Molecular Genetics of Y Chromosome Infertility
-
Click here to view the Y chromosome using the NCBI Map Viewer. Use the Zoom feature at left to see the complete list of genes.
-
For a list of gene symbols and descriptions by cytogenetic location, click here.
Chromosome Region | Gene Symbol | Chromosomal Locus | Protein Name |
---|
AZFc | CDY1 | Yq11 | Testis-specific chromodomain protein Y 1 |
AZFc | DAZ1 | Yq11 | Deleted in azoospermia protein 1 |
AZFa | DDX3Y | Yq11 | ATP-dependent RNA helicase DDX3Y |
AZFb | HSFY1 | Yq11 | Heat shock transcription factor, Y-linked |
AZFb | RBMY1A1 | Yq11 | RNA-binding motif protein, Y chromosome, family 1 member A1 |
AZFa | USP9Y | Yq11 | Probable ubiquitin carboxyl-terminal hydrolase FAF-Y |
400003 | DELETED IN AZOOSPERMIA; DAZ |
400005 | UBIQUITIN-SPECIFIC PROTEASE 9, Y CHROMOSOME; USP9Y |
400006 | RNA-BINDING MOTIF PROTEIN, Y CHROMOSOME, FAMILY 1, MEMBER A1; RBMY1A1 |
400010 | DEAD/H BOX 3, Y-LINKED; DBY |
400016 | CHROMODOMAIN PROTEIN, Y CHROMOSOME, 1; CDY1 |
400029 | HEAT-SHOCK TRANSCRIPTION FACTOR, Y-LINKED; HSFY |
415000 | SPERMATOGENIC FAILURE, NONOBSTRUCTIVE, Y-LINKED |
Locus symbols: Originally, three azoospermia regions (a, b, and c) were defined as AZFA, AZFB, and AZFC. However, because AZFB and AZFC overlap, a new nomenclature was developed to distinguish deletions based on the flanking palindromic repeat names [Repping et al 2002]. It is likely that additional deletion types will be discovered (see Table 2).
Gene symbols: For a listing of genes located on the long arm of the Y chromosome, refer to NCBI, where the functional annotation of the genes is kept current. Specific genes are included in the AZF regions. USP9Y and DDX3Y are located in AZFA. HSFY1, XKRY, RBMY1A1, DAZ, JARID1D, EIF1AY, RPS4Y2, PRY, CDY1, CDY2, BPY2, CsSPG4LY, GOLGA2LY, and eightf TTTY transcripts are located in AZFB and C.
Chromosomal locus: The male infertility phenotype maps to relatively broad regions defined on the Y chromosome (Figure 1). The regions have been defined on the basis of deletion intervals found in infertile males. These massive interstitial deletions are mediated by recombination between palindromic repeats on the Y chromosome.
AZFA is 792 kb long and just distal to the centromere of the Y chromosome [Kamp et al 2001]. Recombination between two HERV15 (HERV15yq1-HERV15yq2) proviral sequences located around AZFA has been identified as the mechanism that generates AZFA deletions [Kamp et al 2000, Sun et al 2000, Kamp et al 2001].
AZFB and AZFC overlap, with distal AZFC located just proximal to the Y chromosome heterochromatic band Yq12. The most common Y chromosome deletion, formerly known as AZFC deletion, removes 3.5 Mb between palindromes b2 and b4 [Kuroda-Kawaguchi et al 2001, Vogt 2005]. Two of the largest interstitial deletions in the AZFB/C region remove either 6.2 Mb between palindromes P5 and proximal P1 (formerly known as AZFB deletion) or 7.7 Mb between palindromes P5 and distal P1 (formerly, deletion AZFB plus AZFC) [Repping et al 2002]. Additional deletions, for example a 7-Mb deletion between palindromes P4 and distal P1, have been described but are less common.
Some Y deletions appear to be terminal by cytogenetic and PCR analyses. These deletions remove either all or part of the AZF regions along with the terminal q12 band of the Y chromosome, depending on the breakpoints. They may be associated with pseudodicentric or ring Y chromosomes.
Specific genes within the deletions have been mapped. However, so far only one gene (USP9Y) has been implicated in the infertility phenotype by the finding of gene-limited mutations in two individuals [Sun et al 1999].
