Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy

Estelle Colin (1) , Jens Daniel , Alban Ziegler (1) , Jamal Wakim (2, 3, 4) , Aurora Scrivo , Tobias B. Haack , Salim Khiati (5) , Anne-Sophie Denommé (1) , Patrizia Amati-Bonneau (6, 5) , Majida Charif (7) , Vincent Procaccio (5) , Pascal Reynier (6) , Kyrieckos A. Aleck , Lorenzo D. Botto , Claudia Lena Herper , Charlotte Sophia Kaiser , Rima Nabbout (8) , Sylvie N'Guyen (9) , José Antonio Mora-Lorca , Birgit Assmann , Stine Christ , Thomas Meitinger (10) , Tim M. Strom (10) , Holger Prokisch (10) , Frex Consortium , Antonio Miranda-Vizuete , Georg F. Hoffmann , Guy Lenaers (6) , Pascale Bomont (7) , Eva Liebau , Dominique Bonneau (11, 1)

1 Service de génétique [Angers]
2 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
3 CNRS - Centre National de la Recherche Scientifique
4 INSERM - Institut National de la Santé et de la Recherche Médicale
5 BNMI - Biologie Neurovasculaire et Mitochondriale Intégrée
6 CHU Angers - Centre Hospitalier Universitaire d'Angers
7 INM - Institut des Neurosciences de Montpellier
8 U1129 - Epilepsies de l'Enfant et Plasticité Cérébrale
9 Clinique Médicale Pédiatrique
10 Institute of Human Genetics
11 Mitochondrie : Régulations et Pathologie

Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.

Domaines: Sciences du Vivant [q-bio]

Estelle Colin, Jens Daniel, Alban Ziegler, Jamal Wakim, Aurora Scrivo, et al.. Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy. American Journal of Human Genetics, 2016, Equipe 3 Equipe 4, 99 (3), pp.695--703. ⟨10.1016/j.ajhg.2016.06.030⟩. ⟨hal-01831597⟩