Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1

Keiko Yamamoto-Shimojima, Taichi Imaizumi, Yusuke Aoki, Ken Inoue, Tadashi Kaname, Yusuke Okuno, Hideki Muramatsu, Kohji Kato, Toshiyuki Yamamoto

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder caused by abnormalities in the gene PLP1. Most females harboring heterozygous PLP1 abnormalities are basically asymptomatic. However, as a result of abnormal patterns of X-chromosome inactivation, it is possible for some female carriers to be symptomatic. Whole-exome sequencing of a female patient with unknown spastic paraplegia was performed to obtain a molecular diagnosis. As a result, a de novo heterozygous single-nucleotide deletion in PLP1 [NM_000533.5(PLP1_v001):c.783del; p.Thr262Leufs*20] was identified. RNA sequencing was performed in a patient-derived lymphoblastoid cell line, confirming mono-allelic expression of the mutated allele and abnormal inactivation of the wild-type allele. The patient-derived lymphoblastoid cell line was then treated with VX680 or 5azadC, which resulted in restored expression of the wild-type allele. These two agents thus have the potential to reverse inappropriately-skewed inactivation of the X-chromosome.

Original languageEnglish
Pages (from-to)665-671
Number of pages7
JournalJournal of Human Genetics
Volume64
Issue number7
DOIs
Publication statusPublished - Jul 1 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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