Normal allelic variants: The normal Y chromosome contains all AZF regions. A complete sequence analysis of the Y chromosome and a listing of Y-linked genes have been reported [Skaletsky et al 2003]. All genes located in the AZF regions on the Y chromosome and specifically expressed in testis (e.g., RBMY1A1, DAZ, VCY, XKRY, CDY1, CDY2, HSFY1, PRY, BPY2) are candidates for a role in male fertility, though their exact function may be presently unknown. Genes that are ubiquitously expressed or expressed in more than one tissue (e.g., RPS4Y2, USP9Y, DDX3Y, UTY, JARID1D, EIF1AY) and other still uncharacterized transcripts could also play a role in male fertility. USP9Y is the only gene that has been directly implicated in male fertility, based on the finding of gene alterations in two infertile males [Sun et al 1999]. The reader is referred to the NCBI Web site for current annotation of Y-linked genes. Below is a short description of some of the genes that are thought to play a role in male fertility. The role of these genes in the disorder is still putative and derives from the gene location, its expression in germ cells, and/or homology to genes involved in fertility in other species. It should be noted that several of the Y-linked genes are present in multiple copies on the Y chromosome; the presence of multiple copies complicates the unraveling of their roles in male fertility.
-
USP9Y (also called DFFRY) is a single-copy gene located in the proximal AZFA region [Brown et al 1998]. USP9Y has a homologue on the X chromosome, USP9X (also called DFFRX). Both X and Y genes are ubiquitously expressed. These genes are homologous to the Drosophila melanogaster gene faf (fat facets) that plays a role in eye development and in female germ cell function. USP9Y-limited alterations in two infertile males have directly implicated this gene in male fertility [Sun et al 1999].
-
DDX3Y (previously called DBY) is another single-copy gene located in AZFA that has a homologue on the X chromosome, DDX3 (previously called DBX). DDX3 and DDX3Y are ubiquitously expressed, but DDX3Y produces an alternative transcript in testis [Lahn & Page 1997].
-
HSFY1 is a member of the family of heat shock transcription factors. Its expression is restricted to Sertoli cells and spermatogenic cells [Shinka et al 2004, Vinci et al 2005].
-
RBMY (previously called YRRM) is a multi-copy gene family located in region AZFB and in other regions on the short and long arms of the Y chromosome. There are about 15-20 copies of RBMY. A homologue, RBMX (previously called HNRPG), is located on the X chromosome [Delbridge et al 1999]. RBMY2 is expressed only in testis.
-
DAZ is a multi-copy gene family. The DAZ gene family on the human Y chromosome is organized in a repeat cluster containing four copies [Saxena et al 2000]. DAZ has a homologue on human chromosome 3 (DAZL). The DAZ gene is homologous to bol in Drosophila melanogaster, in which mutations of bol cause meiotic arrest and azoospermia [Yen 2004, Reynolds & Cooke 2005]. Knock-out of Dazl in mouse results in azoospermia [Ruggiu et al 1997].
-
CDY is a processed transposon from an autosomal gene that has been amplified on the Y chromosome in the simian lineage. The CDY gene is specifically expressed in testis [Dorus et al 2003].
Pathologic allelic variants: The abnormality of the Y chromosome associated with male infertility results in deletion of genes. The Y chromosome deletions are usually very large and thus result in deletion of multiple genes. Several regions of the Y chromosome long arm have been implicated (Figure 1). One gene, USP9Y, has been directly implicated in male infertility. Two allelic variants represent mutations limited to the USP9Y gene in two infertile males.
Note: OMIM lists one AZF locus, AZF1, which comprises AZFA, B, C, and SCOS.
Normal gene product: Several genes are included in the AZF regions deleted in males with infertility. However, as discussed above, their role in normal spermatogenesis is not fully known. Refer to NCBI for a current list of Y-linked genes and their annotation in terms of protein product.
Abnormal gene product: The Y chromosome deletions result in absence of gene products. The deletions often comprise more than one gene or multiple copies of the gene. In the case of USP9Y, a deletion limited to the gene was found as well as one mutation (4-bp deletion) that results in skipping of an exon and protein truncation [Sun et al 2000].