Background: GlcNAc2-epimerase (GNE) myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway. Objective: This multi-centre study aimed to delineate the clinical phenotype and GNE variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations. Methods: We retrospectively analysed GNE variants from 113 patients, integrating these data with external GNE variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity. Results: This study revealed 97 distinct GNE variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic GNE variant, c.620A>T, might underlie the milder phenotype of Chinese patients. Conclusions: Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of GNE variants. Patients with the non-catalytic GNE variant, c.620A>T, had a milder disease progression and later wheelchair use.

Objective: Hereditary spastic paraplegia (HSP) has been reported rarely because of a monoallelic variant in ERLIN2. The present study aimed at describing a novel autosomal dominant ERLIN2 pedigree in a Chinese family and exploring the possible mechanism of HSP caused by ERLIN2 variants.Methods: The proband and his family underwent a comprehensive medical history inquiry and neurological examinations. Whole‐exome sequencing was performed on the proband, and Sanger sequencing was performed on some family members. HeLa cell lines and mouse primary cortical neurons were used for immunofluorescence (IF) and reverse transcription‐PCR (RT‐PCR).Results: Seven patients were clinically diagnosed with pure spastic paraplegia in four consecutive generations with the autosomal dominant inheritance model. All patients presented juvenile‐adolescent onset and gradually worsening pure HSP phenotype. Whole‐exome sequencing of the proband and Sanger sequencing of all available family members identified a novel heterozygous c.212 T>C (p.V71A) variant in exon 8 of the ERLIN2 gene. The c.212 T>C demonstrated a high pathogenic effect score through functional prediction. RT‐PCR and IF analysis of overexpressed V71A revealed an altered ER morphology and increased XBP‐1S mRNA levels, suggesting the activation of ER stress. Overexpression of V71A in primary cultured cortical neurons promoted axon growth.Interpretation: The novel c.212 T>C heterozygous variant in human ERLIN2 caused pure HSP. Moreover, c.212 T>C heterozygous variant in ERLIN2 increased ER stress and affected axonal development.

Ribosome-associated quality control (RQC), a ubiquitous process essential for maintaining protein homeostasis in eukaryotes, acts as a critical surveillance system for protein translation. By identifying and eliminating stalled ribosomes, RQC prevents aberrant translation and the production of potentially toxic misfolded proteins. The review focuses on the role of RQC in mammals, where its complete functionality remains to be elucidated. This study delves into the mechanisms through which dysfunction in RQC plays a role in the development of neurological disorders, focusing on neurodegenerative and neurodevelopmental diseases. We explore the underlying mechanisms by which RQC dysfunction contributes to the pathogenesis of neurological disorders, particularly neurodegenerative and neurodevelopmental diseases. Further research is crucial to unravel the intricate mechanisms governing RQC’s influence on neurological function. This knowledge will pave the way for exploring therapeutic avenues targeting RQC factors as potential interventions for these debilitating diseases. By shedding light on RQC’s contribution to neurological disorders, this review opens doors for developing targeted therapies and interventions.