Mutations of the aurora kinase C gene causing macrozoospermia are the most frequent genetic cause of male infertility in Algerian men

Abstract

Klinefelter syndrome and Y-chromosomal microdeletion analyses were once the only two genetic tests offered to infertile men. Analyses of aurora kinase C (AURKC) and DPY19L2 are now recommended for patients presenting macrozoospermia and globozoospermia, respectively, two rare forms of teratozoospermia particularly frequent among North African men. We carried out genetic analyses on Algerian patients, to evaluate the prevalence of these syndromes in this population and to compare it with the expected frequency of Klinefelter syndrome and Y-microdeletions. We carried out a retrospective study on 599 consecutive patients consulting for couple infertility at the assisted reproduction unit of the Ibn Rochd Clinique, Constantine, Algeria. Abnormal sperm parameters were observed in 404 men. Fourteen and seven men had typical macrozoospermia and globozoospermia profiles, respectively. Molecular diagnosis was carried out for these patients, for the AURKC and DPY19L2 genes. Eleven men with macrozoospermia had a homozygous AURKC mutation (79%), corresponding to 2.7% of all patients with abnormal spermograms. All the men with globozoospermia studied (n = 5), corresponding to 1.2% of all infertile men, presented a homozygous DPY19L2 deletion. By comparison, we would expect 1.6% of the patients in this cohort to have Klinefelter syndrome and 0.23% to have Y-microdeletion. Our findings thus indicate that AURKC mutations are more frequent than Klinefelter syndrome and constitute the leading genetic cause of infertility in North African men. Furthermore, we estimate that AURKC and DPY19L2 molecular defects are 10 and 5 times more frequent, respectively, than Y-microdeletions.

Figure 1

Photographs of representative spermatozoa from (a, a’) a normal donor, (b, b’) a patient with macrozoospermia (with a homozygous aurora kinase C c.144delC mutation) and (c, c’) a patient with globozoospermia (with a homozygous DPY19L2 deletion).

Figure 2

Genetic diagnosis of aurora kinase C (AURKC) exons 3 and 6. Electropherogram showing part of AURKC exons 3 and 6 from a control subject (lane 2) and a patient with a homozygous c.144delC deletion of exon 3 (lane 3, column 2) and another patient with a homozygous p.Y248* mutation of exon 6 (lane 3, column 3). The reference nucleotide sequence and its translation are indicated at the top of the figure.

Figure 3

Multiplex ligation-dependent probe amplification (MLPA) analysis of DPY19L2 exons 1, 17 and 22. The probe set contained three control probes for normalization purposes (c1, c2, c3) and three specific DPY19L2 probes (X1, X17 and X22) corresponding to exons 1, 17 and 22 of DPY19L2, respectively. Lane 1: MLPA profile of a normal DNA sample (control). Lane 2: MLPA profile of a patient with a homozygous deletion, showing a total absence of DPY19L2 exon signals. Lane 3: MLPA profile of a patient with a heterozygous deletion, showing a halving of the intensity of the DPY19L2 signals.