title: Copy-number variations in Y-chromosomal azoospermia factor regions identified by multiplex ligation-dependent probe amplification.
abstract: Although copy-number variations (CNVs) in Y-chromosomal azoospermia factor (AZF) regions have been associated with the risk of spermatogenic failure (SF), the precise frequency, genomic basis and clinical consequences of these CNVs remain unclear. Here we performed multiplex ligation-dependent probe amplification (MLPA) analysis of 56 Japanese SF patients and 65 control individuals. We compared the results of MLPA with those of conventional sequence-tagged site PCR analyses. Eleven simple and complex CNVs, including three hitherto unreported variations, were identified by MLPA. Seven of the 11 CNVs were undetectable by conventional analyses. CNVs were widely distributed in AZF regions and shared by ~60% of the patients and ~40% of the controls. Most breakpoints resided within locus-specific repeats. The majority of CNVs, including the most common gr/gr deletion, were identified in the patient and control groups at similar frequencies, whereas simple duplications were observed exclusively in the patient group. The results imply that AZF-linked CNVs are more frequent and heterogeneous than previously reported. Non-allelic homologous recombination likely underlies these CNVs. Our data confirm the functional neutrality of the gr/gr deletion in the Japanese population. We also found a possible association between AZF-linked simple duplications and SF, which needs to be evaluated in future studies.
authors.affiliation: 1] Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan [2] Department of Comprehensive Reproductive Medicine, Tokyo Medical and Dental University, Tokyo, Japan [3] Division of Reproductive Medicine, Center for Maternal-Fetal-Neonatal and Reproductive Medicine, National Medical Center for Children and Mothers, Tokyo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Miyado
authors.affiliation: Department of Urology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Kobori
authors.affiliation: Department of Pediatrics, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Reproduction Center, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ishikawa
authors.affiliation: Reproduction Center, Kiba Park Clinic, Tokyo, Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Momori
authors.initials: M
authors.lastname: Katsumi
authors.affiliation: Division of Reproductive Medicine, Center for Maternal-Fetal-Neonatal and Reproductive Medicine, National Medical Center for Children and Mothers, Tokyo, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of Comprehensive Reproductive Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Urology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okada
authors.affiliation: 1] Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan [2] Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
mesh_terms: D053713:Azoospermia / Q000235:genetics*; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D041322:Chromosomes, Human, Y / Q000235:genetics*; D056915:DNA Copy Number Variations; D006801:Humans; D008297:Male; D008957:Models, Genetic; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods*; D009845:Oligospermia / Q000235:genetics; D011995:Recombination, Genetic; D012307:Risk Factors; D013091:Spermatogenesis / Q000235:genetics