#243060
Table of Contents
Alternative titles; symbols
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.
Spermatogenic failure-5 (SPGF5) 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).
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).
The transmission pattern of SPGF5 in the families reported by Dieterich et al. (2007) was consistent with autosomal recessive inheritance.
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.
Ben Khelifa, M., Zouari, R., Harbuz, R., Halouani, L., Arnoult, C., Lunardi, J., Ray, P. F. A new AURKC mutation causing macrozoospermia: implications for human spermatogenesis and clinical diagnosis. Molec. Hum. Reprod. 17: 762-768, 2011. [PubMed: 21733974, images, related citations] [Full Text]
Benzacken, B., Gavelle, F. M., Martin-Pont, B., Dupuy, O., Lievre, N., Hugues, J.-N., Wolf, J.-P. Familial sperm polyploidy induced by genetic spermatogenesis failure: case report. Hum. Reprod. 16: 2646-2651, 2001. [PubMed: 11726589, related citations] [Full Text]
Chelli, M. H., Albert, M., Ray, P. F., Guthauser, B., Izard, V., Hammoud, I., Selva, J., Vialard, F. Can intracytoplasmic morphologically selected sperm injection be used to select normal-sized sperm heads in infertile patients with macrocephalic sperm head syndrome? Fertil. Steril. 93: 1347e1-1347e5, 2010. Note: Electronic Article. [PubMed: 19062000, related citations] [Full Text]
Devillard, F., Metzler-Guillemain, C., Pelletier, R., DeRobertis, C., Bergues, U., Hennebicq, S., Guichaoua, M., Sele, B., Rousseaux, S. Polyploidy in large-headed sperm: FISH study of three cases. Hum. Reprod. 17: 1292-1298, 2002. [PubMed: 11980754, related citations] [Full Text]
Dieterich, K., Soto Rifo, R., Faure, A. K., Hennebicq, S., Amar, B. B., Zahi, M., Perrin, J., Martinez, D., Sele, B., Jouk, P.-S., Ohlmann, T., Rousseaux, S., Lunardi, J., Ray, P. F. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nature Genet. 39: 661-665, 2007. [PubMed: 17435757, related citations] [Full Text]
Dieterich, K., Zouari, R., Harbuz, R., Vialard, F., Martinez, D., Bellayou, H., Prisant, N., Zoghmar, A., Guichaoua, M. R., Koscinski, I., Kharouf, M., Noruzinia, M., and 13 others. The aurora kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population. Hum. Molec. Genet. 18: 1301-1309, 2009. [PubMed: 19147683, related citations] [Full Text]
German, J., Rasch, E. M., Huang, C. Y., MacLeod, J., Imperato-McGinley, J. Human infertility due to production of multiple-tailed spermatozoa with excessive amounts of DNA. (Abstract) Am. J. Hum. Genet. 33: 64A only, 1981.
German, J. Personal Communication. New York, N. Y. 10/20/1989.
Alternative titles; symbols
SNOMEDCT: 236806004; ORPHA: 137893, 399808; DO: 0070183;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.43 | Spermatogenic failure 5 | 243060 | Autosomal recessive | 3 | AURKC | 603495 |
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.
Spermatogenic failure-5 (SPGF5) 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).
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).
The transmission pattern of SPGF5 in the families reported by Dieterich et al. (2007) was consistent with autosomal recessive inheritance.
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.
Ben Khelifa, M., Zouari, R., Harbuz, R., Halouani, L., Arnoult, C., Lunardi, J., Ray, P. F. A new AURKC mutation causing macrozoospermia: implications for human spermatogenesis and clinical diagnosis. Molec. Hum. Reprod. 17: 762-768, 2011. [PubMed: 21733974] [Full Text: https://doi.org/10.1093/molehr/gar050]
Benzacken, B., Gavelle, F. M., Martin-Pont, B., Dupuy, O., Lievre, N., Hugues, J.-N., Wolf, J.-P. Familial sperm polyploidy induced by genetic spermatogenesis failure: case report. Hum. Reprod. 16: 2646-2651, 2001. [PubMed: 11726589] [Full Text: https://doi.org/10.1093/humrep/16.12.2646]
Chelli, M. H., Albert, M., Ray, P. F., Guthauser, B., Izard, V., Hammoud, I., Selva, J., Vialard, F. Can intracytoplasmic morphologically selected sperm injection be used to select normal-sized sperm heads in infertile patients with macrocephalic sperm head syndrome? Fertil. Steril. 93: 1347e1-1347e5, 2010. Note: Electronic Article. [PubMed: 19062000] [Full Text: https://doi.org/10.1016/j.fertnstert.2008.10.059]
Devillard, F., Metzler-Guillemain, C., Pelletier, R., DeRobertis, C., Bergues, U., Hennebicq, S., Guichaoua, M., Sele, B., Rousseaux, S. Polyploidy in large-headed sperm: FISH study of three cases. Hum. Reprod. 17: 1292-1298, 2002. [PubMed: 11980754] [Full Text: https://doi.org/10.1093/humrep/17.5.1292]
Dieterich, K., Soto Rifo, R., Faure, A. K., Hennebicq, S., Amar, B. B., Zahi, M., Perrin, J., Martinez, D., Sele, B., Jouk, P.-S., Ohlmann, T., Rousseaux, S., Lunardi, J., Ray, P. F. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nature Genet. 39: 661-665, 2007. [PubMed: 17435757] [Full Text: https://doi.org/10.1038/ng2027]
Dieterich, K., Zouari, R., Harbuz, R., Vialard, F., Martinez, D., Bellayou, H., Prisant, N., Zoghmar, A., Guichaoua, M. R., Koscinski, I., Kharouf, M., Noruzinia, M., and 13 others. The aurora kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population. Hum. Molec. Genet. 18: 1301-1309, 2009. [PubMed: 19147683] [Full Text: https://doi.org/10.1093/hmg/ddp029]
German, J., Rasch, E. M., Huang, C. Y., MacLeod, J., Imperato-McGinley, J. Human infertility due to production of multiple-tailed spermatozoa with excessive amounts of DNA. (Abstract) Am. J. Hum. Genet. 33: 64A only, 1981.
German, J. Personal Communication. New York, N. Y. 10/20/1989.
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