X Chromosome-Linked CNVs in Male Infertility : Discovery of Overall Duplication Load and Recurrent, Patient-Specific Gains with Potential Clinical Relevance
Chianese, Chiara (Institut d'Investigació Biomèdica Sant Pau)
Gunning, Adam C. (University of Florence and Centre of Excellence DeNothe, Florence, Italy)
Giachini, Claudia (University of Florence and Centre of Excellence DeNothe, Florence, Italy)
Daguin, Fabrice (University of Florence and Centre of Excellence DeNothe, Florence, Italy)
Balercia, Giancarlo (Polytechnic University of Marche, Ancona, Italy)
Ars, Elisabet (Institut d'Investigació Biomèdica Sant Pau)
Giacco, Deborah Lo (Institut d'Investigació Biomèdica Sant Pau)
Ruiz-Castañé, Eduardo (Institut d'Investigació Biomèdica Sant Pau)
Forti, Gianni (University of Florence and Centre of Excellence DeNothe, Florence, Italy)
Krausz, Csilla (Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona

Data:	2014
Resum:	Spermatogenesis is a highly complex process involving several thousand genes, only a minority of which have been studied in infertile men. In a previous study, we identified a number of Copy Number Variants (CNVs) by high-resolution array-Comparative Genomic Hybridization (a-CGH) analysis of the X chromosome, including 16 patient-specific X chromosome-linked gains. Of these, five gains (DUP1A, DUP5, DUP20, DUP26 and DUP40) were selected for further analysis to evaluate their clinical significance. The copy number state of the five selected loci was analyzed by quantitative-PCR on a total of 276 idiopathic infertile patients and 327 controls in a conventional case-control setting (199 subjects belonged to the previous a-CGH study). For one interesting locus (intersecting DUP1A) additional 338 subjects were analyzed. All gains were confirmed as patient-specific and the difference in duplication load between patients and controls is significant (p = 1. 65×10 −4). Two of the CNVs are private variants, whereas 3 are found recurrently in patients and none of the controls. These CNVs include, or are in close proximity to, genes with testis-specific expression. DUP1A, mapping to the PAR1, is found at the highest frequency (1. 4%) that was significantly different from controls (0%) (p = 0. 047 after Bonferroni correction). Two mechanisms are proposed by which DUP1A may cause spermatogenic failure: i) by affecting the correct regulation of a gene with potential role in spermatogenesis; ii) by disturbing recombination between PAR1 regions during meiosis. This study allowed the identification of novel spermatogenesis candidate genes linked to the 5 CNVs and the discovery of the first recurrent, X-linked gain with potential clinical relevance.
Ajuts:	Ministerio de Sanidad y Consumo FIS-11/02254 European Commission 289880
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	PloS one, Vol. 9 (june 2014) , ISSN 1932-6203

DOI: 10.1371/journal.pone.0097746
PMID: 24914684

7 p, 268.2 KB

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