Spermatogenic Failure 6

A number sign (#) is used with this entry because of evidence that spermatogenic failure-6 (SPGF6) is caused by homozygous mutation in the SPATA16 gene (609856) on chromosome 3q26. One such family has been reported.

Description

Spermatogenic failure-6 is a form of male infertility with globozoospermia. The acrosome is a unique structure of the mature spermatozoon, which plays an important role at the site of sperm-zonapellucida binding during the fertilization process. Globozoospermia (also called round-headed spermatozoa) is a human infertility syndrome caused by spermatogenesis defects (Lalonde et al., 1988, Singh, 1992). The most prominent feature of globozoospermia is the malformation of the acrosome and, in the most severe cases, the acrosome is totally absent. Globozoospermia is also characterized by abnormal nuclear shape as well as abnormal arrangement of the mitochondria of the spermatozoon (Battaglia et al., 1997).

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

Clinical Features

Vegni-Talluri et al. (1977) observed acrosome malformations of spermatids and spermatozoa in the testes of 2 infertile males who were investigated by light and electron microscopy. The first visible abnormality appeared at early spermatid stages. Defective differentiation of the acrosome granule in spermatids appeared to be responsible for the malformation of mature spermatozoa. The fact that about half the early spermatids lacked the acrosome granule suggested that the original cause is genetic and that the gene is expressed in the haploid phase. The authors referred to comparable abnormalities of the acrosome observed in bulls and boars and thought to have a mendelian basis. Complete lack of the acrosome during spermiogenesis, resulting in round-headed spermatozoa incapable of fertilization, has been observed in man and has been thought to have a primary genetic basis. Furthermore, the authors drew analogies to abnormalities of spermatozoa related to the T-locus of the mouse. Abnormalities of spermiogenesis in mammals were reviewed by Bishop (1972). Kullander and Rausing (1975) observed only round-headed spermatozoa in 2 infertile brothers and suggested that homozygosity for an autosomal gene defect underlies this phenotype. In Friesian bulls, a characteristic defect of the acrosome ('knobbed' spermatozoa) associated with sterility appears to be autosomal recessive.

Florke-Gerloff et al. (1983) showed that the acrosomal membrane proteins are first detectable in early spermatids. (The acrosome is a caplike compartment in the apical part of the sperm head. It is a lysosome-like organelle derived from the Golgi apparatus. In the fertilization process, fusion of the sperm plasma membrane and outer acrosomal membrane (OAM) occurs with discharge of the acrosomal endosol.) Florke-Gerloff et al. (1983) found that the round-headed spermatozoa of an infertile patient with globozoospermia lacked the constituting components of the outer acrosomal membrane as well as the intraacrosomal acrosin system (see 102480).

Nistal et al. (1978) observed 2 infertile brothers with round-headed spermatozoa. Florke-Gerloff et al. (1984) also found 2 affected brothers and studied their father as well. Whereas the brothers, like other reported cases, had all round-headed spermatozoa, the father had more than 94% normally shaped sperm. Theirs was the first study to quantitate the abnormality; in 9 infertile men the proportion of round-headed sperm varied from 14 to 71%. They showed that the round-headed spermatozoa lacked both acrosin and OAM, as indicated by immunofluorescent and immunoperoxidase staining techniques and confirmed by the gelatinolysis test. The normally shaped sperm of 6 of the 9 men were positive for acrosin and OAM. In the father of the affected brothers, only 10% of the normally shaped spermatozoa were acrosin positive and only 30% were positive for OAM. Florke-Gerloff et al. (1984) suggested that the round-headed spermatozoa syndrome is polygenic in its inheritance.

Kilani et al. (2004) evaluated familial globozoospermia in 5 brothers.

Dam et al. (2007) described an Ashkenazi Jewish family with 6 brothers of whom 3 were affected. The affected brothers presented with a fertility disorder due to oligoasthenoteratozoospermia, showing the characteristics of total globozoospermia such as roundheadedness and acrosomelessness.

Population Genetics

Dam et al. (2007) stated that globozoospermia has an incidence of less that 0.1% in male infertile patients.

Mapping

Using homozygosity mapping, Dam et al. (2007) found linkage of globozoospermia to a 17-Mb region of chromosome 3q26 in a family with six brothers from an isolated Jewish population.

Molecular Genetics

Dam et al. (2007) presented a consanguineous family in which 3 brothers with globozoospermia were found to be homozygous for a mutation in the spermatogenesis-specific gene SPATA16 (609856.0001). The authors stated that this was the first example of a nonsyndromic male infertility condition in humans caused by a defect in a single autosomal gene.

Animal Model

Yao et al. (2002) showed that the Golgi-associated PDZ- and coiled-coil motif-containing protein (GOPC; 606845) is predominantly localized at the trans-Golgi region in round spermatids, and male mice in which GOPC has been disrupted are infertile with globozoospermia. Two other recessive mouse models of globozoospermia involve CSNK2A2 (115442) and HRB (600862).