MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated  serum creatine kinase

• Published in: Brain (London, England : 1878) England : 1878), 2021-10, Vol.144 (9), p.2722-2731
• Main Authors: Lopes Abath Neto, Osorio, Medne, Livija, Donkervoort, Sandra, Rodríguez-García, Maria Elena, Bolduc, Véronique, Hu, Ying, Guadagnin, Eleonora, Foley, A Reghan, Brandsema, John F, Glanzman, Allan M, Tennekoon, Gihan I, Santi, Mariarita, Berger, Justin H, Megeney, Lynn A, Komaki, Hirofumi, Inoue, Michio, Cotrina-Vinagre, Francisco Javier, Hernández-Lain, Aurelio, Martin-Hernández, Elena, Williams, Linford, Borell, Sabine, Schorling, David, Lin, Kimberly, Kolokotronis, Konstantinos, Lichter-Konecki, Uta, Kirschner, Janbernd, Nishino, Ichizo, Banwell, Brenda, Martínez-Azorín, Francisco, Burgon, Patrick G, Bönnemann, Carsten G
• Format: Article
• Language: English
• Subjects: Adolescent; Child; Child, Preschool; Co-Repressor Proteins - genetics; Creatine Kinase - blood; Female; Genetic Variation - genetics; Humans; Male; Muscular Diseases - blood; Muscular Diseases - diagnostic imaging; Muscular Diseases - genetics; Myalgia - blood; Myalgia - diagnostic imaging; Myalgia - genetics; Nuclear Proteins - genetics; Original; Rhabdomyolysis - blood; Rhabdomyolysis - diagnostic imaging; Rhabdomyolysis - genetics; Young Adult
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awab275

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds with biallelic variants in MLIP, which encodes the muscular lamin A/C-interacting protein, MLIP. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. The biallelic truncating variants were predicted to result in disruption of the nuclear localizing signal of MLIP. Additionally, reduced overall RNA expression levels of the predominant MLIP isoform were observed in patients' skeletal muscle. Collectively, our data increase the understanding of the genetic landscape of rhabdomyolysis to now include MLIP as a novel disease gene in humans and solidifies MLIP's role in normal and diseased skeletal muscle homeostasis.