RT Journal Article SR Electronic T1 Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e289 DO 10.1212/NXG.0000000000000289 VO 4 IS 6 A1 Dorboz, Imen A1 Dumay-Odelot, Hélene A1 Boussaid, Karima A1 Bouyacoub, Yosra A1 Barreau, Pauline A1 Samaan, Simon A1 Jmel, Haifa A1 Eymard-Pierre, Eleonore A1 Cances, Claude A1 Bar, Céline A1 Poulat, Anne-Lise A1 Rousselle, Christophe A1 Renaldo, Florence A1 Elmaleh- Bergès, Monique A1 Teichmann, Martin A1 Boespflug-Tanguy, Odile YR 2018 UL http://ng.neurology.org/content/4/6/e289.abstract AB Objective To identify the genetic cause of hypomyelinating leukodystrophy in 2 consanguineous families.Methods Homozygosity mapping combined with whole-exome sequencing of consanguineous families was performed. Mutation consequences were determined by studying the structural change of the protein and by the RNA analysis of patients' fibroblasts.Results We identified a biallelic mutation in a gene coding for a Pol III–specific subunit, POLR3K (c.121C>T/p.Arg41Trp), that cosegregates with the disease in 2 unrelated patients. Patients expressed neurologic and extraneurologic signs found in POLR3A- and POLR3B-related leukodystrophies with a peculiar severe digestive dysfunction. The mutation impaired the POLR3K-POLR3B interactions resulting in zebrafish in abnormal gut development. Functional studies in the 2 patients' fibroblasts revealed a severe decrease (60%–80%) in the expression of 5S and 7S ribosomal RNAs in comparison with control.Conclusions These analyses underlined the key role of ribosomal RNA regulation in the development and maintenance of the white matter and the cerebellum as already reported for diseases related to genes involved in transfer RNA or translation initiation factors.HLD=hypomyelinating leukodystrophy