Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology,
ACECR, Isfahan, Iran
Department of Reproductive Biotechnology, Reproductive Biomedicine Research Center,
Royan Institute for Biotechnology, ACECR, Isfahan, Iran
Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran
Isfahan Fertility and Infertility Center, Isfahan, Iran
Department of Cellular Biotechnology
Science Research Center
Royan Institute for Biotechnology
Department of Reproductive Biotechnology
Royan Institute for Biotechnology
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Deemeh Mohammad Reza,
Nasr-Esfahani Mohammad Hossein.
Assessment of DPY19L2 Deletion in Familial and
Non-Familial Individuals with Globozoospermia and
DPY19L2 Genotyping .
Int J Fertil Steril.
Globozoospermia is a rare syndrome with an incidence of less than 0.1%
among infertile men. Researchers have recently identified a large deletion, about 200 kbp,
encompassing the whole length of DPY19L2 or mutations in SPATA16 and PICK1 genes
associated with globozoospermia. The aim of this study was to analyze the DPY19L2
gene deletion using polymerase chain reaction technique for the exons 1, 48, 11 and 22
as well as break point (BP) “a” in globozoospermic men.
Materials and Methods
In this experimental study, genome samples were collected
from 27 men with globozoospermia (cases) and 36 fertile individuals (controls), and
genomic analysis was carried out on each sample.
Deletion of DPY19L2 gene accounted for 74% of individuals with globozoospermia. DPY19L2 gene deletion was considered as the molecular pathogenic factor for the onset
of globozoospermia in infertile men. By quantitative real-time polymerase chain reaction
(qPCR), we genotyped DPY19L2 deletion and identified carriers within the population.
This technique may be considered as a method for family counseling and
has the potential to be used as a pre-implantation genetic diagnosis, especially in ethnic
community with high rate of consanguineous marriages.
Globozoospermia is a rare autosomal
recessive genetic syndrome with an incidence
of less than 0.1%. In this syndrome, due to
defect in the process of acrosome biogenesis,
the sperm contains a round head shape, con-
sequently leading to no penetration into the
oocyte during fertilization. Thus, direct intra-
cytoplasmic sperm insemination (ICSI) along
with artificial oocyte activation is the only so-
lution to gain pregnancy at couples suffering
this abnormality (1). Genetic pedigree assess-
ment of these individuals indicates the con-
genital origin of globozoospermia. To define
molecular defects involved in this disorder,
several autosomal genes have been identified
in knockout mice models including: Csnk2a2,
Hrb, Gopc, Pick1, Gba2, Vps54, Zpbp1 and
Hsp90b1 (2-9). Defect of these genes in mouse
models represented phenotypically similar
abnormalities to human globozoospermia.
However, among the aforementioned genes,
only PICK1 mutation was yet detected in hu-
man. PICK1 protein is involved in subcellular
trafficking in brain, pancreas and testis. The
respective gene is located on human chromosome 22, and contains 13 exons. In spermatogenesis, PICK1 is involved in trafficking
of pro-acrosomal vesicles from golgi apparatus to acrosome. Liu et al. (10) showed a ho-
mozygous missense mutation (G198A) at the
C-terminal domain of PICK1 which disrupted
PvuII site, culminating in formation of sperms
with round head shape in human. Other human
autosomal genes involved in globozoospermia
are SPATA16 and DPY19L2 (11-13). SPATA16
is a testis specific gene, translating a protein
which is localized in the golgi apparatus and
plays a role in the transportation of pro-acro-
somal vesicles from golgi to the acrosome in
the round and elongated spermatids (14). Dam
et al. (11) found a homozygous sequence vari-
ation in the last nucleotide of exon 4 (G848A)
of this gene which impaired NciI or HpaII recognition site, in three infertile brothers of a
Jewish family with globozoospermia.
However, the most likely considered gene
to have a pivotal role in globozoospermia is
DPY19L2. This gene is expressed primarily in
spermatids with a specific localization limited to
the inner nuclear membrane, facing the acroso-
mal vesicle. Lack of the relevant protein causes
instability of acrosome vesicles and thereby loss
of acrosome (15). It has been demonstrated that
complete deletion of DPY19L2 by non-allelic
homologous recombination (NAHR) results in
globozoospermia (12, 13). Recent studies have
revealed that DPY19L2 gene function could be
eliminated at nine possible breakpoints covering
three regions, known as breakpoints “a, b and
c” in two low copy flanking repeats (LCRs) of
DPY19L2 gene. High incidence (96.5%) of LCR
sequences facilitates the occurrence of NAHR in
this region (16).
