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 page: 73
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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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