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


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.

SUBMITTER: Colin E 

PROVIDER: S-EPMC5011045 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Colin Estelle E   Daniel Jens J   Ziegler Alban A   Wakim Jamal J   Scrivo Aurora A   Haack Tobias B TB   Khiati Salim S   Denommé Anne-Sophie AS   Amati-Bonneau Patrizia P   Charif Majida M   Procaccio Vincent V   Reynier Pascal P   Aleck Kyrieckos A KA   Botto Lorenzo D LD   Herper Claudia Lena CL   Kaiser Charlotte Sophia CS   Nabbout Rima R   N'Guyen Sylvie S   Mora-Lorca José Antonio JA   Assmann Birgit B   Christ Stine S   Meitinger Thomas T   Strom Tim M TM   Prokisch Holger H   Miranda-Vizuete Antonio A   Hoffmann Georg F GF   Lenaers Guy G   Bomont Pascale P   Liebau Eva E   Bonneau Dominique D  

American journal of human genetics 20160818 3


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 t  ...[more]

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