MORICE-PICARD, Fanny; BENARD, Giovanni; REZVANI, Hamid Reza; LASSEAUX, Eulalie; SIMON, Delphine; MOUTTON, Sébastien; ROORYCK, Caroline; LACOMBE, Didier; BAUMANN, Clarisse; ARVEILER, Benoit

doi:10.1038/ejhg.2016.139

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MORICE-PICARD, Fanny
Service de génétique médicale
Centre Hospitalier Universitaire de Bordeaux [CHU Bordeaux]
CHU de Bordeaux Pellegrin [Bordeaux]
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

BENARD, Giovanni
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

REZVANI, Hamid Reza
Biothérapies des maladies génétiques et cancers
BoRdeaux Institute in onCology [Inserm U1312 - BRIC]

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European Journal of Human Genetics. 2016-01-01, vol. 25, n° 1, p. 52-58

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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.< Réduire

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Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype.

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