Spermatogenic Failure 3

A number sign (#) is used with this entry because of evidence that spermatogenic failure-3 (SPGF3) is caused by heterozygous mutation in the SLC26A8 gene (608480) on chromosome 6p21.

Description

In spermatogenic failure-3, primary infertility is associated with nonobstructive asthenozoospermia (Dirami et al., 2013).

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

Clinical Features

Dirami et al. (2013) studied 3 men with primary infertility and moderate to severe asthenozoospermia associated with mutations in the SLC26A8 gene. The first was a 44-year-old man who had low ejaculate volume and a frequency of sperm morphologic abnormalities moderately higher than normal, with 19% coiled tails and 63% abnormally shaped posterior sperm heads; he also had increased polymorphonuclear leukocytes. He was an only child with an unknown father; his mother had 1 brother with no children. The second was a 42-year-old man with flagellar defects in about 10% of sperm, although other semen parameters were normal. He had 2 sisters and 4 brothers, all of whom had children. The third was a 31-year-old man who had a low sperm count and a very high frequency of combined morphologic defects, including abnormal head shape (98%), midpiece abnormalities (27%), and flagellar defects (38%). He was conceived after primary infertility of 10 years' duration, and was an only child like his father; his mother had 1 brother and 1 sister with children. In all 3 patients, no bacteria were detected in semen cultures.

Mapping

The technical developments and expanded indications for testicular sperm extraction (TESE) with intracytoplasmic sperm injection (ICSI) provide great advantages for patients with nonobstructive azoospermia. Such success, however, also means that genetic abnormalities in nonobstructive azoospermia can be transmitted to the next generation, demonstrating the importance of understanding the genetic background of nonobstructive azoospermia. Tsujimura et al. (2002) reported that human leukocyte antigens (HLA)-A33 (see 142800) and -B44 (see 142830) in the HLA class I region and the HLA-DRB1*1302 allele (see 142857) in the HLA class II region are linked to susceptibility to nonobstructive azoospermia in Japanese men. However, strong linkage of HLA-DRB1*1302 with HLA-A33 and -B44 was evident in the Japanese population. No statistically significant association was found with microsatellite markers in the HLA class I region or the class III region, but some of the microsatellite markers in the HLA class II region and at the HLA-DRB1 and -DQB1 (604305) loci displayed strong associations with nonobstructive azoospermia. Taken together, the data suggested that a critical region for development of nonobstructive azoospermia is near the HLA-DRB1 and -DQB1 segments in the HLA class II region.

In a 3-stage genomewide association study involving a total of 2,226 Han Chinese men with nonobstructive azoospermia and 4,576 controls, Zhao et al. (2012) found significant association with 2 SNPs on chromosome 6p22: rs3129878, located in intron 1 of HLA-DRA (142860) (combined p = 3.70 x 10(-16); odds ratio, 1.37), and rs498422, located within C6ORF10 and near the BTNL2 gene (606000) (combined p = 2.43 x 10(-12); odds ratio, 1.42).

Molecular Genetics

In a cohort of 146 men being treated for infertility, Dirami et al. (2013) analyzed the coding sequence of the candidate gene SLC26A8 by DHPLC and direct sequencing and identified heterozygosity for 3 missense mutations in 3 men (608480.0001-608481.0003, respectively). No family members were available for genetic study. The mutations were not present in 121 ethnically matched controls, and for all 3 variants, the frequency of the mutant allele was significantly higher in the cohort of asthenozoospermic individuals than in 8,600 controls of unknown sex and fertility status. Analysis of physical interactions between the mutant SLC26A8 and CFTR (602421), a protein present in mature sperm and required for sperm motility and capacitation, showed that although protein-protein interactions were partly conserved, the capacity to activate CFTR-dependent anion transport was completely abolished for all 3 mutants.