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Human Molecular Genetics Pages 2013-2017 © Oxford University Press
The human autosomal gene DAZLA: testis specificity and a candidate for male infertility
Introduction
Results
Discussion
Materials And Methods
Acknowledgements
References

The human autosomal gene DAZLA: testis specificity and a candidate for male infertility

The human autosomal gene DAZLA : testis specificity and a candidate for male infertility Pauline H. Yen*, Ning Ning Chai and Eduardo C. Salido1

Division of Medical Genetics, Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502-2064, USA and 1Department of Pathology, Universidad de La Laguna, Spain

Received August 16, 1996; Revised and Accepted October 4, 1996DDBJ/EMBL/GenBank accession nos U66077U66077, U66078U66078

The DAZ (Deleted in AZoospermia) and DAZLA (DAZ-like autosomal) genes may be determinants of male infertility. The DAZ gene on the long arm of the human Y chromosome is a strong candidate for the `azoospermia factor' (AZF). Its role in spermatogenesis is supported by its exclusive expression in testis, its deletion in a high percentage of males with azoospermia or severe oligospermia, and its homology with a Drosophila male infertility gene boule. No DAZ homologous sequences have been found on the mouse Y chromosome. Instead, a Dazla gene was isolated from mouse chromosome 17 and has been considered to be a murine homologue of DAZ. However, the homology between human DAZ and mouse Dazla is not strong, and Dazla contains only one of the seven DAZ repeats found in DAZ. We report the isolation of the human DAZLA gene by screening a human testis cDNA library with a DAZ cDNA clone. DAZLA encodes only one DAZ repeat and shares high homology with the mouse Dazla, indicating that these two genes are homologues. Using a panel of rodent-human somatic cell lines and fluorescence in situ hybridization, the DAZLA gene was mapped to 3p24, a region not known to share homology with mouse chromosome 17. The DAZLA gene may be involved in some familial cases of autosomal recessive male infertility.

INTRODUCTION

Mammalian spermatogenesis is a developmental process in which male germ cells undergo meiosis and complex morphological changes to form mature sperm. Many genes affecting male fertility have been identified in mice, and they are located both on autosomes and the sex chromosomes (1 ,2 ). The search for human genes involved in spermatogenesis has been focused on the Y chromosome long arm, specifically distal Yq11. This region has been thought to contain an `azoospermia factor' (AZF), because a high percentage of males with idiopathic azoospermia or severe oligospermia have deletion of Yq11 sequences (3 -10 ). A recent survey on a large number of infertile men found that deletions can occur in any one of three non-overlapping regions, indicating that at least three genes on Yq11 are required for normal spermatogenesis (11 ). Two candidate genes (or gene families), RBM and DAZ/SPGY1, have been isolated from Yq11 (8 ,12 ,13 ). Both show testis specific expression, and both encode proteins with an RNA binding motif. In addition, RBM encodes four copies of a 37 amino acid (aa) SRGY repeat whereas DAZ encodes seven or 11 copies of a 24 aa DAZ repeat. The functions of these repeats are unknown. The RBM family consists of 20-40 genes and pseudogenes scattered over the long arm and the proximal short arm of the Y chromosome (14 ). Its mouse homologue Rbm is also present on the Y chromosome in multiple copies (15 ,16 ). There appears to be more than one copy of the DAZ/SPGY1 gene on distal Yq11 (8 ,11 ; unpublished data). However, DAZ/SPGY1 homologous sequences cannot be detected on the mouse Y chromosome. Instead, a Dazla (Daz like, autosomal)/Dazh (DAZ homolog) gene was isolated and mapped to chromosome 17 band b1 (17 ,18 ). The homology between DAZ and Dazla is 72% identity and 79% similarity at the peptide level, and 83% similarity in the coding region of the cDNA. In addition, Dazla contains only one DAZ repeat.

The evidence for DAZ being AZF is only circumstantial. It maps within the most distal of the three regions that are deleted in some males with low or no sperm count, but no mutations within the gene have been identified in infertile males. However, the involvement of DAZ in spermatogenesis is further supported by a recent discovery that it shares considerable homology with a Drosophila male infertility gene, boule (19 ). The boule gene was identified during screening for transposon-induced, male sterility mutations in Drosophila (20 ). Loss of boule function results in a block of meiotic division and no sperm production. The boule gene encodes an RNA-binding motif with 42% identity to that encoded by DAZ/Dazla. In addition, it contains one copy of the DAZ repeat with 33% identity to that encoded by DAZ/Dazla. The autosomal localization of boule and the single copy of the DAZ repeat indicate that boule is more like Dazla than DAZ.

