A HOMOZYGOUS DELETION OF THE DPY19L2 GENE IS A CAUSE OF GLOBOZOOSPERMIA IN MEN FROM THE REPUBLIC OF MACEDONIA
Noveski P1, Madjunkova S1, Maleva I1, Sotiroska V2, Petanovski Z2, Plaseska-Karanfilska D1,*
*Corresponding Author: Professor Dijana Plaseska-Karanfilska, Macedonian Academy of Sciences and Arts, Research Center for Genetic Engineering and Biotechnology, Av. Krste Misirkov 2, POB 428, 1000 Skopje, Republic of Macedonia; Tel.: +389-2-3235-410; Fax: +389-2-3115-434; E-mail: dijana@manu.edu.mk
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INTRODUCTION

Globozoospermia is a rare but severe form of teratozoospermia, accounting for less than 0.1% of male infertility [1]. It is characterized by ejaculates consisting completely of round-headed spermatozoa that lack an acrosome (total globozoospermia) or, in partial globozoospermia, containing a variable proportion (20.0-90.0%) of acrosomeless spermatozoa. The genetic component to globozoospermia was suggested many years ago by several case reports which demonstrated that two or more siblings were affected in each family [2-5]. Furthermore, genetic studies in mice have provided direct evidence that disruption of several genes, including GOPC (Golgiassociated PDZ and coiled-coil motif containing protein), HRB (HIV-1 Rev binding protein) and CSNK2A2 (casein kinase 2, a prime polypeptide) results in a globozoospermia phenotype with decreased fertility. However, there has not been a clear link between homozygous mutations in these genes and globozoospermia in humans [6]. Currently, three genes are known to be associated with total globozoospermia in humans. In 2007, a genome-wide study of six brothers from a consanguineous Ashkenazi Jewish family suggested that a homozygous mutation (c.848G>A or R283Q) in SPATA16 (spermatogenesis-associated 16) was associated with male infertility in human globozoospermia [7]. Later, using the candidate gene screening strategy, a homozygous missense mutation (G198A) in exon 13 of the PICK1 (protein interacting with C kinase 1) gene was identified in a Chinese family. The family member affected by this homozygous missense mutation showed a complete lack of acrosome [8]. However, no mutations in these genes were detected in other men with globozoospermia, thus suggesting that SPATA16 and PICK1 genes are not the main loci associated with this condition [9]. In 2011, a large homozygous deletion, encompassing ~200 kb, including the entire DPY19L2 (protein dpy-19 homolog 2) gene was identified in four (out of 21 screened) unrelated patients [10]. At the same time, a study of 20 patients with globozoospermia originating mainly from Tunisia identified the DPY19L2 deletion, at a much higher rate (75.0%), thus suggesting that deletions involving this gene might be a major cause of globozoospermia [11]. This was confirmed when a larger cohort including 64 globozoospermic patients was screened. This study showed that the DPY19L2 gene was mutated in 66.7% (36 out of 64) globozoospermic patients [12]. In addition to the deletion, several point mutations were also identified. Out of 36 patients with the mutated gene, 69.4% were homozygotes, 19.4% were compound heterozygotes for both this deletion and a point mutation and 11.1% showed a homozygous point mutation. Molecular analysis of the DPY19L2 gene among Chinese globozoospermic patients revealed that a genetic defect was present in nine (60.0%) of the 15 unrelated patients [13]. Four patients were homozygous for the deletion and five were homozygous for a point mutation. This study confirmed that DPY19L2 mutations are the major cause of globozoospermia in patients from different ethnic origins and different geographic regions.



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