title: Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype.
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.
authors.affiliation: Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM) EA4576, Bordeaux, France. fanny.morice-picard@chu-bordeaux.fr.|CHU de Bordeaux, Service de Génétique Médicale, Bordeaux, France. fanny.morice-picard@chu-bordeaux.fr.
authors.forename: Fanny
authors.initials: F
authors.lastname: Morice-Picard
authors.affiliation: Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM) EA4576, Bordeaux, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Benard
authors.affiliation: INSERM, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France.
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Rezvani
authors.affiliation: CHU de Bordeaux, Service de Génétique Médicale, Bordeaux, France.
authors.forename: Eulalie
authors.initials: E
authors.lastname: Lasseaux
authors.affiliation: Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM) EA4576, Bordeaux, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Simon
authors.affiliation: Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM) EA4576, Bordeaux, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moutton
authors.affiliation: Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM) EA4576, Bordeaux, France.|CHU de Bordeaux, Service de Génétique Médicale, Bordeaux, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rooryck
authors.affiliation: Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM) EA4576, Bordeaux, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Hôpital Robert Debré, Service de Génétique Médicale, Paris, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM) EA4576, Bordeaux, France.|CHU de Bordeaux, Service de Génétique Médicale, Bordeaux, France.
authors.forename: Benoit
authors.identifier: http://orcid.org/0000-0002-2987-2932
authors.initials: B
authors.lastname: Arveiler
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004260:DNA Repair / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D044767:Ubiquitin-Protein Ligases; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D020662:Guanine Nucleotide Exchange Factors; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases