Session Information
Date: Tuesday, June 6, 2017
Session Title: Genetics (Non-PD)
Session Time: 1:45pm-3:15pm
Location: Exhibit Hall C
Objective: The aim of this study is to reveal molecular pathogenicity and genotype-phenotype correlations in Spastic Paraplegia type 31 (SPG31).
Background: Mutations in REEP1 have been identified in two types of neurological disorders, autosomal dominant form of Hereditary Spastic Paraplegia type 31 (SPG31) and autosomal dominant distal hereditary motor neuronopathy type VB (HMN5B). Previous studies demonstrated various molecular pathogenesis in SPG31, including loss-of-function, gain-of-function and haploinsufficiency.
Methods: A four generation family originated from Japan, including seven affected and three unaffected members, was investigated clinically and genetically. Initial diagnostic approach included targeted resequencing of currently-known HSP genes or resequencing of whole exomes. Biological effects by nucleotide variation were predicted using bioinformatic tools and confirmed by reverse transcription polymerase chain reaction (RT-PCR) experiment. Measurement of REEP1 transcripts were conducted in cultured T cells treated with nonsense mRNA mediated decay (NMD) inhibitor.
Results: A novel REEP1 intronic variant was found in six affected members and one unaffected member. The variant is located at the second position at 5′-splice-site of intron 4, c.303+2T>A. Skipping of exon 4 was shown by RT-PCR experiment, presumably leading to generation of frame shift and premature stop codon (p.Phe62Lysfs*25; NM_022912). Measurement of REEP1 transcripts in lymphocytes demonstrated a reduction through NMD. Intra-familial phenotypic variations were observed, including age-at-onset, severity of spasticity, as well as the presence of asymptomatic carrier.
Conclusions: Our study demonstrated further evidence of allelic heterogeneity in SPG31, dosage effects through NMD, and phenotypic variation of REEP1 mutation.
To cite this abstract in AMA style:
M. Kamada, T. Kawarai, R. Miyamoto, Y. Tojima, A. Orlacchio, R. Kaji. Hereditary spastic paraplegia type 31: a novel splice site donor mutation and intra-familial phenotypic variability [abstract]. Mov Disord. 2017; 32 (suppl 2). https://www.mdsabstracts.org/abstract/hereditary-spastic-paraplegia-type-31-a-novel-splice-site-donor-mutation-and-intra-familial-phenotypic-variability/. Accessed June 14, 2025.« Back to 2017 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/hereditary-spastic-paraplegia-type-31-a-novel-splice-site-donor-mutation-and-intra-familial-phenotypic-variability/