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

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

Fingerprint

Paraplegia
X Chromosome Inactivation
Nucleotides
Alleles
Pelizaeus-Merzbacher Disease
Exome
RNA Sequence Analysis
Cell Line
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1. / Yamamoto-Shimojima, Keiko; Imaizumi, Taichi; Aoki, Yusuke; Inoue, Ken; Kaname, Tadashi; Okuno, Yusuke; Muramatsu, Hideki; Kato, Kohji; Yamamoto, Toshiyuki.

In: Journal of Human Genetics, Vol. 64, No. 7, 01.07.2019, p. 665-671.

Research output: Contribution to journalArticle

Yamamoto-Shimojima, Keiko ; Imaizumi, Taichi ; Aoki, Yusuke ; Inoue, Ken ; Kaname, Tadashi ; Okuno, Yusuke ; Muramatsu, Hideki ; Kato, Kohji ; Yamamoto, Toshiyuki. / Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1. In: Journal of Human Genetics. 2019 ; Vol. 64, No. 7. pp. 665-671.
@article{d58e6ef36d84434892e66fa3fc45aeb1,
title = "Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1",
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.",
author = "Keiko Yamamoto-Shimojima and Taichi Imaizumi and Yusuke Aoki and Ken Inoue and Tadashi Kaname and Yusuke Okuno and Hideki Muramatsu and Kohji Kato and Toshiyuki Yamamoto",
year = "2019",
month = "7",
day = "1",
doi = "10.1038/s10038-019-0600-x",
language = "English",
volume = "64",
pages = "665--671",
journal = "Journal of Human Genetics",
issn = "1434-5161",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1

AU - Yamamoto-Shimojima, Keiko

AU - Imaizumi, Taichi

AU - Aoki, Yusuke

AU - Inoue, Ken

AU - Kaname, Tadashi

AU - Okuno, Yusuke

AU - Muramatsu, Hideki

AU - Kato, Kohji

AU - Yamamoto, Toshiyuki

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85064629274&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064629274&partnerID=8YFLogxK

U2 - 10.1038/s10038-019-0600-x

DO - 10.1038/s10038-019-0600-x

M3 - Article

C2 - 31004103

AN - SCOPUS:85064629274

VL - 64

SP - 665

EP - 671

JO - Journal of Human Genetics

JF - Journal of Human Genetics

SN - 1434-5161

IS - 7

ER -