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

Abstract

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.

Biallelic truncating variants in the muscular A‐type lamin‐interacting protein (MLIP) gene cause myopathy with hyperCKemia

“…Cardiac muscle involvement is consistent with findings from previous studies that demonstrated the role of MLIP as a negative regulator of cardiac hypertrophy and cardiomyopathy in mice [8,9] and the impaired cardiac adaptation to stress in Mlip knockout mice [10] Further experiments and investigation are needed to elucidate potential correlations between tissue and isoform expression, as well as age-related expressivity of the phenotype in MLIP-associated disease. [7] reported this gene-disease association, corroborated by our findings. Recent in vitro and in vivo studies suggest a regulatory role of MLIP in myoblast differentiation [14] as well as in the organization of myonuclear positioning in skeletal muscle [15] and as previously mentioned, in cardiomyocyte adaptation and cardiomyopathy [8][9][10].…”

“…Mild proximal muscle weakness was reported in five of them, whereas the other two had normal strength on examination. Mild left ventricular dysfunction on echocardiogram was noted in one of these children, and the others were reported to have no clinically significant cardiac involvement [7].…”

“…It is possible that the skeletal muscle phenotype is more severe and noticeable in children, whereas in adults muscle pain may be uncommon or less severe and therefore less of a concern, but cardiac muscle involvement may be a later onset manifestation of MLIP ‐associated disease and worsen with age. Nevertheless, the single case of a child with mild left ventricular dysfunction reported by Lopes Abath Neto et al [7] suggests that cardiac involvement may variably manifest at an earlier age. Cardiac muscle involvement is consistent with findings from previous studies that demonstrated the role of MLIP as a negative regulator of cardiac hypertrophy and cardiomyopathy in mice [8,9] and the impaired cardiac adaptation to stress in Mlip knockout mice [10] Further experiments and investigation are needed to elucidate potential correlations between tissue and isoform expression, as well as age‐related expressivity of the phenotype in MLIP ‐associated disease.…”

“…MLIP colocalizes and interacts with lamins A/C, alternately spliced products of the LMNA gene, in the nuclear envelope, and as previously mentioned, is most abundantly expressed in skeletal and cardiac muscle [11,12]. Pathogenic LMNA variants result in a wide range of inherited diseases known as laminopathies, including several cardiac and skeletal muscle disorders (MIM*150330) [13] MLIP , however, has not been shown to be associated with disease in humans until only very recently, when Lopes Abath Neto et al [7] reported this gene–disease association, corroborated by our findings. Recent in vitro and in vivo studies suggest a regulatory role of MLIP in myoblast differentiation [14] as well as in the organization of myonuclear positioning in skeletal muscle [15] and as previously mentioned, in cardiomyocyte adaptation and cardiomyopathy [8–10].…”

Cardiac ISL1-Interacting Protein, a Cardioprotective Factor, Inhibits the Transition From Cardiac Hypertrophy to Heart Failure

“…An exonic mutation of CIP gene was reported to associate with human dilated cardiomyopathy ( 16 ). Recently, loss-of-function of CIP induced by DNA mutations was demonstrated to cause myopathy with hyperCKemia in human ( 20 , 21 ). CIP is specifically expressed in cardiomyocyte in the heart, but the regulatory mechanism of CIP’s expression remains unclear.…”