Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation

Imen Dorboz (1) , Hélène Dumay-Odelot (2) , Karima Boussaid (3, 4) , Yosra Bouyacoub (5) , Pauline Barreau (1) , Simon Samaan (1) , Haifa Jmel (5) , Eléonore Eymard-Pierre (6) , Claude Cances (7) , Céline Bar (8) , Anne-Lise Poulat (9) , Christophe Rousselle (10) , Florence Renaldo (3, 4) , Monique Elmaleh- Bergès (11) , Martin Teichmann (12) , Odile Boespflug-Tanguy (3, 4, 1, 12)

1 PROTECT - Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies
2 LBPA - Laboratoire de Biologie et de Pharmacologie Appliquée
3 Service de neurologie pédiatrique et maladies métaboliques
4 LEUKOFRANCE - Centre de référence des leucodystrophies et leucoencéphalopathies de cause rare [AP-HP Hôpital Robert-Debré]
5 LR11IPT05 - Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory
6 Service de Cytogénétique Médicale [CHU Clermont-Ferrand]
7 Pôle Enfants [CHU Toulouse]
8 Service Endocrinologie, génétique et gynécologie médicale pédiatrique [CHU Toulouse]
9 Hôpital Femme Mère Enfant - Service de neurologie pédiatrique [HCL, Lyon]
10 ANSES - Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail
11 Département de Radiologie Pédiatrique [AP-HP Hôpital Robert-Debré]
12 ARNA - Acides Nucléiques : Régulations Naturelle et Artificielle

Objective To identify the genetic cause of hypomyelinating leukodystrophy in 2 consanguineous families. Methods Homozygosity mapping combined with whole-exome sequencing of consanguineous families was performed. Mutation consequences were determined by studying the structural change of the protein and by the RNA analysis of patients' fibroblasts. Results We identified a biallelic mutation in a gene coding for a Pol III-specific subunit, POLR3K (c.121C>T/p.Arg41Trp), that cosegregates with the disease in 2 unrelated patients. Patients expressed neurologic and extraneurologic signs found in POLR3A-and POLR3B-related leu-kodystrophies with a peculiar severe digestive dysfunction. The mutation impaired the POLR3K-POLR3B interactions resulting in zebrafish in abnormal gut development. Functional studies in the 2 patients' fibroblasts revealed a severe decrease (60%-80%) in the expression of 5S and 7S ribosomal RNAs in comparison with control. Conclusions These analyses underlined the key role of ribosomal RNA regulation in the development and maintenance of the white matter and the cerebellum as already reported for diseases related to genes involved in transfer RNA or translation initiation factors.

Domains: Life Sciences [q-bio]

Imen Dorboz, Hélène Dumay-Odelot, Karima Boussaid, Yosra Bouyacoub, Pauline Barreau, et al.. Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation. Neurology Genetics, 2018, 4 (6), pp.e289. ⟨10.1212/nxg.0000000000000289⟩. ⟨pasteur-02000258⟩