Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation

Objective To identify the genetic cause of hypomyelinating leukodystrophyin 2 consanguineousfamilies. Methods Homozygosity mapping combined with whole- exome sequencingof consanguineousfamilies was performed. Mutation consequences were determined by studying the structural change of the protein and by the RNA analysis of patients9 fibroblasts. Results We identified a biallelic mutation in a gene coding for a Pol III–specific subunit, POLR3K (c.121C>T/p.Arg41Trp), that cosegregateswith the disease in 2 unrelated patients. Patients expressed neurologic and extraneurologic signs found in POLR3A - and POLR3B -related leukodystrophieswith a peculiar severe digestive dysfunction. The mutation impaired the POLR3K-POLR3B interactions resulting in zebrafish in abnormal gut development. Functional studies in the 2 patients9 fibroblasts revealed a severe decrease (60%–80%) in the expression of 5S and 7S ribosomal RNAsin comparison with control. Conclusions These analyses underlined the key role of ribosomal RNAregulation in the development and maintenance of the white matter and the cerebellum as already reported for diseases related to genes involved in transfer RNAor translation initiation factors.