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POLR3A gene
URL of this page: https://medlineplus.gov/genetics/gene/polr3a/

POLR3A gene

RNA polymerase III subunit A

Normal Function

The POLR3A gene provides instructions for making the largest piece (subunit) of an enzyme called RNA polymerase III. This enzyme is involved in the production (synthesis) of RNA, a chemical cousin of DNA. The RNA polymerase III enzyme attaches (binds) to DNA and synthesizes RNA molecules using the instructions carried by the DNA, a process called transcription. RNA polymerase III helps synthesize several forms of RNA, including ribosomal RNA (rRNA) and transfer RNA (tRNA). Molecules of rRNA and tRNA assemble protein building blocks (amino acids) into working proteins; this process is essential for the normal functioning and survival of cells.

Health Conditions Related to Genetic Changes

Pol III-related leukodystrophy

Many POLR3A gene variants (also called mutations) have been found to cause Pol III-related leukodystrophy. Leukodystrophies are conditions that involve abnormalities of the nervous system's white matter. White matter consists of nerve fibers covered by a fatty substance called myelin, which insulates nerve fibers and promotes the rapid transmission of nerve impulses. A reduced ability to form myelin (hypomyelination) leads to the signs and symptoms of Pol III-related leukodystrophy, which include intellectual disabilities and difficulty with coordination and balance (ataxia). Development of the teeth (dentition) is also abnormal in people with this disorder.

In people with Pol III-related leukodystrophy, POLR3A gene variants may prevent the subunits of the RNA polymerase III enzyme from assembling properly. Variants may also prevent RNA polymerase III from binding to DNA. Reduced function of the RNA polymerase III molecule likely affects development of many parts of the body, but the relationship between POLR3A gene variants and the specific signs and symptoms of this disorder is unknown.

People with Pol III-related leukodystrophy may have different combinations of signs and symptoms. These varied combinations of clinical features were originally described as separate disorders. Affected individuals may be diagnosed with ataxia, delayed dentition, and hypomyelination (ADDH); hypomyelination, hypodontia, and hypogonadotropic hypogonadism (4H syndrome); tremor-ataxia with central hypomyelination (TACH); leukodystrophy with oligodontia (LO); or hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Because these disorders were later found to have the same genetic cause, researchers now group them together as variations of Pol III-related leukodystrophy.

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Wiedemann-Rautenstrauch syndrome

Variants in the POLR3A gene cause cause Wiedemann-Rautenstrauch syndrome. People with this condition appear older than they are. Affected individuals grow slowly before and after birth. They have a characteristic facial appearance, a lack of fatty tissue under the skin (lipodystrophy), sparse hair on their head, and abnormal tooth development.

The POLR3A gene variants that cause Wiedemann-Rautenstrauch syndrome alter the instructions for making the RNA polymerase III subunit. These variants result in the production of abnormal subunit proteins that are thought to impair the function of RNA polymerase III. The resulting shortage of RNA likely impairs the production of many proteins, which affects development. However, it is not known exactly how variants in the POLR3A gene lead to the specific features of Wiedemann-Rautenstrauch syndrome.

Researchers suspect that the variants that cause Wiedemann-Rautenstrauch syndrome affect the function of RNA polymerase III more drastically than the variants that cause Pol III-related leukodystrophy (described above), which may explain why development is affected even before birth in individuals with Wiedemann-Rautenstrauch syndrome. Because of its distinct signs and symptoms, Wiedemann-Rautenstrauch syndrome is not thought to be part of the Pol III-related leukodystrophy spectrum.

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Shingles

MedlinePlus Genetics provides information about Shingles

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Other disorders

Variants in the POLR3A gene have been found in individuals with ataxia and dental abnormalities. Unlike in Pol III-related leukodystrophy (described above), these individuals do not have reduced myelination in the nervous system. Ataxia that is caused by POLR3A gene variants typically begins in adolescence. Affected individuals may also develop rhythmic shaking (tremor) in their arms or legs and have a reduced ability to sense vibrations, particularly in the feet. Researchers are unsure if this condition is part of the spectrum of Pol III-related leukodystrophy. It is unclear why variants in the same gene lead to several disorders of varying severity.