Considering the role of aforementioned genes
in globozoospermia and in line with our per-
vious study (16), the aim of this study was to
evaluate the prevalence of missense mutations,
G848A, in exon 4 of SPATA16 gene and G198A
in exon 13 of PICK1, as well as DPY19L2 de-
letion in Iranian infertile individuals with globozoospermia referring to Isfahan fertility and
infertility center (IFIC). Herein, we observed
complete deletion of DPY19L2 gene in 20 out of
27 globozoospermic individuals, but no mutation was detected in SPATA16 or PICK1 gene.
We also performed quantitative real-time polymerase chain reaction (qPCR) assay to identify
individuals with homo/hemizygous deletion of
Materials and Methods
Mutational analysis of SPATA16, PICK1 and
This experimental study was approved by
Institutional Review Board (IRB) of Royan
Institute. In this case-control study, 27 male
with globozoospermia from Iranian population
were contributed. An arbitrary number was assigned to each globozoospermic individual (G1
to G29), out of whole two individuals, G11 and
G17, were omitted due to missing. We assessed
the mutations for SPATA16 and PICK1 genes
and provided pedigrees for two families with
complete deletion of DPY19L2 and one family
with deletion of exon 5, 6 and 7 in DPY19L2
In this process, blood samples were taken
from 27 individuals, with globozoospermia
with round-headed spermatozoa who referred
to IFIC, as well as their family members after completing a consent form. Two out of 27
persons with more than 50% acrosomeless
spermatozoa in their normal and round-headed
sperm samples were considered to have partial
globozoospermia, while the rest of individuals were suffering from total globozoospermia.
Peripheral blood samples were also taken from
30 fertile men as well as the parents of three
individuals with globozoospermia (G8, 14 and
21). In the sample group, except three brothers
(G21, 22, and 23) and two cases of five (G5,
6, 20, 26, and 27) and two (G9 and 29) cousin subjects, the remaining 17 individuals with
globozoospermia belonged to unrelated families (Table 1,).
Genomic DNA was extracted from individuals’
peripheral blood samples using standard salting out
procedure and kept at -20 C until usage (17). Specific primers for identification of G848A, in exon 4
of SPATA16 gene and G198A in exon 13 of PICK1
gene were designed by oligo7 primer designing
software (Molecular Biology Insights, CO, USA)
according to the respective sequences obtained
from National Center for Biotechnology Information (NCBI) database, whereas primer sequences
(Table 2,) for assessment of DPY19L2 deletion were
ordered according to previous report (16). Missense
mutations of SPATA16 and PICK1 genes were assessed using Restriction Fragment Length Polymorphism PCR (RFLP-PCR) assay, due to ability
of their PCR products digestion by NciI and PvuII
restriction enzymes, respectively. Indeed, G848A
nucleotide variation in SPATA16 gene causes disruption of NciI site in this location. Thus, a partial
PCR product (635 bp) of this gene encompassing
G848A could not be cut to produce 283 and 352
bp fragments. Similarly, mutation of G198A region
in PICK1 gene disrupts one of two PvuII restriction sites located in this 548 bp PCR product. Thus,
G198A mutation produces two bands after PvuII
cut, lack of which could cause production of three
bands after PvuII digestion. In this study, we did not
evaluate the other mutations in these two genes.
Following identification of three exons (5, 6 and
7) deletion in one of the affected Iranian individual
(G9) which was previously reported by Elinati et
al. (16), and due to the history of infertility in his
family, blood samples of several volunteer family
members were obtained and the target of interest
was analyzed in their DNA samples.
For detection of DPY19L2 deletion, a multiplex
PCR assay was performed for exons 1, 5, 6, 7, 11 and
22 of this gene, together with a part of β-ACTIN or
PROTAMIN 1 genes, as internal control using specific
primers (Table 2,). Lack of amplification for all or some
DPY19L2 exons indicates respectively total or partial
deletion of this gene in the studied cases. To confirm
complete deletion of this gene, specific breakpoint “a”
amplification was performed in the samples with lack
of amplification for all DPY19L2 exons.
