Identification of the POLR3A gene as being responsible for the TACH and LO hypomyelinating leukodystrophies and for the 4H syndrome

Written on Friday 30 March 2012

Leukodystrophies are a heterogeneous group of hereditary neurodegenerative diseases characterised by disorders of the white matter that are visible upon cerebral imaging. We estimate that 30 to 40 % of sick people remain  undiagnosed, despite detailed examinations being carried out.

The TACH leukodystrophy is a form of hypomyelinating leukodystrophy that begins in childhood with severe shaking and cerebellar symptoms. It was recently described in Franco-Canadian individuals and the candidate gene for this pathology has been localised to a specific region of chromosome 10 DNA. The candidate gene for another hypomyelinating leukodystrophy, LO leukodystrophy, has also been localised to this region of chromosome 10 in a Syrian family. These two diseases show clinical and radiological similarities with another form of hypomyelinating leukodystrophy known as the 4H syndrome.

By combining the results obtained for these three hypomyelinating leukodystrophies, the location of the candidate gene has been delimited to a DNA region of about 15 genes. Sequencing of this region of the DNA allowed us to establish that the three leukodystrophies are due to recessive mutations in the POLR3A gene, the gene that codes for the largest subunit of human RNA polymerase III. Thus they form a group of leukodystrophies linked to polymerase III.
RNA polymerase III is a multi-protein complex composed of 17 subunits, which is involved in the transcription  of small RNAs (transfer RNAs and 5S ribosomal RNA) that do not code for proteins  but are essential for protein synthesis.
A detailed analysis of the POLR3A mutations in the different families studied revealed a total of 14 recessive mutations found in the homozygote or composite heterozygote state. Each parent carries one of the POLR3A mutations but is not affected by the disease.

Analyses carried out on a brain autopsy and on skin cells of individuals suffering from the 4H syndrome demonstrated that, whatever the nature of POLR3A mutations, the level of the POL3RA protein was significantly lower than in healthy subjects.

Individuals suffering from a disease of the group of leukodystrophies linked to polymerase III have in common a dysfunction of the upper motoneuron, a certain degree of cerebellar ravages and cognitive regression. The loss of the ability to walk occurs on average at age 16.1 years. All patients display hypomyelination by MRI, with a preferential attack of the profound white matter.
Despite their similarities, TACH and LO leukodystrophies and the 4H syndrome show specific particularities, which are accompanied by inter- and intra-familial variations. In individuals with TACH leukodystrophy, the illness breaks out earlier than for the other diseases and delays in development are apparent during childhood. The severity of the disease is highly variable even where individuals with TACH leukodystrophy carry the same mutation, irrespective of whether or not they belong to the same family. Disorders of eye movement are more frequent in patients with TACH leukodystrophy and the 4H syndrome than in those suffering from LO leukodystrophy. Optical atrophy is a frequent characteristic of TACH leukodystrophy, but is not seen for LO leukodystrophy or the 4H syndrome. The damage of peripheral nerves is, for its part, inconstant. Hypodontia and hypogonadism are not universally seen in polymerase III-linked leukodystrophies, but their presence should encourage clinicians to seek out POLR3A mutations. The identification of a larger number of cases of hypomyelinating leukodystrophies with POLR3A mutations is necessary for a better definition of this group of leukodystrophies and for the genotype-phenotype correlation to be studied.

Illnesses: A group of leukodystrophies linked to polymerase III, comprised of TACH and LO leukodystrophies and the 4H syndrome.
Subjects: 6 patients suffering from TACH leukodystrophy, 5 patients suffering from the 4H syndrome and 8 patients with LO leukodystrophy.
Study type: Genetic


  • Dr. Bernard Brais, Department of Pediatrics, Neurology and Neurosurgery, Division of Pediatric Neurology, Montreal Childrens’ Hospital, Medical Center of the University of McGill, Montreal, Quebec, Canada
  • Dr. André Mégarbane, Medical Genetic Unit and associated laboratory, INSERM Unit UMR_S 910, Medical Faculty, Saint Joseph University, Beirut, Lebanon
  • Pr. Odile Boespflug-Tanguy, Public Assistance of Paris Hospitals (AP-HP), Reference Centre for Leukodystrophies, Robert Debré Hospital, Paris, France
  • Pr. Diana Rodriguez, AP-HP, Pediatrics Neurology Service, Armand Trousseau Hospital, Paris, France

Funding: ELA

Source : Geneviève Bernard, Eliane Chouery, Maria Lisa Putorti, Martine Tétreault, Asako Takanohashi, Giovanni Carosso, Isabelle Clément, Odile Boespflug-Tanguy, Diana Rodriguez, Valérie Delague, Joelle Abou Ghoch, Nadine Jalkh, Imen Dorboz, Sebastien Fribourg, Martin Teichmann, André Megarbane, Raphael Schiffmann, Adeline Vanderver, Bernard Brais. Mutations of POLR3A Encoding a Catalytic Subunit of RNA Polymerase Pol III Cause a Recessive Hypomyelinating Leukodystrophy. The American Journal of Human Genetics, 2011, 89: 1–9.

Medical Abbreviations:

  • TACH for “Tremor-Ataxia with Central Hypomyelination”
  • LO for “Leukodystrophy with Oligodontia”
  • 4H Syndrome for “Hypomyelination with Hypodontia and Hypogonadotropic Hypogonadism”