Abstract
The ubiquitin-proteasome pathway is involved in the pathogenesis of several neurogenetic diseases. We describe a Mauritanian patient harboring a homozygous deletion restricted to two contiguous genes HERC2 and OCA2 and presenting with severe developmental abnormalities. The deletion causes the complete loss of HERC2 protein function, an E3-ubiquitin ligase. HERC2 is known to target XPA and BRCA1 for degradation and a mechanism whereby it is involved in DNA repair and cell cycle regulation. We showed that loss of HERC2 function leads to the accumulation of XPA and BRCA1 in the patient’s fibroblasts and generates decreased sensitivity to apoptosis and increased level of DNA repair. Our data describe for the first time the phenotypic consequences, both at the clinical and cellular levels, of a complete loss of HERC2 function in a patient. They strongly suggest that profound ubiquitin ligase – associated dysfunction is responsible for the severe phenotype in this patient, and that dysfunction of this pathway may be involved in other patients with similar neurodevelopmental diseases.
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Acknowledgements
The authors are grateful to the patient and his family for their participation in this study. This work was supported by Genespoir (French Albinism Association) by the Ministry of Health and by the Ministry of Research of France. Funding: This work was supported by Genespoir (French Albinism Association), by Union Nationale des Aveugles et Déficients Visuels (France), by the Ministry of Health and by the Ministry of Research of France. FMP had a PhD studentship from the Fondation pour la Recherche Médicale (France). Sanger DNA Sequencing was performed at the Genome Transcriptome Platform of Bordeaux (grants from the Conseil Régional d’Aquitaine no 20030304002FA and 20040305003FA and from the European Union, FEDER no 2003227).
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Morice-Picard, F., Benard, G., Rezvani, H. et al. Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype. Eur J Hum Genet 25, 52–58 (2017). https://doi.org/10.1038/ejhg.2016.139
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DOI: https://doi.org/10.1038/ejhg.2016.139
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