List of primers used for polymerase chain reaction and real time PCR analysis
Primer sequence (5'→3')
Annealing temperature (°C)
Product length (bp)
Break point “a”
Quantitative assessment of mutated DPY19L2 alleles
qPCR was implemented by two alternative methods, to analyze the genotyping of DPY19L2 gene
for the family members of three cases (G8, 14 and
21) in terms of homo/hemizygosity deletion or
normal state of DPY19L2 gene. Specific DPY19L2
and β-ACTIN primer pairs were designed to quantify both the target and reference genes (Table
2). Of note, primer efficiencies for target gene
(DPY19L2) and reference gene (β-ACTIN) were
almost equal (Fig .1,).
In the first method, samples were quantified absolutely, using a control blood sample obtained
from a healthy fertile donor, who voluntarily participated in this study. After genomic DNA extraction by standard salting out procedure, 60 ng
of standard genomic DNA was used as a template
for further serial dilution preparations. Different
amounts of DNA (60, 12, 2.5, 0.5, 0.1 ng) from
this fertile donor were used as template in each
PCR reaction in three set of PCR to draw a standard threshold cycle (Ct) curve (red squares shown
in the Fig.1). Then, 60 ng of sample tests were
subjected to PCR reactions (blue squares shown
in the Fig.1). The quantity of the target gene
(DPY19L2, lower curve shown in the Fig.1) and
the reference gene (β-ACTIN, upper curve shown
in the Fig.1) of each subject was calculated based
on their Ct in the standard curve which was drawn with different amounts of DNA from the fertile
(control) sample in ABI step one plus real-time
PCR system (Life Technologies, CA, USA). Proportion of PCR products of DPY19L2 to β-ACTIN
quantities was considered for further analyses.
This proportion for fertile was considered between 0.8-1, for carrier and patient cases was
approximately 0.5 (ranged 0.3-0.7) and 0 respectively, as reported earlier (18). Additionally, to
assess the accuracy of this method, equal volume
of DNA extracts from blood samples taken from
the fertile individual (control sample) and a patient with globozospermia (G14) were mixed and
the resulting mixture was used as a heterozygous
In the second method, conventional relative
quantification (RQ, using 2-ΔΔCt
equation) method was used with the same samples, utilizing 60
ng of DNA templates to quantify PCR-products
of DPY19L2 relative to β-ACTIN. In this study,
RQ level was considered 0.8-1 for normal cases,
while this level was approximately 0.5 (ranged
0.3-0.7) and 0 in carrier and patients respectively,
as previously reported (18). All PCR reactions
contained 5 µl SYBR Green (TaKaRa, Japan), 0.2
µl Rox and 5 µM of each specific primer (0.2 µl)
for DPY19L2 or for β-ACTIN (0.5 µl) in a 10 µl
final volume of PCR reaction.
Clinical characteristics of the patients with
Clinical parameters of the patients who participated in this study are depicted in the Table 3.
Analyses showed lower sperm motility of the patients, compared to the highlighted standard criteria
by World Health Organization (WHO). Regarding the round-headed shape of the sperms, in this
study, ICSI technique was used to obtain successful
fertilization culminated in three healthy births
(Table 3,). In this survey, three pedigree members
that suffered from globozospermia were further
- A standard threshold cycle (Ct) curve was drawn to calculate the allele quantities of DPY19L2 and β-ACTIN for individuals who
are suspected to be carrier for pathogenic allele of DPY19L2. As described in materials and methods, a standard Ct curve was drawn
using different amounts of DNA from a fertile donor (60, 12, 2.5, 0.5 and 0.1 ng, red squares) through qPCR. Then, the quantity of
the target gene (DPY19L2, lower curve) and the reference gene (β-ACTIN, upper curve) of each tested sample, for individuals who
were suspected carriers of the pathogenic allele of DPY19L2, was calculated based on their Ct on the standard curve. The primer
efficiency for both genes was almost similar. Meanwhile, regression coefficients (R2) and the slope of Ct curves were mostly equal
(approximately 0.99, and-3.8 respectively).
