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Publication Details

Title :

Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development

Journal:

Brain

Impact Factor:

10.292

Authors:

Nahorski MS1, Maddirevula S2, Ishimura R3, Alsahli S2, Brady AF4, Begemann A5, Mizushima T6, Guzmán-Vega FJ7, Obata M3, Ichimura Y3, Alsaif HS2, Anazi S2, Ibrahim N2, Abdulwahab F2, Hashem M2, Monies D2,8, Abouelhoda M2,8, Meyer BF2,8, Alfadhel M9, Eyaid W9, Zweier M5, Steindl K5, Rauch A5,10, Arold ST7, Woods CG1, Komatsu M3, Alkuraya FS2,8,11.

Affiliations:

1 Cambridge Institute for Medical Research, Wellcome Trust MRC Building Addenbrookes Hospital, Hills Rd, Cambridge, UK.

2 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

3 Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Japan.

4 North West Thames Genetics Service, Level 8V, St Mark’s Hospital, Northwick Park Hospital Watford Road, Harrow, UK.

5 Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland.

6 Picobiology Institute, Graduate School of Life Science, University of Hyogo, Ako-gun, Hyogo, Japan.

7 King Abdullah University of Science and Technology, Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering, Thuwal, Saudi Arabia.

8 Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.

9 King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia.

10 Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.

11 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

Year of Publication:

2018

DOI:

10.1093/brain/awy135.

Abstract:

The post-translational modification of proteins through the addition of UFM1, also known as ufmylation, plays a critical developmental role as revealed by studies in animal models. The recent finding that biallelic mutations in UBA5 (the E1-like enzyme for ufmylation) cause severe early-onset encephalopathy with progressive microcephaly implicates ufmylation in human brain development. More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation. This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins. Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.