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

Am J Hum Genet. 2016 Sep 1;99(3):695-703. doi: 10.1016/j.ajhg.2016.06.030.

Estelle Colin ¹, Jens Daniel ², Alban Ziegler ¹, Jamal Wakim ³, Aurora Scrivo ⁴, Tobias B Haack ⁵, Salim Khiati ³, Anne-Sophie Denommé ¹, Patrizia Amati-Bonneau ¹, Majida Charif ³, Vincent Procaccio ¹, Pascal Reynier ¹, Kyrieckos A Aleck ⁶, Lorenzo D Botto ⁷, Claudia Lena Herper ², Charlotte Sophia Kaiser ², Rima Nabbout ⁸, Sylvie N'Guyen ⁹, José Antonio Mora-Lorca ¹⁰, Birgit Assmann ¹¹, Stine Christ ¹¹, Thomas Meitinger ¹², Tim M Strom ¹², Holger Prokisch ¹², FREX Consortium, Antonio Miranda-Vizuete ¹⁰, Georg F Hoffmann ¹¹, Guy Lenaers ³, Pascale Bomont ⁴, Eva Liebau ², Dominique Bonneau ¹³

Affiliations

1 Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
2 Department of Molecular Physiology, Westfälische Wilhelms-University Münster, 48143 Münster, Germany.
3 UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
4 Avenir-Atip team, INSERM U1051, Institute of Neurosciences of Montpellier, University of Montpellier, 34091 Montpellier Cedex 5, France.
5 Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
6 Department of Genetics and Metabolism, Phoenix Children's Medical Group, Phoenix, AZ 85016, USA.
7 Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84132, USA.
8 Department of Pediatric Neurology, National Reference Center for Rare Epilepsies, University Hospital Necker-Enfants-Malades, 75015 Paris, France.
9 Department of Pediatric Neurology, University Hospital, 49933 Angers Cedex 9, France.
10 Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
11 Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
12 Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
13 Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France. Electronic address: [email protected].

PMID: 27545681 DOI: 10.1016/j.ajhg.2016.06.030

Abstract

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.

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