Recessive Ttn Truncating Mutations Define Novel Forms of Core Myopathy with Heart Disease

Core myopathies (CM), the main non-dystrophic myopathies in childhood, remain genetically unexplained in many cases. Heart disease is not considered part of the typical CM spectrum. No congenital heart defect has been reported, and childhood-onset cardiomyopathy has been documented in only two CM families with homozygous mutations of the TTN gene. TTN encodes titin, a giant protein of striated muscles. Recently, heterozygous TTN truncating mutations have also been reported as a major cause of dominant dilated cardiomyopathy. However, relatively few TTN mutations and phenotypes are known, and titin pathophysiological role in cardiac and skeletal muscle conditions is incompletely understood. We analyzed a series of 23 families with congenital CM and primary heart disease using TTN M-line-targeted sequencing followed in selected patients by whole-exome sequencing and functional studies. We identified seven novel homozygous or compound heterozygous TTN mutations (five in the M-line, five truncating) in 17 patients. Heterozygous parents were healthy. Phenotype analysis identified four novel titinopathies, including cardiac septal defects, left ventricular non-compaction, EmeryDreifuss muscular dystrophy or arthrogryposis. Additionally, in vitro studies documented the first-reported absence of a functional titin kinase domain in humans, leading to a severe antenatal phenotype. We establish that CM are associated with a large range of heart conditions of which TTN mutations are a major cause, thereby expanding the TTN mutational and phenotypic spectrum. Additionally, our results suggest titin kinase implication in cardiac morphogenesis and demonstrate that heterozygous TTN truncating mutations may not manifest unless associated with a second mutation, reassessing the paradigm of their dominant expression.Wo

Drug addiction

Drug addiction is a pervasive worldwide problem characterized by compulsive drug use that continues despite negative consequences and treatment attempts. Historically, the biological basis of drug addiction has focused principally on neuronal activity. However, despite their pivotal role in the underlying pathology of drug addiction, neurons are not the only central nervous system (CNS) component involved. The role of additional cell types, especially the CNS immunocompetent microglial cells, in the development of tolerance and related neuroplastic changes during drug taking, addiction, and withdrawal is also emerging. Within this perspective, this chapter reviews the roles of microglial cells in several aspects of drug addiction and its behavioural consequences, including reward, tolerance, dependence, and withdrawal. The cellular and molecular mechanisms which are particularly recruited will be emphasized. Lastly, we will also summarize the development of pharmacological modulators of microglial activation that offer novel treatment strategies and highlight the need to better understand the roles of microglia in the context of drug addiction.Xiaohui Wang, Thomas A. Cochran, Mark R. Hutchinson, Hang Yin, and Linda R. Watkin