Title |
Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development
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Published in |
Brain, June 2018
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DOI | 10.1093/brain/awy135 |
Pubmed ID | |
Authors |
Michael S Nahorski, Sateesh Maddirevula, Ryosuke Ishimura, Saud Alsahli, Angela F Brady, Anaïs Begemann, Tsunehiro Mizushima, Francisco J Guzmán-Vega, Miki Obata, Yoshinobu Ichimura, Hessa S Alsaif, Shams Anazi, Niema Ibrahim, Firdous Abdulwahab, Mais Hashem, Dorota Monies, Mohamed Abouelhoda, Brian F Meyer, Majid Alfadhel, Wafa Eyaid, Markus Zweier, Katharina Steindl, Anita Rauch, Stefan T Arold, C Geoffrey Woods, Masaaki Komatsu, Fowzan S Alkuraya |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United Kingdom | 1 | 50% |
Unknown | 1 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 50% |
Scientists | 1 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 72 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Bachelor | 16 | 22% |
Student > Ph. D. Student | 11 | 15% |
Student > Master | 8 | 11% |
Researcher | 6 | 8% |
Student > Doctoral Student | 5 | 7% |
Other | 5 | 7% |
Unknown | 21 | 29% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 31 | 43% |
Medicine and Dentistry | 6 | 8% |
Agricultural and Biological Sciences | 5 | 7% |
Chemistry | 3 | 4% |
Business, Management and Accounting | 2 | 3% |
Other | 6 | 8% |
Unknown | 19 | 26% |