PMP22-related disease: A novel splice site acceptor variant and intrafamilial phenotype variability

Toshitaka Kawarai, Hiroki Yamazaki, Ryosuke Miyamoto, Naoko Takamatsu, Atsuko Mori, Yusuke Osaki, Antonio Orlacchio, Hiroyuki Nodera, Akihiro Hashiguchi, Yujiro Higuchi, Akiko Yoshimura, Hiroshi Takashima, Ryuji Kaji

Research output: Contribution to journalArticlepeer-review


PMP22 is the most frequent mutated gene in Charcot-Marie-Tooth disease (CMT)type 1A. Another phenotype, hereditary neuropathy with pressure palsies (HNPP), could be caused by PMP22 mutations. PMP22 encodes a peripheral myelin protein with molecular weight 22-kDa. Various pathomechanisms have been postulated in PMP22-related disease, including dysfunction due to missense mutations, and alteration of a gene dose due to duplication/deletion mutations. We identified a novel PMP22 splice site acceptor variant, c.179–1G>A, in a patient with adult-onset chronic generalized polyneuropathy and two asymptomatic family members. Pathophysiological features of the members mainly overlapped with those reported in HNPP, but broad intrafamilial clinical variations were observed. PMP22 transcripts lacking of exon 4 were produced by the variant, presumably leading to in-frame deletion of 47 amino acids. The variant was also shown to exert effect on dosage of PMP22 mRNA. The complex molecular pathology would lead to the unique clinical and pathophysiological conditions.

Original languageEnglish
JournalNeuromuscular Disorders
Publication statusPublished - Jan 1 2019


  • Gene dose effect
  • Overlapped pathophysiology
  • PMP22 protein with in-frame deletion
  • PMP22-related disease
  • Splice site acceptor variant

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neurology
  • Clinical Neurology
  • Genetics(clinical)

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