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Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

ABSTRACT: A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy.

SUBMITTER: Thiffault I

PROVIDER: S-EPMC4506509 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

Thiffault Isabelle I Wolf Nicole I NI Forget Diane D Guerrero Kether K Tran Luan T LT Choquet Karine K Lavallée-Adam Mathieu M Poitras Christian C Brais Bernard B Yoon Grace G Sztriha Laszlo L Webster Richard I RI Timmann Dagmar D van de Warrenburg Bart P BP Seeger Jürgen J Zimmermann Alíz A Máté Adrienn A Goizet Cyril C Fung Eva E van der Knaap Marjo S MS Fribourg Sébastien S Vanderver Adeline A Simons Cas C Taft Ryan J RJ Yates John R JR Coulombe Benoit B Bernard Geneviève G

Nature communications 20150707

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodyst ...[more]

PMID: 26151409

Dataset Information

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

Publications

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

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