Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.
Congenital hypomyelinating disorders are a heterogeneous group of inherited leukoencephalopathies characterized by abnormal myelin formation. We have recently reported a hypomyelinating syndrome characterized by diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). We performed whole-exome sequencing of three unrelated individuals with HCAHC and identified compound heterozygous mutations in POLR3B in two individuals. The mutations include a nonsense mutation, a splice-site mutation, and two missense mutations at evolutionally conserved amino acids. Using reverse transcription-PCR and sequencing, we demonstrated that the splice-site mutation caused deletion of exon 18 from POLR3B mRNA and that the transcript harboring the nonsense mutation underwent nonsense-mediated mRNA decay. We also identified compound heterozygous missense mutations in POLR3A in the remaining individual. POLR3A and POLR3B encode the largest and second largest subunits of RNA Polymerase III (Pol III), RPC1 and RPC2, respectively. RPC1 and RPC2 together form the active center of the polymerase and contribute to the catalytic activity of the polymerase. Pol III is involved in the transcription of small noncoding RNAs, such as 5S ribosomal RNA and all transfer RNAs (tRNA). We hypothesize that perturbation of Pol III target transcription, especially of tRNAs, could be a common pathological mechanism underlying POLR3A and POLR3B mutations.
Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. hsaitsu@yokohama-cu.ac.jp
Hirotomo
H
Saitsu
Hitoshi
H
Osaka
Masayuki
M
Sasaki
Jun-Ichi
J
Takanashi
Keisuke
K
Hamada
Akio
A
Yamashita
Hidehiro
H
Shibayama
Masaaki
M
Shiina
Yukiko
Y
Kondo
Kiyomi
K
Nishiyama
Yoshinori
Y
Tsurusaki
Noriko
N
Miyake
Hiroshi
H
Doi
Kazuhiro
K
Ogata
Ken
K
Inoue
Naomichi
N
Matsumoto
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D018389:Codon, Nonsense; D003337:Corpus Callosum / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics; D010375:Pedigree; D012320:RNA Polymerase III / Q000235:genetics*; D022821:RNA Splice Sites; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
D018389:Codon, Nonsense; D022821:RNA Splice Sites; C468558:POLR3B protein, human; D012320:RNA Polymerase III