Clinical parameters of patients with globozoospermia
Consanguinity of the parents
ICSI attempts and results
Sperm concentration (106/mL)
Progressive motility (%)
Number of ICSI (ET cycles)
Clinical pregnancy (Abortion)
Live delivery (Sexuality)
1 Singleton (Girl)
1 Singleton (Boy)
1 Singleton (Girl)
Two samples of G11 and G17 were lost, thus they were deleted. ET; Freeze-thawed embryo transfer, ICSI; Intra-cytoplasmic sperm inseminaton, NA; Not assigned, ND; Not done, +; Stands for successful pregnancy, -; Stands for abortion, and
*; Globo 23 is single and not married.
Mutational analysis in SPATA16 and PICK1
In this study, 27 cases with globozoospermia and
30 fertile men as control group were analyzed for
detection of nucleotide variation (Table 1,). In our
first screening, regarding that digestion of the PCR
products resulted in similar pattern to the fertile cases (data not shown), we did identify missense mutations of neither G848A in exon 4 of SPATA16 gene
(Fig .2,, left panel) nor G198A in exon 13 of PICK1
gene in the studied cases (Fig .2,, right panel).
- Assessment of missense mutations of G848A in the exon 4
of SPATA16 (left panel) and G198A in the exon 13 of PICK1 (right
panel) genes using NciI and PvuII restriction endonuclease enzymes, respectively. No mutation was observed due to complete
digestion of amplified fragments as described in materials and
methods. M; 50 bp DNA ladder.
Analysis of DPY19L2 deletion in the cases with
We have previously reported that DPY19L2 gene
deletion leads to globozoospermia (16). In this
study, further to 14 (out of 18) individuals who had
shown some deletion in DPY19L2 gene, six (out of
nine) new cases with globozoospermia, missed the
entire length of DPY19L2 gene (G21, 22, 23, 24,
26 and 27, Table 1,). One of these six individuals
was unrelated (G24), while the remaining individuals were originated from two different pedigrees
This experiment was carried out by several multiplex PCR on exon 1 (Fig .3A,), exon
11 (Fig .3B,) and exon 22 of DPY19L2 gene
(Fig .3C,) with a part of β-ACTIN or PROTAMINE1 gene. Two new individuals (G25 and
28), with partially globozoospermia demonstrations, showed a wild-type condition for
DPY19L2 gene (Table 1,). Furthermore, data
indicated the presence of breakpoint “a” (BPa)
in most of the new cases (five out of six) with
entire DPY19L2 gene deletion (Fig .3D,, Fig respective lanes for G21 and 26).
Moreover, DPY19L2 gene hemizygosity (complete deletion of one DPY19L2 gene allele) was
evaluated in parents of one case (G8), who has
previously been recognized to suffer from deletion
of entire length of DPY19L2 gene (16). Here we
confirmed hemizygosity of DPY19L2 for both parents of G8, by amplification of BPa (Fig .4A,) and
exon 11 (Fig .4B,). Of note that other siblings of this
family were fertile.
- Analysis of DPY19L2 gene deletion in exons 1, 11 and 22 as well as identification of breakpoint “a” (BPa) in a number of in-
dividuals with globozoospermia (G#). Multiplex PCR products of A. Exon 1(504 bp, upper band), B. Multiplex PCR products of exon
22 of DPY19L2 gene (313 bp, lower band) and part of PROTAMINE1 gene (530 bp, upper band). Co+ or positive control in A, B and C
is a fertile specimen and Coor negative control is no template sample, C. Exon 11 (516 bp, upper band) of DPY19L2 gene together
with a part of β-ACTIN gene (375 bp, lower band) and D. PCR analysis of BPa. P1 and P2 are parents of globozoospermia patient
(G21) and B1 is his fertile brother and negative control is a fertile specimen, F, and positive control is a case with globozoospermia,
which has been confirmed to have BPa. M; 50 bp DNA ladder in panel A and 100 bp DNA ladder for the rest of the panels and PCR;
Polymerase chain reaction.
