RT Journal Article SR Electronic T1 POLR1C variants dysregulate splicing and cause hypomyelinating leukodystrophy JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e524 DO 10.1212/NXG.0000000000000524 VO 6 IS 6 A1 Kashiki, Hitoshi A1 Li, Heng A1 Miyamoto, Sachiko A1 Ueno, Hiroe A1 Tsurusaki, Yoshinori A1 Ikeda, Chizuru A1 Kurata, Hirofumi A1 Okada, Takumi A1 Shimazu, Tomoyuki A1 Imamura, Hoseki A1 Enomoto, Yumi A1 Takanashi, Jun-ichi A1 Kurosawa, Kenji A1 Saitsu, Hirotomo A1 Inoue, Ken YR 2020 UL http://ng.neurology.org/content/6/6/e524.abstract AB Objective To further clarify the molecular pathogenesis of RNA polymerase III (Pol III)-related leukodystrophy caused by biallelic POLR1C variants at a cellular level and potential effects on its downstream genes.Methods Exome analysis and molecular functional studies using cell expression and long-read sequencing analyses were performed on 1 family with hypomyelinating leukodystrophy showing no clinical and MRI findings characteristic of Pol III–related leukodystrophy other than hypomyelination.Results Biallelic novel POLR1C alterations, c.167T>A, p.M56K and c.595A>T, p.I199F, were identified as causal variants. Functional analyses showed that these variants not only resulted in altered protein subcellular localization and decreased protein expression but also caused abnormal inclusion of introns in 85% of the POLR1C transcripts in patient cells. Unexpectedly, allelic segregation analysis in each carrier parent revealed that each heterozygous variant also caused the inclusion of introns on both mutant and wild-type alleles. These findings suggest that the abnormal splicing is not direct consequences of the variants, but rather reflect the downstream effect of the variants in dysregulating splicing of POLR1C, and potentially other target genes.Conclusions The lack of characteristic clinical findings in this family confirmed the broad clinical spectrum of Pol III–related leukodystrophy. Molecular studies suggested that dysregulation of splicing is the potential downstream pathomechanism for POLR1C variants.Pol III=polymerase III