England, Eleina M., Patrick, Jane, Al-Husayni, Sundos, Biancalana, Valerie, Beggs, Alan H., Bodi, Istvan, Bommireddipalli, Shobhana, Bnnemann, Carsten G., Cairns, Anita, Chiew, Mei-Ting, Claeys, Kristl G., Cooper, Sandra T., Davis, Mark R., Donkervoort, Sandra, Erasmus, Corrie E., Fassad, Mahmoud R., Genetti, Casie A., Grosmann, Carla, Jungbluth, Heinz, Kamsteeg, Erik-Jan, Lornage, Xavire, Lscher, Wolfgang N., Malfatti, Edoardo, Manzur, Adnan, Mart, Pilar, Mongini, Tiziana E., Muelas, Nuria, Nishikawa, Atsuko, ODonnell-Luria, Anne, Ogonuki, Narumi, OGrady, Gina L., OHeir, Emily, Paquay, Stphanie, Phadke, Rahul, Pletcher, Beth A., Romero, Norma B., Schouten, Meyke, Shah, Snehal, Smuts, Izelle, Sznajer, Yves, Tasca, Giorgio

Issue&Volume: 2024-03-01

Abstract: In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3/; ttn.1+/) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

DOI: 10.1038/s41588-023-01651-0

Source: https://www.nature.com/articles/s41588-023-01651-0