We report the isolation and characterization of a human DAZLA on chromosome 3. Sequence comparison among DAZ, DAZLA and the mouse Dazla showed that Dazla is the mouse homologue of DAZLA instead of DAZ. The involvement of DAZLA in families with autosomal recessive male infertility can now be addressed (21 ).

RESULTS

The presence of DAZ homologous sequences on human autosomes was indicated by Southern hybridization of a DAZ cDNA probe to a dosage blot containing DNA from a normal male (XY) and from a cell line with five X chromosomes (5X) (Fig. 1 A). Weak hybridizing bands were present in the 5X sample, and the lack of dosage difference of these bands between the XY and 5X samples indicates that the DAZ homologous sequences are on autosomes. A human testis cDNA library was therefore screened with the DAZ cDNA probe, and 15 independent clones were isolated. Comparison of the restriction maps of the clones with that of DAZ cDNA showed that seven clones, with inserts ranging from 1.1 to 3.2 kb, encode a different gene. Hybridization of one of the clones, f2, to a dosage blot showed autosomal localization of the gene, which was designated DAZLA (Fig. 1 B). DNA sequence was determined for the entire length of the two longer clones, f2 and f7, and a few selected regions of the smaller clones. The 3 kb cDNA includes a 226 bp 5' untranslated region (UTR), an open reading frame for a protein of 295 aa residues with an RNA recognition motif, and a 1.9 kb 3' UTR (Fig. 2 , accession number U66078). Clone f7 contains a 273 bp insertion after nucleotide 376, which was shown to represent an unspliced intron on the basis of PCR amplification of DAZLA genomic clones using primers flanking the insertion site (data not shown). Clone f23 contains a smaller insert with a poly A tail attached after nucleotide 1442, representing the product of alternative polyadenylation. Several single base differences were observed among the cDNA clones. In the coding region, the T at position 234 in f2 is replaced by a C in f7 and in three other clones, with a corresponding amino acid change from isoleucine to threonine. In the 3' UTR, f2 and two other clones have three Cs at nucleotides 2248-2250 whereas f7 has only two Cs at the same position. At the 3' end, the nucleotide at 2968 is a C in f2 and in one other clone, and a G in f7.


Figure 1. DAZ homologous sequences in the human genome. Genomic DNAs from a normal male (XY) and a female cell line with five X chromosomes (5X) were digested with EcoRI and hybridized with (A) a DAZ cDNA clone, (B) DAZLA cDNA clone f7 and (C) a DAZLA cDNA fragment containing 3' UTR.


Figure 2.Nucleotide and deduced amino acid sequences of the DAZLA cDNA. The RNA recognition motif (aa 32-117) is in parentheses, the DAZ repeat (aa 167-190) is underlined and the 130 bp segment (nt 832-961) that is unique to DAZLA is boxed. Sites where an intron interrupts in clone f7 (after nt 376) and where alternative polyadenylation occurs in clone f23 (after nt 1442) are indicated with an open and a closed triangle underneath the sequence, respectively. The three polymorphic sites at positions 234, 2248-2250 and 2968 are double underlined.

The sequences of DAZLA, DAZ and the mouse Dazla were compared using the GCG gap program. Although the major transcripts of all three genes are ~3 kb in length, only 1.4 kb of Dazla sequence and 1.9 kb of DAZ sequence are available in the database. We sequenced one of the DAZ cDNA clones that we isolated to obtain the remaining sequence of the DAZ transcripts (accession no. U66077). As for Dazla, comparison is limited to the available sequence which includes only 200 bp of 3' UTR. The overall structure of DAZLA and its predicted protein product is more similar to that of Dazla than DAZ. Both DAZLA and Dazla proteins contain only one copy of the DAZ repeat (nt 725-796), in contrast to the DAZ proteins which contain seven or more DAZ repeats (8 ,11 ; unpublished data). In addition, both DAZLA and Dazla contain a 130 bp segment (nt 832-961) at the 3' portion of the coding region that is absent in DAZ. The peptide sequences are 86% identical and 91% similar between DAZLA and Dazla, as compared with 78% identical and 83% similar between DAZ and Dazla, excluding the extra DAZ repeats in DAZ (Fig. 3 ). Therefore DAZLA is the human homologue of Dazla. At the DNA level, DAZLA and Dazla show high similarity only in the coding region (89%), whereas the 5' UTR (48% similarity) and 3' UTR (75% similarity) are much less conserved. On the other hand, DAZLA and DAZ share high homology throughout the entire length, excluding the two segments not shared by the two genes. These are the 432 bp segment in DAZ that encodes six extra DAZ repeats and the 130 bp segment in DAZLA mentioned above. Sequence similarity for the 5' UTR, coding region and the 3' UTR are 81, 90 and 88%, respectively.


Figure 3. Sequence comparison of the human DAZ, DAZLA and the mouse Dazla proteins. The complete sequence of the DAZLA peptide is shown, with the different amino acid residues in DAZ and Dazla shown above and below, respectively. The RRM is in parentheses and the consensus RNP-1 and RNP-2 are underlined. The DAZ repeat is boxed. The segment in DAZ protein that encodes an extra six DAZ repeats is excluded for comparison and is not shown here.

The expression of DAZLA was studied using both northern blot and RT-PCR. For northern analysis a cDNA fragment from the 3' UTR of DAZLA was used as a probe to minimize hybridization with DAZ transcripts. To test the specificity of this probe, Southern hybridization with a dosage blot was performed. Under stringent conditions the probe detected a strong 4.3 kb autosomal fragment and a faint 4.5 kb fragment on the Y chromosome (Fig. 1 C). On three northern blots that included poly A+ RNA from 17 human tissues (see Material and Methods), this probe detected a major 3.5 kb transcript in testis only (Fig. 4 A). Transcripts of smaller size were also detected, however, they were present at a much lower level. No signal was detected in ovary, indicating that DAZLA is not expressed there, or only at a very low level (data not shown). Despite the limitation that the probe also detected DAZ transcripts to some extent, the absence of hybridization signals in other tissues supports the conclusion that the expression of DAZLA is testis specific. In our screening of the testis cDNA library, about equal numbers of DAZ and DAZLA cDNA clones were isolated, indicating that DAZ and DAZLA are expressed at comparable levels in testis. The expression of DAZLA in male germ cells was studied by RT-PCR using RNA samples from testicular biopsies of normal and infertile males (22 ; Fig. 4 B). Specific amplification of the DAZLA transcripts was achieved by selecting one of the primer sequences from the 130 bp segment that is not shared by the DAZ gene. The primer set spans several introns, and a 4 kb fragment would occur for genomic DNA amplification (data not shown). The primer set amplified a 467 bp fragment from DAZLA cDNA clone f2, but not from DAZ cDNA clone e11. The same PCR products are present in two samples from males with normal spermatogenesis (hT10 and hT2), but not in two samples from males with Sertoli cells only (hT3 and hT4). The testicular cDNA samples were used for the amplification of a ubiquitously expressed gene, MIC2, to ensure that adequate cDNA was present in the samples (23 ). All the samples amplified a predicted 360 bp product (data not shown). These results are consistent with germ cell expression of the DAZLA genes. However, the possibility that the DAZLA gene is expressed in Sertoli cells only in the presence of normal germ cells cannot be ruled out.


Figure 4. Testis specific expression of the DAZLA gene. (A) Hybridization of a multiple tissue northern blot with a DAZLA cDNA fragment containing 3' UTR. (B) RT-PCR of testicular RNA using a primer set specific for the DAZLA transcripts. Samples hT10 and hT2 are from testicular biopsies with normal spermatogenesis, whereas hT3 and hT4 have Sertoli cells only. Clones f2 and e11 are DAZLA and DAZ cDNA clones, respectively. In the H2O lane, no cDNA was added in the PCR reaction.

The DAZLA gene was mapped initially to human chromosome 3 by Southern hybridization of a DAZLA cDNA probe to a panel of 15 rodent-human somatic cell hybrids containing various combinations of human chromosomes (24 ; data not shown). To fine map the gene on chromosome 3, several genomic clones were isolated after screening a human genomic library with DAZLA cDNA. One clone [lambda]g12, which was shown to encode the DAZLA gene by sequencing some of the exons, was used as a probe in fluorescence in situ hybridization (FISH) mapping on metaphase human chromosomes. A strong hybridization signal was observed at 3p24, confirming chromosome 3 localization of the gene (Fig. 5 ). No consistent hybridization signal was observed in any other region of the genome.


Figure 5. FISH mapping of the DAZLA gene on human metaphase chromosomes. (a) A portion of a metaphase chromosome spread showing hybridization of a DAZLA genomic clone to chromosome 3p24. (b) The same portion stained with DAPI to identify chromosome 3.

DISCUSSION

Male infertility is a common problem, affecting 1-3% of couples (14 ). Although it can be caused by many different factors, genetics undoubtedly plays a role in this disorder. The formation of a mature sperm is a very complex process involving many genes. Defects in any one of these genes can result in impaired sperm or no sperm at all. Among infertile males with azoospermia or severe oligospermia, ~5-10% have a deletion of the AZF locus on Yq11. These deletions most likely represent new mutations, since defects on the Y chromosome that severely affect the fertility of an individual are not likely to be transmitted. In a rare case where the father has the same deletion as a severely oligospermic son, it is likely that one of the father's sperm, although greatly reduced in number, was able to fertilize an egg (11 ). Defects in autosomal genes required for spermatogenesis will be inherited in a male-limited autosomal fashion. Families with multiple infertile males have been reported (21 ). In a case-control study to determine whether infertility in men is familial, it was concluded that infertility may be inherited in an autosomal recessive mode for over half of the cases. No linkage study to map the male infertility gene has been reported so far. The DAZLA gene we have isolated is a definite candidate gene for autosomal recessive male infertility. The mapping of DAZLA to 3p24-25 will permit linkage studies using polymorphic markers from this region. In addition, we have identified three polymorphisms within the DAZLA gene. In fact among the DAZLA cDNA clones isolated, we have already identified three haplotypes. They are C3C in f1, T3C in f2 and C2G in f7, in which the first letter denotes the base at position 234, the middle number denotes the number of Cs at positions 2248-2250, and the last letter denotes the base at position 2968. (Note that the testis cDNA library used was constructed from RNAs pooled from four males.) The putative polymorphisms within the DAZLA gene may be useful for linkage studies, although we do not yet know their frequencies in the general population.

Because the mouse Dazla is located on chromosome 17 band b1, it was predicted that the human DAZLA would be on the short arm of human chromosome 6, based on homology between the mouse and human gene maps (25). However, by a somatic cell mapping panel and FISH, DAZLA was mapped to human chromosome 3p24, a region not known to contain sequences homologous to mouse chromosome 17 (26). It is likely that 3p24 represents a new syntenic region for mouse chromosome 17. However, the possibility that there are additional DAZ-like genes in the human genome, although unlikely, cannot be ruled out. Southern hybridization of female DNA with a DAZ cDNA probe detected more than one fragment (Fig. 1A). Further studies, characterizing DAZLA genomic clones, will determine whether all of the hybridizing fragments belong to the DAZLA gene on chromosome 3.

MATERIALS AND METHODS

The human testis cDNA library (939202) was purchased from Stratagene (La Jolla, CA), whereas the human genomic library (HL1067J) was purchased from Clontech (Palo Alto, CA). The libraries were plated out at a density of 3 * 104 p.f.u. per 100 mm plate and screened with a DAZ or DAZLA cDNA probe according to standard protocols (27 ).

Three human multiple tissue northern blots were purchased from Clontech. Blot no. 7760-1 contains poly A+ RNAs from heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas and blot no. 7766-1 contains RNAs from spleen, thymus, prostate, testis, uterus, small intestine, colon (mucosal lining) and peripheral blood leukocytes. Blot no. 7759-1 is similar to blot 7766-1 except that it contains ovary RNA instead of uterus RNA. Hybridization was carried out in ExpressHyb Hybridization Solution (#8015, Clontech) at 68oC for 1 h according to the manufacturer's protocol. The probe was a 772 bp HindIII-EcoRI fragment (nt 1837-2608) from the 3' UTR of the DAZLA cDNA clone.

Purification of RNA from testicular samples and RT-PCR were carried out as described previously (22 ). The PCR primers were PRDAZ28: 5'-ATGACGTGGATGTGCAG (nt 492-508) and PRDAZ29: 5'-TTGTGGGCCATTTCCAG (nt 958-942). Reactions were carried out at 94oC for 1 min, 52oC for 1 min and 72oC for 1 min for 30 cycles with a final extension at 72oC for 10 min. The products were separated on a 3% Nusieve-agarose (3:1) gel.

FISH mapping of the DAZLA gene was carried out using the services of SeeDNA Biotech Inc. (North York, Ontario, Canada). DAZLA genomic clone [lambda]DAZLA-g12 with an insert of 15 kb, was used as a probe for FISH studies. Slides preparation, in situ hybridization and signal detection were carried out according to Heng et al. (28 ). Regional assignment was based on superimposing FISH signals with DAPI banded chromosomes. Ten photographs were analyzed.

ACKNOWLEDGEMENTS

We thank D. Page for the DAZ cDNA clone, Ann Chandley, Henry Lin and T. K. Mohandas for helpful discussion, and Hsiao-fen Huang for excellent technical assistance. The work was supported by grant HD28009 from the National Institutes of Health.

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*To whom correspondence should be addressed

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From the Cover: A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans
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