- Detection of exon 11 and BPa in parents of one case with globozoospermia (G8). A. Amplification of BPa implied hemizygosity state
for DPY19L2 gene in the parents. DNA sample of fertile individual (F) was not amplified for BPa as expected, Co+; Globozoospermia who
previously proved to have BPa, , P1, P2; Parents of G8, Co-; No template sample and B. Multiplex PCR products for exon 11 of DPY19L2
gene (516 bp, upper band) together with a part of β-ACTIN gene (375 bp, lower band), Co+; Sample from a fertile man, Co-; No DNA
template, M; 100 bp DNA ladder and P1, P2; Parents of G8.
Evaluation of familial globozoospermia
In this experiment study, two cases (G5 and 9)
were selected for sibling analysis. As shown in
the Figure 5, the genetic pedigree belongs to family of G5 (with the history of reproductive failure
and miscarriage) revealed that all of five members
(G5, 6, 20, 26, and 27) had globozoospermia associated with complete deletion of DPY19L2 gene.
We have previously demonstrated (16) a partial
deletion of DPY19L2 including exons 5, 6 and 7 in
one case (G9, Table 1,). Due to infertility history of
his family (,Fig .6,) and access to DNA samples of
all family members, multiplex PCR of the aforementioned exons was performed. Curiously, we
determined similar mutations pattern of DPY19L2
gene to G9 patient, in the cousin with complete
globozoospermia (G29). Indeed, detection of exons 4 and 8 by PCR confirmed this partial deletion
(data not shown).
- Pedigree of one case with globozoospermia (G5) and repeated pregnancy loss. There is more consanguineous marriage in this fam-
ily but for simplicity detailed data are not depicted in the pedigree. Polymerase chain reaction (PCR) analysis showed G26, 27, 5, 6 and 20
suffering from globozoospermia due to complete deletion of DPY19L2 gene. II2, III11 and III15 are infertile individuals with performing no
genetic analysis. The inset numbers which are shown in the squares/circles represent the numbers of healthy (fertile) siblings who were
not shown in this pedigree.
- Consanguineous pedigree of the G9 family, with partial deletion of DPY19L2 gene. Only one cousin (G29) who was also suffering
from globozoospermia had deletion of exons 5, 6 and 7. The inset numbers which are shown in the squares/circles represent the numbers
of healthy (fertile) siblings who were not shown in this pedigree. n; The sexuality and numbers of siblings were not determined.
DPY19L2 genotyping analysis
To set a reliable method for homo/hemizygosity
state of DPY19L2 deletion, we performed qPCR
based genotyping analysis for family members
of one case who showed whole DPY19L2 gene
deletion, G21. The DPY19L2 deletion consan-
guineous pedigree for G21 patient is shown in
the Figure 7. Data analyses demonstrated whole
DPY19L2 gene deletion of one allele for the G21
parents. Quantity proportion values of DPY19L2
to β-ACTIN for carriers of DPY19L2 deletion
were almost between 0.40.6, while in normal
cases, it ranged between 0.8-1 based on two
calculated methods (quantities ratio and 2-∆∆Ct
presented in the Table 3). In addition, no amplification plot was detected for G21, 22 and 23 indicating lack of the mentioned gene in these subjects. In addition, detection of BPa in hemizygote
individuals of the family confirmed the outcomes
of qPCR assay (Fig .3D,, Fig where P1 and P2 are parents of G21 patient,, B1 is the hemizygote fertile
brother. G21 is proband person) (Table 4,).
- Consanguineous pedigree of G21 with complete deletion of DPY19L2 gene in BPa. DPY19L2 genotyping analysis in this pedigree
indicated that B2 and wives of G21 and B2 are hemizygote. Three pedigree members (B1 wife, G21 sister and B2 daughter) did not par-
ticipate in the analysis and their zygousity state remained undefined (NA)
Ct; Threshold cycle and PCR; Polymerase chain reaction.
To extend the application of previously suggest-
ed method (quantities ratio) for identification of
gene homo/hemizygosity at different individuals,
we performed further analyses on the G8 and 14
patients’ parents, besides of the hemizygote sam-
ple (hetero) as notified in materials and methods.
Data affirmed the hemizygote status of the parents
and hetero case by two alternatively implicated
calculation methods (Table 5,).
