Spermatogenic Failure 5

A number sign (#) is used with this entry because of evidence that spermatogenic failure-5 (SPGF5) is caused by homozygous or compound heterozygous mutation in the AURKC gene (603495) on chromosome 19q13.

Description

Spermatogenic failure-5 is a form of male infertility associated with large-headed, multiflagellar, polyploid spermatozoa (Dieterich et al., 2007).

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

Clinical Features

In the son of Libyan first-cousin parents, German et al. (1981) found infertility apparently related to an abnormality of spermatozoa manifested morphologically by bulky, irregularly shaped heads and as many as 4 tails. Sperm heads showed excessive DNA, approximately 4 times the normal haploid amount, as measured in Feulgen-stained preparations. By electron microscopy, 4 centrioles were demonstrated; hence, the 4 tails (German, 1989). Blood lymphocytes in metaphase had 46 chromosomes but about a third of metaphases from a dermal fibroblast line at its eighth passage had 92 chromosomes.

Semen from men with large-headed multiflagellar polyploid spermatozoa consistently show close to 100% morphologically abnormal spermatozoa with low motility, oversized irregular heads, abnormal midpiece and acrosome, and up to 6 flagella (Benzacken et al., 2001; Devillard et al., 2002).

Molecular Genetics

Dieterich et al. (2007) carried out a genomewide microsatellite scan of 10 infertile men with a large-headed sperm phenotype. Four were unrelated French citizens of African descent, all born from first-degree cousins, leading to a suspicion of autosomal recessive mode of inheritance. The small genealogic distance between the 4 index individuals and a postulated morbid ancestor chromosome present in their respective great-grandmother or great-grandfather (3 meioses) was compatible with large homozygous regions. The other 6 men all came from the Rabat region in Morocco, suggesting the possibility of a founder effect. In that case, owing to probable greater genealogic distances, Dieterich et al. (2007) expected smaller regions of homozygosity. In all 10 men, Dieterich et al. (2007) identified a region of homozygosity harboring the AURKC gene with a single-nucleotide deletion in its coding sequence (c.144delC; 603495.0001). They showed that this founder mutation resulted in premature termination of translation, yielding a truncated protein that lacks the kinase domain. They concluded that the absence of AURKC causes male infertility owing to the production of large-headed multiplex flagella polyploid spermatozoa.

Dieterich et al. (2009) established a carrier frequency of 1 in 50 for the c.144delC AURKC mutation in the Maghrebian general population. Of 62 patients with large-headed spermatozoa who were genotyped, 32 had a typical phenotype with close to 100% large-headed spermatozoa, and 31 of these patients were homozygous for c.144delC. The remaining patient with a typical phenotype was compound heterozygous for c.144delC and a missense mutation (C229Y; 603495.0002). No AURKC mutations were detected in the 30 patients who did not present with a typical phenotype. Two homozygous females were identified, and both were fertile, indicating that AURKC is dispensable in oogenesis. All spermatozoa contained homogeneous 4C DNA content and were thus blocked before the first meiotic division. The authors concluded that functional AURKC protein is necessary for male meiotic cytokinesis, whereas its absence does not impair oogenesis.

Ben Khelifa et al. (2011) studied 2 infertile brothers of Tunisian descent who both had nearly 100% large-headed spermatozoa that were 28 to 52% multiflagellate, with sperm counts of 0.8 to 0.9 x 10(6) per ml. Sequencing of the AURKC gene in the family revealed that both brothers and 1 of their sisters were compound heterozygous for the c.144delC mutation and a splice site mutation (603495.0003). Multiple intracytoplasmic sperm injection (ICSI) attempts for both brothers were unsuccessful; although fertilization could be achieved by 47 of the gametes, no pregnancy was obtained after 8 embryo transfers. Their compound heterozygous sister had not yet tried to achieve pregnancy. Noting that FISH analysis of morphologically normal-appearing sperm from AURKC-mutated men showed aneuploidy in all sperm (Chelli et al., 2010), Ben Khelifa et al. (2011) cautioned that the identification of AURKC mutations indicates that all spermatozoa will be chromosomally abnormal, and that ICSI should not be attempted even after very thorough morphologic selection.