Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability

Masaki Kamada, Toshitaka Kawarai, Ryosuke Miyamoto, Rie Kawakita, Yuki Tojima, Celeste Montecchiani, Laura D'Onofrio, Carlo Caltagirone, Antonio Orlacchio, Ryuji Kaji

Research output: Contribution to journalArticlepeer-review


Mutations in REEP1 have been identified in three types of neurological disorders, autosomal dominant form of Hereditary Spastic Paraplegia type 31 (SPG31), autosomal dominant distal hereditary motor neuronopathy type VB (HMN5B), and autosomal recessive form of congenital axonal neuropathy and diaphragmatic palsy. Previous studies demonstrated different molecular pathogenesis in SPG31, including loss-of-function, gain-of-function and haploinsufficiency. A four-generation family from Japan, including 12 members, was investigated clinically and genetically. Seven affected members displayed pure spastic paraplegia. Impression of genetic anticipation was observed in the family, including tendency of earlier age-at-onset and increasing severity in subsequent generations. Genetic analysis revealed a heterozygous intronic variant, c.303+2T > A, in REEP1, which segregated with disease, and was also identified in one unaffected member. The variant causes exon 4 skipping leading to frame shift and a truncated transcript identified by complementary DNA sequencing of reverse transcription polymerase chain reaction products. Measurement of REEP1 transcripts in lymphocytes demonstrated a reduction through nonsense mediated mRNA decay (NMD). Our study demonstrated further evidence of allelic heterogeneity in SPG31, mutant REEP1 mRNA dosage effects through NMD and intra-familial phenotype variability.

Original languageEnglish
Pages (from-to)79-83
Number of pages5
JournalParkinsonism and Related Disorders
Publication statusE-pub ahead of print - Oct 21 2017


  • Asymptomatic carrier
  • Nonsense-mediated mRNA decay (NMD)
  • Phenotype variability
  • Receptor expression-enhancing protein 1 (REEP1)
  • Spastic paraplegia type 31 (SPG31)
  • Splice site donor variant

ASJC Scopus subject areas

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology


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