Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy

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Muona , M , Ishimura , R , Laari , A , Ichimura , Y , Linnankivi , T , Keski-Filppula , R , Herva , R , Rantala , H , Paetau , A , Pöyhönen , M , Obata , M , Uemura , T , Karhu , T , Bizen , N , Takebayashi , H , McKee , S , Parker , M J , Akawi , N , McRae , J , Hurles , M E , Kuismin , O , Kurki , M I , Anttonen , A-K , Tanaka , K , Palotie , A , Waguri , S , Lehesjoki , A-E , Komatsus , M & DDD Study 2016 , ' Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy ' , American Journal of Human Genetics , vol. 99 , no. 3 , pp. 683-694 .

Title: Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy
Author: Muona, Mikko; Ishimura, Ryosuke; Laari, Anni; Ichimura, Yoshinobu; Linnankivi, Tarja; Keski-Filppula, Riikka; Herva, Riitta; Rantala, Heikki; Paetau, Anders; Pöyhönen, Minna; Obata, Miki; Uemura, Takefumi; Karhu, Thomas; Bizen, Norihisa; Takebayashi, Hirohide; McKee, Shane; Parker, Michael J.; Akawi, Nadia; McRae, Jeremy; Hurles, Matthew E.; Kuismin, Outi; Kurki, Mitja I.; Anttonen, Anna-Kaisa; Tanaka, Keiji; Palotie, Aarno; Waguri, Satoshi; Lehesjoki, Anna-Elina; Komatsus, Masaaki; DDD Study
Contributor organization: Institute for Molecular Medicine Finland
Research Programme for Molecular Neurology
Research Programs Unit
Neuroscience Center
Children's Hospital
Lastenneurologian yksikkö
Department of Pathology
Minna Pöyhönen / Principal Investigator
Department of Medical and Clinical Genetics
Anna-Elina Lehesjoki / Principal Investigator
Aarno Palotie / Principal Investigator
HUS Children and Adolescents
Genomics of Neurological and Neuropsychiatric Disorders
Date: 2016-09-01
Language: eng
Number of pages: 12
Belongs to series: American Journal of Human Genetics
ISSN: 0002-9297
Abstract: The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBAS, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBAS variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.A1a371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg5SHis, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.A1a371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufml in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.A1a371Thr variant in trans with a loss-of-function allele in UBAS underlies a severe infantile-onset encephalopathy.
3112 Neurosciences
3111 Biomedicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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