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Novel stop-gain RNF170 variation detected in a Chinese family with adolescent-onset hereditary spastic paraplegia
Jing-Xin Fu1, Qiao Wei1, Yu-Lan Chen1,2
1Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Insights
A novel mutation in the RNF170 gene was identified in a Chinese family with adolescent-onset hereditary spastic paraplegia (HSP). This discovery expands the known genetic causes of HSP and highlights RNF170
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative disorders.
- RNF170 gene variants have been linked to autosomal recessive HSP with early onset.
- The genetic basis for adolescent-onset HSP remains incompletely understood.
Purpose of the Study:
- To identify the genetic cause of adolescent-onset HSP in a consanguineous Chinese family.
- To characterize the functional consequences of a novel RNF170 mutation.
- To expand the genotypic and phenotypic spectrum of RNF170-associated HSP.
Main Methods:
- Whole-exome sequencing (WES) was performed on affected individuals and family members.
- Segregation analysis confirmed co-occurrence of the mutation with the disease phenotype.
- Quantitative real-time PCR (RT-qPCR) and Western blot were used to assess mRNA and protein levels.
Main Results:
- A novel nonsense mutation, c.190C>T (p.R64*), in the RNF170 gene was identified.
- The mutation co-segregated with HSP in the studied family.
- Reduced mRNA and protein levels of mutant RNF170 confirmed a loss-of-function mechanism.
Conclusions:
- This study identifies a novel RNF170 mutation causing adolescent-onset HSP, expanding the disease spectrum.
- The findings underscore the role of RNF170 in neurodegenerative motor neuron disorders.
- Further research into RNF170's role in inositol 1,4,5-trisphosphate receptor degradation is warranted.
Abstract:
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.
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