title: Novel compound heterozygous mutations of POLR3A revealed by whole-exome sequencing in a patient with hypomyelination.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo 162-8666, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimojima
authors.affiliation: Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo 162-8666, Japan; Department of Pediatrics, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Shino
authors.initials: S
authors.lastname: Shimada
authors.affiliation: Division of Child Neurology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tamasaki
authors.affiliation: Department of Pediatrics, National Hospital Organization Tottori Medical Center, Tottori 689-0203, Japan.
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Akaboshi
authors.affiliation: Department of Hygiene and Public Health, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Komoike
authors.affiliation: StaGen Co., Ltd., Tokyo 111-0051, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.affiliation: Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo 162-8666, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Tokyo Women's Medical University Institute for Integrated Medical Sciences, Tokyo 162-8666, Japan. Electronic address: yamamoto.toshiyuki@twmu.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis / Q000379:methods; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D009154:Mutation; D012320:RNA Polymerase III / Q000235:genetics* / Q000378:metabolism; D020733:RNA, Small Cytoplasmic / Q000378:metabolism; D018271:Signal Recognition Particle / Q000378:metabolism; D012867:Skin / Q000378:metabolism
chemical_list: C115990:7SL RNA; D020733:RNA, Small Cytoplasmic; D018271:Signal Recognition Particle; C585825:POLR3A protein, human; D012320:RNA Polymerase III
keywords: Hypomyelination; Hypomyelination with hypodontia and hypogonadotropic hypogonadism (4H) syndrome; Leukodystrophy; POLR3A; RNA polymerase III (Pol III); Whole-exome sequencing