Novel stop‐gain RNF170 variation detected in a Chinese family with adolescent‐onset hereditary spastic paraplegia

• Published in: Clinical genetics 2023-01, Vol.103 (1), p.87-92
• Main Authors: Fu, Jing‐Xin, Wei, Qiao, Chen, Yu‐Lan, Li, Hong‐Fu
• Format: Article
• Language: English
• Subjects: Adolescent; Chinese; East Asian People; Gait; Hereditary spastic paraplegia; Humans; Inositol 1,4,5-trisphosphate receptors; loss‐of‐function; mRNA; Neurodegenerative Diseases; RNF170; Spastic Paraplegia, Hereditary - genetics; Spasticity; Ubiquitin-Protein Ligases - genetics
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.14219

Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disease characterized by progressive lower limb spasticity. Recent studies revealed that biallelic variants in RNF170 gene cause autosomal recessive complicated HSP with infancy onset. Here, we report an adolescent‐onset HSP patient from a consanguineous Chinese family, with lower extremity stiffness, spastic gait, and unstable straight‐line walking as the main manifestations. Whole‐exome sequencing identifies a novel RNF170 mutation c.190C>T (p.R64*), which co‐segregates with the disease in this pedigree. Functional analysis, including quantitative real‐time PCR (RT‐qPCR) and Western blot, indicates that both the mRNA and protein levels of mutant RNF170 are significantly reduced, which confirms the loss‐of‐function mechanism. Our study expands the spectrum of RNF170‐associated HSP, while the RNF170 protein‐involved degradation of the inositol 1,4,5‐trisphosphate receptor in neurodegenerative motor neuron disorders deserves further investigation. We identified a novel RNF170 mutation p.R64* in a Chinese pedigree with adolescent‐onset hereditary spastic paraplegia (HSP). Both mRNA and protein levels of mutant RNF170 are significantly reduced in the patient, confirming the loss‐of‐function mechanism of mutant RNF170. Our study expands the clinical spectrum of RNF170‐associated HSP.