Biallelic variants in the COQ4 gene caused hereditary spastic paraplegia predominant phenotype

• Published in: CNS neuroscience & therapeutics 2024-04, Vol.30 (4), p.e14529-n/a
• Main Authors: Wei, Qiao, Yu, Hao, Wang, Pei‐Shan, Xie, Juan‐Juan, Dong, Hai‐Lin, Wu, Zhi‐Ying, Li, Hong‐Fu
• Format: Article
• Language: English
• Subjects: Age; Amino acids; Ataxia; Chinese; Convulsions & seizures; COQ4; Fibroblasts; Genes; Genomes; Hereditary spastic paraplegia; Humans; Magnetic resonance imaging; Mitochondrial Diseases - genetics; Mitochondrial Proteins - genetics; Motor neurons; Mutation; Mutation - genetics; Neurodegeneration; Neurodegenerative diseases; novel phenotype; Original; Paralysis; Pathogenicity; Patients; Pedigree; Phenotype; Phenotypes; Plasmids; Software; Spastic Paraplegia, Hereditary - genetics; Spasticity; Variance analysis
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.14529

Introduction Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by progressive degeneration of upper motor neurons. Homozygous or compound heterozygous variants in COQ4 have been reported to cause primary CoQ10 deficiency‐7 (COQ10D7), which is a mitochondrial disease. Aims We aimed to screened COQ4 variants in a cohort of HSP patients. Methods A total of 87 genetically unidentified HSP index patients and their available family members were recruited. Whole exome sequencing (WES) was performed in all probands. Functional studies were performed to identify the pathogenicity of those uncertain significance variants. Results In this study, five different COQ4 variants were identified in three Chinese HSP pedigrees and two variants were novel, c.87dupT (p.Arg30*), c.304C>T (p.Arg102Cys). More importantly, we firstly described two early‐onset pure HSP caused by COQ4 variants. Functional studies in patient‐derived fibroblast lines revealed a reduction cellular CoQ10 levels and the abnormal mitochondrial structure. Conclusions Our findings revealed that bilateral variants in the COQ4 gene caused HSP predominant phenotype, expanding the phenotypic spectrum of the COQ4‐related disorders. Five COQ4 variants were identified in three Chinese HSP pedigrees. Functional studies revealed reduced CoQ10 level and fragmented mitochondria in patient's fibroblast.