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

Saitsu, Hirotomo; Osaka, Hitoshi; Sasaki, Masayuki; Takanashi, Jun‐ichi; Hamada, Keisuke; Yamashita, Akio; Shibayama, Hidehiro; Shiina, Masaaki; Kondo, Yukiko; Nishiyama, Kiyomi; Tsurusaki, Yoshinori; Miyake, Noriko; Doi, Hiroshi; Ogata, Kazuhiro; Inoue, Ken; Matsumoto, Naomichi

doi:10.1016/j.ajhg.2011.10.003

Cited by 148 publications

(160 citation statements)

References 27 publications

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“…Pol III synthesizes certain small untranslated RNAs (e.g., tRNAs, 5S rRNA, U6 snRNA, and 7SL RNA) involved in RNA processing and translation and in protein translocation (2,3). Human Pol III mutations have been implicated in a neurodegenerative disorder, hypomyelinating leukodystrophy (4)(5)(6).…”

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confidence: 99%

RNA polymerase III subunit architecture and implications for open promoter complex formation

Herzog²,

Jennebach

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Transcription initiation by eukaryotic RNA polymerase (Pol) III relies on the TFIIE-related subcomplex C82/34/31. Here we combine crosslinking and hydroxyl radical probing to position the C82/34/31 subcomplex around the Pol III active center cleft. The extended winged helix (WH) domains 1 and 4 of C82 localize to the polymerase domains clamp head and clamp core, respectively, and the two WH domains of C34 span the polymerase cleft from the coiled-coil region of the clamp to the protrusion. The WH domains of C82 and C34 apparently cooperate with other mobile regions flanking the cleft during promoter DNA binding, opening, and loading. Together with published data, our results complete the subunit architecture of Pol III and indicate that all TFIIE-related components of eukaryotic and archaeal transcription systems adopt an evolutionarily conserved location in the upper part of the cleft that supports their functions in open promoter complex formation and stabilization. R NA polymerase III (Pol III) is the largest eukaryotic RNA polymerase, composed of 17 subunits with a total molecular weight of ∼0.7 MDa (1). Pol III synthesizes certain small untranslated RNAs (e.g., tRNAs, 5S rRNA, U6 snRNA, and 7SL RNA) involved in RNA processing and translation and in protein translocation (2, 3). Human Pol III mutations have been implicated in a neurodegenerative disorder, hypomyelinating leukodystrophy (4-6).The three eukaryotic RNA polymerases share a similar 12-subunit core as represented by the X-ray structure of yeast Pol II (1). In addition to the core, Pol III contains five specific subunits forming two subcomplexes, C37/53 and C82/34/31. The C37/53 subcomplex participates in promoter opening, transcription termination, and polymerase reinitiation (7-9). The C34 subunit of the C82/34/31 subcomplex plays a role in open complex formation and in recruiting Pol III to the preinitiation complex (PIC) through interaction with TFIIB-related factor 1 (Brf1) (10-13). The human RPC62/39/32 subcomplex, homologous to the yeast C82/34/31 complex, is dissociable and required for promoter-specific initiation (11).The two Pol III-specific subcomplexes contain structural domains homologous to domains in the Pol II transcription factors TFIIF and TFIIE, including the TFIIF-related dimerization module in the C37/53 subcomplex and several TFIIE-related winged helix (WH) domains in subunits C82 and C34 (14-20). TFIIE is composed of two subunits, Tfa1 and Tfa2, in yeast, or TFIIEα and TFIIEβ in humans. Whereas Tfa1 bears an extended WH (eWH) domain in its N-terminal region, Tfa2 has two adjacent WH domains (21,22). Two adjacent Tfa2-related WH domains are also present in the C34 subunit and its human homolog RPC39. Pol I contains the A49/34.5 subcomplex that features a TFIIF-like dimerization module and a tandem WH domain that contains two Tfa2-like WH folds in the C-terminal region of the A49 subunit (18). The crystal structure of the human C82 homolog RPC62 contains four Tfa1-like eWH domains (eWH1-4) that are structurally organized aroun...

