RRC ID 53515
著者 Colin E, Daniel J, Ziegler A, Wakim J, Scrivo A, Haack TB, Khiati S, Denommé AS, Amati-Bonneau P, Charif M, Procaccio V, Reynier P, Aleck KA, Botto LD, Herper CL, Kaiser CS, Nabbout R, N'Guyen S, Mora-Lorca JA, Assmann B, Christ S, Meitinger T, Strom TM, Prokisch H, FREX Consortium, Miranda-Vizuete A, Hoffmann GF, Lenaers G, Bomont P, Liebau E, Bonneau D.
タイトル Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy.
ジャーナル Am J Hum Genet
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.
巻・号 99(3)
ページ 695-703
公開日 2016-9-1
DOI 10.1016/j.ajhg.2016.06.030
PII S0002-9297(16)30268-3
PMID 27545681
PMC PMC5011045
MeSH Age of Onset Alleles* Animals Brain Diseases / genetics* Brain Mapping Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Child Child, Preschool Cholinergic Neurons / metabolism Endoplasmic Reticulum / metabolism Endoplasmic Reticulum / pathology Epilepsy / genetics Exome / genetics Female Fibroblasts Genes, Recessive / genetics Humans Intellectual Disability / genetics Magnetic Resonance Imaging Male Microcephaly / genetics Movement Disorders Mutation / genetics* Proteins / genetics Proteins / metabolism* Synaptic Transmission / genetics Ubiquitin / genetics Ubiquitin / metabolism Ubiquitin-Activating Enzymes / deficiency Ubiquitin-Activating Enzymes / genetics* Ubiquitin-Activating Enzymes / metabolism Ubiquitins / genetics Ubiquitins / metabolism Zebrafish / genetics Zebrafish Proteins / deficiency Zebrafish Proteins / genetics Zebrafish Proteins / metabolism
IF 9.924
引用数 35
リソース情報
線虫 tm5221 tm5790 tm4876