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


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.

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We would like to express our gratitude to the patient and her family for their cooperation. This work was supported by a Grant-in-Aid for Young Scientists (B) (17K18133) and a Restart Postdoctoral Fellowship (17J40108) from the Japan Society for the Promotion of Science (JSPS) for KY. This study was also funded by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED 18ek0109270, TY, KI) and JSPS KAKENHI JP18K07803 (TY). We are also thankful for the support from the Initiative on Rare and Undiagnosed Diseases (IRUD) via the Japan Agency for Medical Research and Development (AMED).

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Correspondence to Toshiyuki Yamamoto.

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Yamamoto-Shimojima, K., Imaizumi, T., Aoki, Y. et al. Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1. J Hum Genet 64, 665–671 (2019).

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