Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism - PubMed (original) (raw)
doi: 10.1136/jmedgenet-2012-101357. Epub 2013 Jan 25.
Martine Tétreault, William Gibson, Kether Guerrero, Ana Cohen, Janina Gburek-Augustat, Matthis Synofzik, Bernard Brais, Cathy A Stevens, Rocio Sanchez-Carpintero, Cyril Goizet, Sakkubai Naidu, Adeline Vanderver, Geneviève Bernard
Affiliations
- PMID: 23355746
- DOI: 10.1136/jmedgenet-2012-101357
Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism
Hussein Daoud et al. J Med Genet. 2013 Mar.
Abstract
Background: Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterised by abnormal central nervous system white matter. Mutations in POLR3A and POLR3B genes were recently reported to cause four clinically overlapping hypomyelinating leukodystrophy phenotypes. Our aim was to investigate the presence and frequency of POLR3A and POLR3B mutations in patients with genetically unexplained hypomyelinating leukodystrophies with typical clinical and/or radiologic features of Pol III-related leukodystrophies.
Methods: The entire coding region and the flanking exon/intron boundaries of POLR3A and/or POLR3B genes were amplified and sequenced in 14 patients.
Results: Recessive mutations in POLR3A or POLR3B were uncovered in all 14 patients. Eight novel mutations were identified in POLR3A: six missenses, one nonsense, and one frameshift mutation. Seven patients carried compound heterozygous mutations in POLR3B, of whom six shared the common mutation in exon 15 (p.V523E). Seven novel mutations were identified in POLR3B: four missenses, two splice sites, and one intronic mutation.
Conclusions: To date, our group has described 37 patients, of whom 27 have mutations in POLR3A and 10 in POLR3B, respectively. Altogether, our results further support the proposal that POLR3A and POLR3B mutations are a major cause of hypomyelinating leukodystrophies and suggest that POLR3A mutations are more frequent.
Similar articles
- Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy.
Tétreault M, Choquet K, Orcesi S, Tonduti D, Balottin U, Teichmann M, Fribourg S, Schiffmann R, Brais B, Vanderver A, Bernard G. Tétreault M, et al. Am J Hum Genet. 2011 Nov 11;89(5):652-5. doi: 10.1016/j.ajhg.2011.10.006. Epub 2011 Oct 27. Am J Hum Genet. 2011. PMID: 22036172 Free PMC article. - Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.
Saitsu H, Osaka H, Sasaki M, Takanashi J, Hamada K, Yamashita A, Shibayama H, Shiina M, Kondo Y, Nishiyama K, Tsurusaki Y, Miyake N, Doi H, Ogata K, Inoue K, Matsumoto N. Saitsu H, et al. Am J Hum Genet. 2011 Nov 11;89(5):644-51. doi: 10.1016/j.ajhg.2011.10.003. Epub 2011 Oct 27. Am J Hum Genet. 2011. PMID: 22036171 Free PMC article. - The leukodystrophy mutation Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis.
Choquet K, Pinard M, Yang S, Moir RD, Poitras C, Dicaire MJ, Sgarioto N, Larivière R, Kleinman CL, Willis IM, Gauthier MS, Coulombe B, Brais B. Choquet K, et al. Mol Brain. 2019 Jun 20;12(1):59. doi: 10.1186/s13041-019-0479-7. Mol Brain. 2019. PMID: 31221184 Free PMC article. - POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?
Coulombe B, Derksen A, La Piana R, Brais B, Gauthier MS, Bernard G. Coulombe B, et al. Fac Rev. 2021 Feb 5;10:12. doi: 10.12703/r/10-12. eCollection 2021. Fac Rev. 2021. PMID: 33659930 Free PMC article. Review. - RNA Polymerase III Subunit Mutations in Genetic Diseases.
Lata E, Choquet K, Sagliocco F, Brais B, Bernard G, Teichmann M. Lata E, et al. Front Mol Biosci. 2021 Jul 30;8:696438. doi: 10.3389/fmolb.2021.696438. eCollection 2021. Front Mol Biosci. 2021. PMID: 34395528 Free PMC article. Review.
Cited by
- Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.
Thiffault I, Wolf NI, Forget D, Guerrero K, Tran LT, Choquet K, Lavallée-Adam M, Poitras C, Brais B, Yoon G, Sztriha L, Webster RI, Timmann D, van de Warrenburg BP, Seeger J, Zimmermann A, Máté A, Goizet C, Fung E, van der Knaap MS, Fribourg S, Vanderver A, Simons C, Taft RJ, Yates JR 3rd, Coulombe B, Bernard G. Thiffault I, et al. Nat Commun. 2015 Jul 7;6:7623. doi: 10.1038/ncomms8623. Nat Commun. 2015. PMID: 26151409 Free PMC article. - Expanding the phenotypic and molecular spectrum of RNA polymerase III-related leukodystrophy.
Perrier S, Gauquelin L, Fallet-Bianco C, Dishop MK, Michell-Robinson MA, Tran LT, Guerrero K, Darbelli L, Srour M, Petrecca K, Renaud DL, Saito M, Cohen S, Leiz S, Alhaddad B, Haack TB, Tejera-Martin I, Monton FI, Rodriguez-Espinosa N, Pohl D, Nageswaran S, Grefe A, Glamuzina E, Bernard G. Perrier S, et al. Neurol Genet. 2020 May 11;6(3):e425. doi: 10.1212/NXG.0000000000000425. eCollection 2020 Jun. Neurol Genet. 2020. PMID: 32582862 Free PMC article. - Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies.
Richards MR, Plummer L, Chan YM, Lippincott MF, Quinton R, Kumanov P, Seminara SB. Richards MR, et al. J Med Genet. 2017 Jan;54(1):19-25. doi: 10.1136/jmedgenet-2016-104064. Epub 2016 Aug 10. J Med Genet. 2017. PMID: 27512013 Free PMC article. - New findings in oligogenic inheritance of congenital hypogonadotropic hypogonadism.
Gach A, Pinkier I, Wysocka U, Sałacińska K, Salachna D, Szarras-Czapnik M, Pietrzyk A, Sakowicz A, Nykel A, Rutkowska L, Rybak-Krzyszkowska M, Socha M, Jamsheer A, Jakubowski L. Gach A, et al. Arch Med Sci. 2020 Sep 18;18(2):353-364. doi: 10.5114/aoms.2020.98909. eCollection 2022. Arch Med Sci. 2020. PMID: 35316923 Free PMC article. - Hypomyelination, hypodontia and craniofacial abnormalities in a Polr3b mouse model of leukodystrophy.
Michell-Robinson MA, Watt KEN, Grouza V, Macintosh J, Pinard M, Tuznik M, Chen X, Darbelli L, Wu CL, Perrier S, Chitsaz D, Uccelli NA, Liu H, Cox TC, Müller CW, Kennedy TE, Coulombe B, Rudko DA, Trainor PA, Bernard G. Michell-Robinson MA, et al. Brain. 2023 Dec 1;146(12):5070-5085. doi: 10.1093/brain/awad249. Brain. 2023. PMID: 37635302 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases