Spermatogenic Failure 9

A number sign (#) is used with this entry because spermatogenic failure-9 (SPGF9) is caused by homozygous or compound heterozygous mutation in the DPY19L2 gene (613893) on chromosome 12q14.

Description

Spermatogenic failure-9 is associated with globozoospermia, a rare phenotype of primary male infertility characterized by the production of a majority of round-headed spermatozoa without an acrosome (summary by Harbuz et al., 2011).

For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Clinical Features

Kilani et al. (2004) studied a consanguineous Jordanian family in which 5 infertile brothers had a complete form of globozoospermia, with 100% of spermatozoa having round heads. There were 5 additional sibs in the family, including 2 sisters and 3 brothers, who were naturally fertile and had 3 to 7 children each. Semen analysis in the 5 infertile brothers showed a median volume of 3.3 mL (range, 1 mL to 4 mL), median concentration of 22 x 10(6)/mL (range, 5 to 60 x 10(6)/mL), and median progressive motility of 30% (range, 7-60%). A total of 20 cycles of intracytoplasmic sperm injection (ICSI) were performed for the 5 infertile brothers, resulting in only 1 full-term pregnancy and 2 miscarriages. Using an indirect immunofluorescence technique to evaluate the acrosomal status of the spermatozoa in 3 fertile and 3 infertile brothers, Kilani et al. (2004) observed that on average, 66% of the spermatozoa from the 3 fertile brothers had acrosomes present, whereas no acrosomes were seen in the globozoospermic brothers.

Koscinski et al. (2011) analyzed semen from an Algerian patient with globozoospermia and deletion of the DPY19L2 gene (613893.0001), and observed all stages of spermatogenesis with no obvious abnormality in earlier stages of germ cells. In contrast, no proacrosomal vesicles were observed in the round spermatids, yet they appeared correctly polarized: the polarization of the spermatid was indicated by the correct positioning of the chromatoid body observed in the elongating spermatids, in the area of the attachment of the flagellum to the spermatid nucleus. In addition, in 2 unrelated French patients with globozoospermia and deletion of the DPY19L2 gene, the authors observed elongating spermatids as well as spermatozoa that were comparable to those of the Algerian patient.

Mapping

In a consanguineous Jordanian family originally studied by Kilani et al. (2004), in which 5 infertile brothers had complete globozoospermia, Koscinski et al. (2011) performed genomewide scan analysis using 10K SNP arrays in 4 affected and 3 unaffected brothers. A 6.4-Mb region on chromosome 12 involving 30 homozygous SNPs was identified in the 4 affected brothers; the fertile brothers were heterozygous for this region.

In 9 probands with typical globozoospermia, including 7 Tunisians, 1 Algerian, and 1 Turkish man, Harbuz et al. (2011) performed whole-genome homozygosity mapping and identified a shared homozygous region in 7 patients that ranged from 49 Mb to 1 Mb and was centered on chromosome 12q14.2.

Molecular Genetics

In a consanguineous Jordanian family originally studied by Kilani et al. (2004), in which 5 infertile brothers had complete globozoospermia mapping to chromosome 12, Koscinski et al. (2011) analyzed the candidate gene DPY19L2 and observed specific amplifications in controls that were not seen in affected individuals, suggesting a large deletion of the whole gene. Further analysis revealed homozygosity for an approximately 200-kb deletion encompassing only the DPY19L2 gene (613893.0001) in the affected brothers; all 3 healthy brothers were homozygous wildtype. The DPY19L2 deletion was then screened in 24 globozoospermic patients from 20 unrelated families, and similar deletions of DPY19L2 were identified in 4 patients from 3 families. Koscinski et al. (2011) noted that, in contrast to globozoospermic patients with mutation in the SPATA16 gene (see SPGF6, 609856), patients with the DPY19L2 deletion presented with complete globozoospermia yet had normal or near-normal concentrations of sperm, suggesting that lack of DPY19L2 may disrupt only spermiogenesis and not germ cell proliferation and meiosis. Deletion of DPY19L2 was not detected in the homozygous state in 105 men of European origin or in 101 fertile Jordanian men.

In 9 probands with globozoospermia mapping to 12q14.2 and in the globozoospermic brother of 1 of the probands, Harbuz et al. (2011) analyzed the candidate gene DPY19L2 and identified homozygosity for deletion of DPY19L2 in 8 of the patients, including the 2 affected brothers. Analysis of DPY19L2 in an additional 10 globozoospermic probands revealed 7 more patients with a homozygous deletion of DPY19L2. Of the 15 patients with the deletion, 12 were Tunisian in origin, 2 were Moroccan, and 1 was Algerian. PCR amplification of exons 1 and 11 of the DPY19L2 gene in 200 fertile North African men and 100 fertile European men indicated that none was homozygous for the DPY19L2 deletion.

In 17 globozoospermic probands previously studied by (Koscinski et al., 2011) and 33 additional probands with globozoospermia, Ellnati et al. (2012) analyzed the DPY19L2 gene and identified homozygosity for the DPY19L2 deletion in 21 probands, compound heterozygosity for the deletion and another mutation in 5 probands (see, e.g., 613893.0002-613893.0005), and homozygosity for other mutations in 4 probands (see, e.g., 613893.0005-613893.0007). Ellnati et al. (2012) noted that overall, including all 21 families previously studied by Koscinski et al. (2011), DPY19L2 mutations were detected in 36 (66.7%) of 54 globozoospermic probands from 13 different countries, indicating that DPY19L2 represents the major gene causing globozoospermia.