Recessive Mutations in POLR3B Encoding the Second Largest Subunit of Pol III Cause a Rare Hypomyelinating Leukodystrophy (P05.136)

Abstract

Objective: Search for mutations in the second largest subunit of RNA polymerase III (Pol III), POLR3B , in case negative for mutation in POLR3A . Background Leukodystrophies are a heterogeneous group of neurodegenerative disorders characterized by abnormal central nervous system white matter. It is estimated that at least 30% to 40% of patients with leukodystrophies remain without a precise diagnosis, despite extensive investigations. We recently demonstrated that mutations in POLR3A, encoding the largest subunit of RNA polymerase III (Pol III), were responsible for the majority of cases presenting with three clinically overlapping hypomyelinating leukodystrophy phenotypes. Design/Methods: We sequenced all exons, exon-intron boundaries and 39 and 59 UTR of POLR3B (NM_018082, hg19) on available genomic DNA from four 4H cases not found previously to carry POLR3A mutations. Results: We uncovered in four cases without POLR3A mutation, recessive mutations in POLR3B which codes for the second largest subunit of Pol III. All four cases were found to be compound heterozygote for mutations in POLR3B , with one missense mutation being common to all individuals. Conclusions: Mutations in genes coding for Pol III subunits are a major cause of childhood-onset hypomyelinating leukodystrophies typically characterized by prominent cerebellar dysfunction, oligodontia and hypogonadotropic hypogonadism. Supported by: Dr G Bernard received fellowship scholarships from the RMGA (Reseau de Medecine Genetique Appliquee) and FRSQ (Fonds de Recherche en Sante du Quebec). M. Tetreault received the Frederick Banting and Charles Best Doctoral scholarship from the CIHR (Canadian Institute of Health Research). This work was supported by Fondation sur les Leucodystrophies and the European Leukodystrophy Association (ELA). Disclosure: Dr. Tetreault has nothing to disclose. Dr. Choquet has nothing to disclose. Dr. Orcesi has nothing to disclose. Dr. Tonduti has nothing to disclose. Dr. Ballotin has nothing to disclose. Dr. Teichmann has nothing to disclose. Dr. Fribourg has nothing to disclose. Dr. Schiffmann has received personal compensation for activities with Amicus Therapeutics and Shire Human Genetic Therapies. Dr. Schiffmann has received research support from Shire Human Genetic Therapies, Amicus Therapeutics, and Genzyme Corporation. Dr. Brais has nothing to disclose. Dr. Vanderver has nothing to disclose. Dr. Bernard has received personal compensation for activities with Actelion Pharmaceuticals Canada Inc, Santhera, Venture in Research as a participant on advisory boards and research teams.