Journal of Human Genetics最新文献

Skeletal muscle channelopathies are genetic disorders associated with variants in genes encoding ion channels and related proteins expressed in skeletal muscle. Most commonly, these involve genes encoding voltage-gated ion channels (VGICs) that regulate sarcolemmal excitability, including CLCN1 for ClC-1, SCN4A for the Nav1.4 α subunit, CACNA1S for the Cav1.1 α subunit, and KCNJ2 for Kir2.1. Skeletal muscle channelopathies primarily manifest with two clinical symptoms: myotonia, characterized by delayed muscle relaxation, and paralysis and classified into two disease types: non-dystrophic myotonia and periodic paralysis. Recent advances in the clinical application of next-generation sequencing have improved diagnostic rate and provided epidemiological evidence of the diseases. Furthermore, atypical phenotypes have been identified, indicating that skeletal muscle channelopathies present a broad clinical spectrum. This review provides an updated overview of the clinical and genetic aspects of skeletal muscle channelopathies and discusses key issues that require further investigation.

The cell surface is covered with a variety of glycan subtypes (sub-glycans) such as N-glycans, O-glycans, glycosphingolipid-glycans, and glycosaminoglycans, which are collectively called the glycocalyx. The expression patterns of sub-glycans change in response to various biological events during disease pathogenesis; however, the structures of all major sub-glycans and their relative concentrations in a cell have been hardly reported. Total glycomic analysis, which comprehensively measures all major sub-glycans, is a powerful tool to discover cellular and clinical biomarkers. In this review, we provide an overview of the analytical methods for sub-glycans and the total glycome in cultured cell lines, human serum, mouse brain tissue, and human osteoarthritis cartilage. This approach not only facilitates characterization of cells, but also has applications for hierarchical clustering analysis, glycan-related biomarker discovery, and investigation of the relationship between sub-glycans and gene expression levels using the total glycome. Moreover, we discuss our recent research focused on identifying potential biomarkers of nonalcoholic fatty liver disease. These glycomic technologies are expected to contribute to diagnostics and drug development for rare diseases in the future.

Glycosphingolipids comprise a hydrophobic ceramide backbone, consisting of a long-chain base (sphingosine) and a fatty acid, conjugated with a hydrophilic oligosaccharide moiety. These amphipathic molecules are integral constituents of cellular membranes, playing pivotal roles in modulating membrane protein functionality and receptor-mediated signaling. Among glycosphingolipids, gangliosides, defined by their inclusion of sialic acid residues, are abundantly enriched in the central nervous system. Notably, four predominant species, GM1, GD1a, GD1b, and GT1b, constitute the majority of gangliosides in the mammalian brain and are indispensable for neuronal development, synaptic architecture, and signal transduction. These gangliosides are critically involved in neurogenesis, differentiation, membrane stability, and the modulation of receptor function, ion channel activity, and immunological signaling within the nervous system. The biosynthesis of these gangliosides is orchestrated by key enzymes, including GM3 synthase (ST3GAL5) and GM2/GD2 synthase (B4GALNT1) catalyzing the formation of downstream intermediates. Pathogenic variants in ST3GAL5 result in GM3 synthase deficiency (GM3SD), an autosomal recessive disorder characterized by infantile-onset epileptic encephalopathy and profound developmental regression. In contrast, biallelic mutations in B4GALNT1 cause a complex form of hereditary spastic paraplegia (SPG26), marked by progressive spasticity and intellectual impairment. ST3GAL3, another α2,3-sialyltransferase, contributes to the synthesis of GD1a and GT1b, as well as to glycoprotein sialylation. Mutations in this gene underlie neurodevelopmental disorders, including developmental and epileptic encephalopathy type 15 (DEE15). In this review, we summarize the current understanding of the molecular pathogenesis of congenital ganglioside biosynthesis disorders, integrating data from genetically engineered mouse models and affected individuals.

Myositis is a heterogeneous group of inflammatory muscular disorders. Although the main etiology is autoimmune chronic inflammation, the underlying pathomechanism remains unclear. Advances in genetic technology have provided important insights into its complex pathophysiology. Large genetic studies on myositis have advocated a relationship with several HLA loci and possible disease susceptibility genes in non-HLA genes. Idiopathic inflammatory myopathy, or autoimmune myositis, was originally divided into polymyositis and dermatomyositis. However, this classification has recently been revised based on updated information on the pathophysiology of autoimmune myositis. Autoimmune myositis is currently understood to include at least four major clinicopathologically distinct entities: dermatomyositis, antisynthetase syndrome, inclusion body myositis, and immune-mediated necrotizing myopathy. This review aims to consolidate knowledge of the genetics of myositis in order to meet the current classification and highlights key findings for a more detailed understanding of the underlying pathomechanism.

NGLY1 deficiency is a rare autosomal recessive genetic disorder caused by biallelic mutations of the human NGLY1 gene. NGLY1 encodes the cytosolic peptide:N-glycanase (PNGase; NGLY1 in mammals), which plays essential roles in cytosolic glycan degradation (non-lysosomal glycan degradation), the endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded proteins, and the complete activation of the transcription factor nuclear factor erythroid 2-like 1 (NEF2L1). NFE2L1 contributes to the regulation of the expression of proteasome subunits and oxidative stress responses. Patients with NGLY1 deficiency exhibit multisystemic clinical features, including global developmental delay, peripheral neuropathy, hypolacrima or alacrima, and the transient elevation of liver transaminases. To date, more than 100 individuals with NGLY1 deficiency and over 70 distinct pathogenic mutations in the NGLY1 gene have been reported. There is currently no approved therapy for this disorder. Moreover, the underlying pathogenic mechanism, including the correlation between patients' symptoms and mutant alleles, remains poorly understood. In this review, we summarize the most frequently reported NGLY1 mutations and their associated clinical features. We also present an overview of the current therapeutic strategy for NGLY1 deficiency.