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confidence: 99%

RNA polymerase III subunit architecture and implications for open promoter complex formation

Herzog²,

Jennebach

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…52 To point out, Next-generation sequencing in Mendelian disorders B Rabbani et al the cause of Schinzel-Giedion syndrome was identified using this strategy. 53 Furthermore, Saitsu et al 54 performed exome sequencing in three unrelated affected individuals with congenital hypomyelination leukoencephalopathy; they found compound heterozygous mutations in POLR3A and POLR3B (encoding RNA polymerase III subunits) in the affected individuals. As in case of Kabuki syndrome, which is a rare disorder worldwide, the majority of cases are sporadic, but parent-to-child transmission has been reported representing the dominant mode of inheritance.…”

Section: Unrelated Individual Studiesmentioning

confidence: 99%

Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders

et al. 2012

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Traditional approaches for gene mapping from candidate gene studies to positional cloning strategies have been applied for Mendelian disorders. Since 2005, next-generation sequencing (NGS) technologies are improving as rapid, high-throughput and cost-effective approaches to fulfill medical sciences and research demands. Using NGS, the underlying causative genes are directly distinguished via a systematic filtering, in which the identified gene variants are checked for novelty and functionality. During the past 2 years, the role of more than 100 genes has been distinguished in rare Mendelian disorders by means of whole-exome sequencing (WES). Combination of WES with traditional approaches, consistent with linkage analysis, has had the greatest impact on those disorders following autosomal mode of inheritance; in more than 60 identified genes, the causal variants have been transmitted at homozygous or compound heterozygous state. Recent literatures focusing on identified new causal genes in Mendelian disorders using WES are reviewed in the present survey.

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“…For example, a study of patients with an inherited leukoencephalopathy (i.e., diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum) identified mutations in subunits of RNA polymerase III as the cause of this syndrome [83]. It suggested that the underlying pathogenic mechanism is deregulation of Pol III-transcribed ncRNAs, which include non-polyadenylated lncRNAs and those that can be cleaved into short ncRNAs.…”

Section: Establishing Paradigms For Lncrna-related Pathologymentioning

confidence: 99%

Long Non-coding RNAs: Novel Targets for Nervous System Disease Diagnosis and Therapy

2013

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The human genome encodes tens of thousands of long non-coding RNAs (lncRNAs), a novel and important class of genes. Our knowledge of lncRNAs has grown exponentially since their discovery within the last decade. lncRNAs are expressed in a highly cell-and tissue-specific manner, and are particularly abundant within the nervous system. lncRNAs are subject to post-transcriptional processing and inter-and intra-cellular transport. lncRNAs act via a spectrum of molecular mechanisms leveraging their ability to engage in both sequence-specific and conformational interactions with diverse partners (DNA, RNA, and proteins). Because of their size, lncRNAs act in a modular fashion, bringing different macromolecules together within the three-dimensional context of the cell. lncRNAs thus coordinate the execution of transcriptional, post-transcriptional, and epigenetic processes and critical biological programs (growth and development, establishment of cell identity, and deployment of stress responses). Emerging data reveal that lncRNAs play vital roles in mediating the developmental complexity, cellular diversity, and activitydependent plasticity that are hallmarks of brain. Corresponding studies implicate these factors in brain aging and the pathophysiology of brain disorders, through evolving paradigms including the following: (i) genetic variation in lncRNA genes causes disease and influences susceptibility; (ii) epigenetic deregulation of lncRNAs genes is associated with disease; (iii) genomic context links lncRNA genes to disease genes and pathways; and (iv) lncRNAs are otherwise interconnected with known pathogenic mechanisms. Hence, Electronic supplementary material The online version of this article

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

Cited by 148 publications

References 27 publications

RNA polymerase III subunit architecture and implications for open promoter complex formation

RNA polymerase III subunit architecture and implications for open promoter complex formation

Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders

Long Non-coding RNAs: Novel Targets for Nervous System Disease Diagnosis and Therapy

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