Other Names for This Gene

  • DNA-directed RNA polymerase III largest subunit
  • DNA-directed RNA polymerase III subunit A
  • polymerase (RNA) III subunit A
  • RNA polymerase III 155 kDa subunit
  • RPC1
  • RPC155
  • RPC1_HUMAN

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Bernard G, Chouery E, Putorti ML, Tetreault M, Takanohashi A, Carosso G, Clement I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teichmann M, Megarbane A, Schiffmann R, Vanderver A, Brais B. Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011 Sep 9;89(3):415-23. doi: 10.1016/j.ajhg.2011.07.014. Citation on PubMed or Free article on PubMed Central
  • Daoud H, Tetreault M, Gibson W, Guerrero K, Cohen A, Gburek-Augustat J, Synofzik M, Brais B, Stevens CA, Sanchez-Carpintero R, Goizet C, Naidu S, Vanderver A, Bernard G. Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism. J Med Genet. 2013 Mar;50(3):194-7. doi: 10.1136/jmedgenet-2012-101357. Epub 2013 Jan 25. Citation on PubMed
  • Jay AM, Conway RL, Thiffault I, Saunders C, Farrow E, Adams J, Toriello HV. Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A. Am J Med Genet A. 2016 Dec;170(12):3343-3346. doi: 10.1002/ajmg.a.37960. Epub 2016 Sep 9. Citation on PubMed
  • Minnerop M, Kurzwelly D, Wagner H, Soehn AS, Reichbauer J, Tao F, Rattay TW, Peitz M, Rehbach K, Giorgetti A, Pyle A, Thiele H, Altmuller J, Timmann D, Karaca I, Lennarz M, Baets J, Hengel H, Synofzik M, Atasu B, Feely S, Kennerson M, Stendel C, Lindig T, Gonzalez MA, Stirnberg R, Sturm M, Roeske S, Jung J, Bauer P, Lohmann E, Herms S, Heilmann-Heimbach S, Nicholson G, Mahanjah M, Sharkia R, Carloni P, Brustle O, Klopstock T, Mathews KD, Shy ME, de Jonghe P, Chinnery PF, Horvath R, Kohlhase J, Schmitt I, Wolf M, Greschus S, Amunts K, Maier W, Schols L, Nurnberg P, Zuchner S, Klockgether T, Ramirez A, Schule R. Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. Brain. 2017 Jun 1;140(6):1561-1578. doi: 10.1093/brain/awx095. Citation on PubMed
  • Paolacci S, Li Y, Agolini E, Bellacchio E, Arboleda-Bustos CE, Carrero D, Bertola D, Al-Gazali L, Alders M, Altmuller J, Arboleda G, Beleggia F, Bruselles A, Ciolfi A, Gillessen-Kaesbach G, Krieg T, Mohammed S, Muller C, Novelli A, Ortega J, Sandoval A, Velasco G, Yigit G, Arboleda H, Lopez-Otin C, Wollnik B, Tartaglia M, Hennekam RC. Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. J Med Genet. 2018 Dec;55(12):837-846. doi: 10.1136/jmedgenet-2018-105528. Epub 2018 Oct 15. Citation on PubMed
  • Perrier S, Gauquelin L, Wambach JA, Bernard G. Distinguishing severe phenotypes associated with pathogenic variants in POLR3A. Am J Med Genet A. 2022 Feb;188(2):708-712. doi: 10.1002/ajmg.a.62553. Epub 2021 Nov 12. Citation on PubMed
  • Potic A, Brais B, Choquet K, Schiffmann R, Bernard G. 4H syndrome with late-onset growth hormone deficiency caused by POLR3A mutations. Arch Neurol. 2012 Jul;69(7):920-3. doi: 10.1001/archneurol.2011.1963. Citation on PubMed
  • 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. Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Am J Hum Genet. 2011 Nov 11;89(5):644-51. doi: 10.1016/j.ajhg.2011.10.003. Epub 2011 Oct 27. Citation on PubMed or Free article on PubMed Central
  • Terao Y, Saitsu H, Segawa M, Kondo Y, Sakamoto K, Matsumoto N, Tsuji S, Nomura Y. Diffuse central hypomyelination presenting as 4H syndrome caused by compound heterozygous mutations in POLR3A encoding the catalytic subunit of polymerase III. J Neurol Sci. 2012 Sep 15;320(1-2):102-5. doi: 10.1016/j.jns.2012.07.005. Epub 2012 Jul 21. Citation on PubMed
  • Vanderver A, Tonduti D, Bernard G, Lai J, Rossi C, Carosso G, Quezado M, Wong K, Schiffmann R. More than hypomyelination in Pol-III disorder. J Neuropathol Exp Neurol. 2013 Jan;72(1):67-75. doi: 10.1097/NEN.0b013e31827c99d2. Citation on PubMed or Free article on PubMed Central

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