Microdeletions in interval 6 of the Y chromosome of males with idiopathic sterility point to disruption of AZF, a human spermatogenesis gene

Abstract

For males with idiopathic sterility, a molecular screen specific for small lesions (microdeletions) in interval 6 of the Y chromosome was set up using 29 Y-DNA probes. A "de novo" microdeletion in Y interval 6 was detected in 2 out of 19 "chromosomally normal" sterile males. The first microdeletion includes the Y-DNA probes pY6HP35 and 12f3; the second microdeletion includes the Y-DNA probes pY6HP52, 49f, FR15-II and the subinterval "C" of probe 50f2. A probe of the pY6H sequence family is present in both deletions. Sequences of this family cross-hybridize to dhMiF1, a DNA sequence of a fertility gene structure on the Y chromosome of Drosophila hydei. It was possible to map the position of the Y-deletion of one patient to the distal part of Yq11.22 or the proximal part of Yq11.23, and the deletion of the second patient to the distal part of Yq11.23. These microdeletions probably do not overlap. Since AZF, a human spermatogenesis gene, has been mapped to Y interval 6, we postulate that the microdeletions detected in this chromosome region affect the functional DNA structure of the AZF gene. If this holds true, it is possible that the AZF locus, cytogenetically mapped to distal Yq11, contains two spermatogenesis genes (AZFa and AZFb) or a large gene structure comparable to the Y fertility genes of Drosophila.

Screening for deletions in interval D16–22 of the Y chromosome in azoospermic and oligozoospermic Japanese men

“…In 1976, Tiepolo and Zuffardi first reported, from microscopic analysis of the Y chromosome in infertile men, that the human Y chromosome played a crucial role in spermatogenesis (Tiepolo and Zuffardi 1976). Since their identification of deletions of the long arm of the Y chromosome in infertile men, the existence of a spermatogenesis gene or azoospermic factor (AZF) on the Y chromosome has been proposed (Vogt et al 1992), and many investigators have focused on where genes related to spermatogenesis exist in the long arm of Y chromosome (Andersson et al 1988;Johnson et al 1989;Vogt et al 1992).…”

“…In order to identify genes involving spermatogenesis, several researchers have analyzed the Y chromosome by various methods, such as Southern blot analysis and polymerase chain reaction (PCR) (Johnson et al 1989;Vogt et al 1992). In 1993, Ma et al reported two cDNAs of a Yspecific gene family named the RNA binding motif (RBM) from a region on the long arm of the Y chromosome that was deleted in some infertile patients (Ma et al 1993).…”

Human Y Chromosome and Male Infertility: Forward and Back from Azoospermia Factor Chromatin Structure to Azoospermia Factor Gene Function

“…These maps were based on the distinct location of Y-specific DNA probes selected from different Y chromosome clone libraries and the analyses of their presence or absence on DNA blots of a series of genomic DNA samples extracted from infertile men with microscopically visible Yq11 deletions and rearrangements [4][5][6] . On this molecular level, for the first time, we observed some interstitial microdeletions in Yq11 when screening azoospermic men with a normal-looking Y chromosome and a normal 46,XY karyotype [7,8] . At that time, interstitial microdeletions were already found in comparable dynamic chromosome regions of different autosomes [9] .…”

Correlation of Various Causes of Secondary Infertility in Males

“…In those males who have spermatogenetic failure, abnormalities of azoospermia factor genes in the euchromatic region on the long arm of the Y chromosome (Yq) have been reported [24] . The Yqmicrodeletions of azoospermia factor (AZF) regions are major causes of infertility associated with severe oligospermia and azoospermia [26] and may also be associated with somatic and germinal gonosomal mosaicism [27]- [29] . In males Y q+ may carry the increased risk of abortion as reported by Patil (1977) and Nielson (1978).…”