In the recent years, there have been an increasing amounts of literatures proposing the molecular mechanisms of globozoospermia (7,9,13,15,16,19,21). Our previous studies have described DPY19L2 gene as a basic factor required for development of normal acrosome biogenesis. Partial or complete deletion of the DPY19L2 gene is pivotal factor in globozoospermia (16).
Therefore, we investigated complete deletion of DPY19L2 gene effects to reaffirm the potential association of DPY19L2 gene and globozoospermia. In addition, deletion of this gene was evaluated in the family members of three globozoospermic individuals. Thus, deletion analysis of DPY19L2 gene (12q14.2) was carried out in three exons 1, 11, 22 of DPY19L2 gene, using multiplex PCR, compared to β-ACTIN or PROTAMINE1 genes as internal controls. Briefly, all of three assessed exons of DPY19L2 gene (1,11,22) were missed in 20 out of 27 cases (74%) suggesting total absence of DPY19L2 gene in these cases.
It should be noted that identification of total deletion of DPY19L2 gene with BPa in 18 cases, out of 27, has previously been reported by Elinati et al. (16). Overall, six out of nine new individuals showed complete deletion of DPY19L2 gene, five of whom carried BPa and the remaining may have unknown BP. Also, one new patient (G29) harbored a partial deletion of this gene and two others (G25 and G28) with partial globozoospermia had two wild type alleles. Previous studies have also demonstrated molecular mutations in DPY19L2 gene (19,21). Deletion of the DPY19L2 gene is a common genomic rearrangement that occurs due to LCRs flanking the gene by NAHR. Concurrent with the cases, family members of three globozoospermic patients were investigated in this study. In this regard, two pedigrees (G5 and 9 pedigrees) from different geographically accommodation regions, similar ethnicity and high rate of consanguineous marriages showed the history of reproductive failure due to globozoospermia. Regarding high tincidence of this rare abnormality among tribal races, diagnosis of carrier individuals could help them, in terms of genetic management, for future family planning.
Several studies have previously detected heterozygosity of the other genes, like SMN1 and DYSTROPHIN, through quantitative real-time PCR based on comparative Ct method (18,22,23). In this article, we identified the carriers in one pedigree (G21 pedigree) by this method and also proposed a modified method, quantities ratio. Thus, we designed qPCR assay for family members of G21. Analyses were performed based on proportion of DPY19L2 to β-ACTIN quantities. After providing the standard curve based on serial diluted DNA samples of a fertile man, quantities of the reference and target gene were estimated. Quantitative analysis of DPY19L2 gene for G21 family members led us to identify individuals with hemizygosity at this gene. We determined that parents with a quantity ratio ranging between 0.4-0.6 are carrier. One of the fertile brothers (B2) as well as partners of G21 and B2, were hemizygote for deletion of DPY19L2 gene. Quantity ratio for normal cases, consisting one of the fertile brother, the grand daughter and partner of G22, were ranging from 0.95-1.3. These results were similar to previously reported threshold cycle method verifying our conclusion to determine the individuals with no gene deletion or carriers (18,22). Considering non-consanguinity of parents, the incidence of the abnormality in this family could be attributed to their accommodation in the same geographical area. To validate our calculation method on the allele hemizygosity, we extended experiments on the G8 and G14 patients’ parents who kindly accepted to participate voluntarily in this survey.
These findings are in agreement with previous studies, indicating a strong relationship between DPY19L2 gene and globozoospermia. However, molecular cause of few cases remains yet unclear, requiring further investigations to identify genetic defect(s) in the other gene(s) affecting globozoospermia.
Regarding the other genes, in the present study mutation screening of the SPATA16 and PICK1 genes were also carried out on 27 cases with globozoospermia and 30 fertile men. Our data revealed that PICK1 and SPATA16 genes were intact in all of studied individuals.
Our result revealed that qPCR analysis can be used for genotyping of DPY19L2 deletion and this may help genetic consolers in family planning. In future, it might also help prevent occurrence of this syndrome in carrier families through pre-implantation genetic diagnosis, especially in ethnic community with high consanguineous marriages.
This study was supported by Royan Institute and we would like to express our gratitude to staff of IFIC for their fully supports. There is no conflict of interest in this study.
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