PT - JOURNAL ARTICLE AU - Hitoshi Kashiki AU - Heng Li AU - Sachiko Miyamoto AU - Hiroe Ueno AU - Yoshinori Tsurusaki AU - Chizuru Ikeda AU - Hirofumi Kurata AU - Takumi Okada AU - Tomoyuki Shimazu AU - Hoseki Imamura AU - Yumi Enomoto AU - Jun-ichi Takanashi AU - Kenji Kurosawa AU - Hirotomo Saitsu AU - Ken Inoue TI - <em>POLR1C</em> variants dysregulate splicing and cause hypomyelinating leukodystrophy AID - 10.1212/NXG.0000000000000524 DP - 2020 Dec 01 TA - Neurology Genetics PG - e524 VI - 6 IP - 6 4099 - http://ng.neurology.org/content/6/6/e524.short 4100 - http://ng.neurology.org/content/6/6/e524.full SO - Neurol Genet2020 Dec 01; 6 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&gt;A, p.M56K and c.595A&gt;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