ACTN2 mutations cause “Multiple structured Core Disease” (MsCD)

Abstract

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alphaactinin-2 can cause a skeletal muscle disorder.

Actininopathy: A new muscular dystrophy caused by ACTN2 dominant mutations

“…Nevertheless, ACTN2 mutations have for long time been linked only to various cardiomyopathies such as HCM, DCM, and other cardiac phenotypes . Two sporadic patients with a congenital core myopathy studied at the same time as our families and carrying 2 ACTN2 variants in the 4th spectrin repeat have been just published …”

“…Despite the crucial role of alpha‐actinin‐2 and its interactions with other clinically relevant sarcomeric proteins, no ACTN2 disease‐causing mutations have been identified in patients with familial myopathies. During the preparation of our work, we were aware of 2 sporadic patients with a different congenital progressive core myopathy being studied for ACTN2 …”

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

“…So far, animal models have been mainly used to prove that a novel gene, previously not reported as disease causing, is implicated in the observed disease (gene discovery) and/or to provide information on the pathophysiological mechanisms triggered by the gene mutations [90,91].…”

Cored in the act: the use of models to understand core myopathies

“…Non-ryanodine mutations RYR1 mutations are the major cause of core myopathies and, as such, have been the most widely studied core myopathy mutation in animal models. Nevertheless, MmD is also caused by mutations in SELENON (Ferreiro et al, 2002a;Kazamel and Milone, 2019), MYH7 (Cullup et al, 2012), ACTA1 (Kaindl, 2004), ACTN2 (Lornage et al, 2019), TTN (Chauveau et al, 2014), MEGF10 (Boyden et al, 2012;Takayama et al, 2016), CCDC78 (Kazamel and Milone, 2019) and FXR1 (Estañ et al, 2019) (Box 3), prompting the development of several non-ryanodine core myopathy models.…”

“…Interestingly, CRISPR-generated mice containing the familial mutations, namely Fxr1 delA/delA and Fxr1 delACAG/delACAG , strikingly recapitulate the severity of the human probands. An alternative strategy to model ACTN2-related (Box 1) core myopathy, also called multiple structured core disease, was recently employed by Lornage et al, who transduced zebrafish and murine muscles with mutant p.Leu727Arg Actn2 (Lornage et al, 2019). Within 4 weeks, mice exhibited muscle weakness and structural changes similar to human probands, including abnormal Z-lines and multiple structured cores (Lornage et al, 2019).…”