Novel compound heterozygous mutations of POLR3A revealed by whole-exome sequencing in a patient with hypomyelination

Keiko Shimojima, Shino Shimada, Akiko Tamasaki, Shinjiro Akaboshi, Yuta Komoike, Akira Saito, Toru Furukawa, Toshiyuki Yamamoto

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Objective: Congenital white matter disorders are a heterogeneous group of hypomyelination disorders affecting the white matter of the brain. Recently, mutations in the genes encoding the subunits of RNA polymerase III (Pol III), POLR3A and POLR3B, have been identified as new genetic causes for hypomyelinating disorders. Method: Whole-exome sequencing was applied to identify responsible gene mutations in a 29-year-old female patient showing hypomyelination of unknown cause. To investigate the pathological mechanism underlying the hypomyelination in this patient, the expression level of 7SL RNA, a transcriptional target of Pol III, was analyzed in cultured skin fibroblasts derived from the patient with POLR3A mutations. Results: Novel compound heterozygous mutations of POLR3A were identified in the patient, who started to show cerebellar signs at 3. years, lost ambulation at 7. years, and became bedridden at 18. years. Brain magnetic resonance imaging showed severe volume loss in the brainstem, the cerebellum, and the white matter associated with hypomyelination. In addition to hypodontia and hypogonadism, she showed many pituitary hormone-related deficiencies. The expression level of 7SL RNA in cultured skin fibroblasts derived from this patient showed no significant abnormality. Conclusion: The many pituitary hormone-related deficiencies identified in this patient may be an essential finding for the Pol III-related leukodystrophies spectrum. Further investigation is needed for a better understanding of the disease mechanism.

Original languageEnglish
Pages (from-to)315-321
Number of pages7
JournalBrain and Development
Issue number4
Publication statusPublished - 2014 Apr


  • Hypomyelination
  • Hypomyelination with hypodontia and hypogonadotropic hypogonadism (4H) syndrome
  • Leukodystrophy
  • POLR3A
  • RNA polymerase III (Pol III)
  • Whole-exome sequencing


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