Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy

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• 作者：Hirotomo Saitsu¹ ;   ; ^{hsaitsu@yokohama-cu.ac.jp} ; Hitoshi Osaka² ; Masayuki Sasaki³ ; Jun-ichi Takanashi⁴ ; Keisuke Hamada⁵ ; Akio Yamashita⁶ ; Hidehiro Shibayama⁷ ; Masaaki Shiina⁵ ; Yukiko Kondo¹ ; Kiyomi Nishiyama¹ ; Yoshinori Tsurusaki¹ ; Noriko Miyake¹ ; Hiroshi Doi¹ ; Kazuhiro Ogata⁵ ; Ken Inoue⁸ ; Naomichi Matsumoto¹ ;   ; ^{naomat@yokohama-cu.ac.jp}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 November 2011
• 年：2011
• 卷：89
• 期：5
• 页码：644-651
• 全文大小：888 K

文摘

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.