Recessive Mutations in POLR3B, Encoding the Second Largest Subunit of Pol III, Cause a Rare Hypomyelinating Leukodystrophy

Tétreault, Martine; Choquet, Karine; Orcesi, Simona; Tonduti, Davide; Balottin, Umberto; Teichmann, Martin; Fribourg, Sébastien; Schiffmann, Raphael; Brais, Bernard; Vanderver, Adeline; Bernard, Geneviève

doi:10.1016/j.ajhg.2011.10.006

Cited by 144 publications

(147 citation statements)

References 21 publications

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“…Lysates from all patients examined were strongly impaired in their ability to convert AT-rich DNA to immune-stimulatory RNA, whereas transcription of 5S rRNA was largely unaffected. Previous studies have identified mutations in POLR3A and POLR3B in patients with autosomal recessive 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy, which is a disease characterized by degeneration of the white matter in the brain (38)(39)(40). However, the functional impact of the POLR3 gene mutations in the 4H leukodystrophy patients on POL III activity remains to be established.…”

Section: Induction Of Ifns By At-rich Dna In Human Pbmcs Is Pol Iii-dmentioning

confidence: 99%

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Ogunjimi¹,

Zhang²,

Sørensen³

et al. 2017

Journal of Clinical Investigation

128

121

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Section: Induction Of Ifns By At-rich Dna In Human Pbmcs Is Pol Iii-dmentioning

confidence: 99%

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Ogunjimi¹,

Zhang²,

Sørensen³

et al. 2017

Journal of Clinical Investigation

128

121

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“…5 Mutations in POLR3A and POLR3B, encoding another subunit of this polymerase, were then shown to also cause 4H, as well as 2 other entities: "hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum," and "leukodystrophy with oligodontia." [6][7][8] The name Pol IIIrelated leukodystrophies has been suggested in order to include all the variations described above. As the term 4H encompasses the nonneurologic symptoms and is therefore clinically helpful for the diagnosis, we chose to refer to the condition as 4H leukodystrophy in this article.…”

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confidence: 99%

Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations

et al. 2014

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Objective: To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B.Methods: We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. Results:The majority of patients presented before 6 years with gross motor delay or regression.Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T.A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. Conclusions: 4H is a well-recognizable clinical entity if all features are present. Mutations inPOLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features. 4H leukodystrophy (4H) (HLD7, OMIM 607694 and HLD8, OMIM 614381) is typically characterized by the triad of hypomyelination, hypodontia, and hypogonadotropic hypogonadism. It was first identified in 4 children too young for the assessment of pubertal development. Clinical hallmarks were early-onset ataxia, delayed dentition, and hypomyelination (ADDH).

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“…1,2 Mutations in the POLR3A and POLR3B genes, which encode for the 2 largest subunits of the RNA polymerase III (POLR3) complex, as well as in POLR1C, also encoding a POLR3 subunit, are responsible for this disease. [6][7][8][9][10][11] With the identification of the causative genes, patients with suggestive clinical or MRI picture can undergo genetic testing, confirming the diagnosis. 12 The MRI pattern of POLR3-related leukodystrophy is suggestive and characterized by diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum.…”

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confidence: 99%

Diffuse hypomyelination is not obligate for POLR3-related disorders

et al. 2016

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Objective: To report atypical MRI patterns associated with POLR3A and POLR3B mutations.Methods: This was a multicenter retrospective study to collect neuroradiologic, clinical, and molecular data of patients with mutations in POLR3A and POLR3B without the classic MRI phenotype, i.e., diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum.Results: Eight patients were identified: 6 carried mutations in POLR3A and 2 in POLR3B. We identified 2 novel MRI patterns: 4 participants presented a selective involvement of the corticospinal tracts, specifically at the level of the posterior limbs of the internal capsules; 4 patients presented moderate to severe cerebellar atrophy. Incomplete hypomyelination was observed in 5 participants.Conclusion: Diffuse hypomyelination is not an obligatory feature of POLR3-related disorders.Two distinct patterns, selective involvement of the corticospinal tracts and cerebellar atrophy, are added to the MRI presentation of POLR3-related disorders. POLR3-related leukodystrophy is a rare autosomal recessive disease characterized by hypomyelination often accompanied by dental abnormalities and hypogonadotropic hypogonadism. [1][2][3][4][5] In its classical form, the association of these features is referred to as 4H syndrome.1,2 Mutations in the POLR3A and POLR3B genes, which encode for the 2 largest subunits of the RNA polymerase III (POLR3) complex, as well as in POLR1C, also encoding a POLR3 subunit, are responsible for this disease. [6][7][8][9][10][11] With the identification of the causative genes, patients with suggestive clinical or MRI picture can undergo genetic testing, confirming the diagnosis. 12 The MRI pattern of POLR3-related leukodystrophy is suggestive and characterized by diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum.12-14 Recognition of this pattern was proven effective in detecting patients with 4H leukodystrophy caused by POLR3A-B or POLR1C mutations and is therefore *These authors contributed equally to this work. ‡Dual last authors.

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Recessive Mutations in POLR3B, Encoding the Second Largest Subunit of Pol III, Cause a Rare Hypomyelinating Leukodystrophy

Cited by 144 publications

References 21 publications

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations

Diffuse hypomyelination is not obligate for POLR3-related disorders

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