Abstract
Background: REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China. The pathological mechanism of REEP1 is not fully understood.Methods: We screened for REEP1 mutations in 31 unrelated probands from Chinese HSP families using next-generation sequencing targeting pathogenic genes for HSP and other related diseases. All variants were validated by Sanger sequencing. The proband family members were also screened for variants for the segregation analysis. All previously reported REEP1 mutations and cases were reviewed to clarify the genetic and clinical features of REEP1-related HSP.Results: A pathogenic mutation, REEP1c. 125G>A (p.Trp42*), was detected in a pure HSP family from North China out of 31 HSP families (1/31). This locus, which is located in the second hydrophobic domain of REEP1, is detected in both Caucasian patients with complicated HSP phenotypes and Chinese pure HSP families.Conclusion: REEP1-related HSP can be found in the Chinese population. The 42nd residue is a novel transethnic mutation hotspot. Mutations in this spot can lead to both complicated and pure form of HSP. Identification of transethnic hotspot will contribute to clarify the underlying pathological mechanisms.
Highlights
Hereditary spastic paraplegia (HSP) comprises a group of neurodegenerative diseases characterized by spastic paraplegia of the lower limbs [1]
Next-generation sequencing targeting ∼160 genes related to Charcot-Marie-Tooth disease, HSP, and amyotrophic lateral sclerosis, including REEP1(NM_022912.2), was conducted
A previously reported [9] pathogenic non-sense mutation of REEP1 c. 125G>A (p.Trp42∗) (RefSeq NM_022912) in exon 3 was detected in a pure HSP proband via next-generation sequencing (NGS) and validated by Sanger sequencing (Figure 1)
Summary
Hereditary spastic paraplegia (HSP) comprises a group of neurodegenerative diseases characterized by spastic paraplegia of the lower limbs [1]. Hereditary spastic paraplegia is classified as pure or complicated HSP based on whether impairment is restricted to the pyramidal system [2]. 79 pathogenic genes for HSPs have been found [3]. These diseases can be inherited in various ways, including autosomal dominant (AD), recessive, X-linked, mitochondrial, and other mechanisms [4]. Because HSPs are monogenic diseases, gene therapies, and precision medicine may be appropriate [3]. REEP1 is a common cause of autosomal dominant hereditary spastic paraplegia (HSP) but is rare in China.
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