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Review Article
273
An Overview of The Globozoospermia as A Multigenic
Identified Syndrome
Parastoo Modarres, M.S.c.1, 2, Marziyeh Tavalaee Ph.D.1, Kamran Ghaedi, Ph.D.2, 3*,
Mohammad Hossein Nasr-Esfahani, Ph.D.1, 3, 4*
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,VIDKDQ,UDQ
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Abstract
Acrosome plays an integral role during fertilization and its absence in individuals with globozoospermia leads to
failure of in vitro fertilization (IVF) and oocyte activation post-intracytoplasmic sperm injection (ICSI). A variety
of processes, organelles and structures are involved in acrosome biogenesis including, trans-golgi network (TGN),
DFURSOD[RPHDQGFHOOXODUWUDI¿FNLQJ7KLVUHYLHZDLPVWRH[SODLQUROHVRIUHODWHGVLJQDOVDQGPROHFXOHVLQYROYHGLQ
this process and also describe how their absence in form of mutation, deletion and knockout model may lead to phe-
nomenon referred to globozoospermia.
Keywords: Acrosome, Globozoospermia, Male Infertility
Citation: 0RGDUUHV37DYDODHH0*KDHGL.1DVU(VIDKDQL0+$QRYHUYLHZRIWKHJORER]RRVSHUPLDDVDPXOWLJHQLFLGHQWL¿HGV\QGURPH,QW-)HUWLO6WHULO
12(4): 273-277. doi: 10.22074/ijfs.2019.5561.
Received: 5/May/2018, Accepted: 16/May/2018
*Corresponding Addresses: Department of Cellular Biotechnology, Cell Science
Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
Department of Reproductive Biotechnology, Reproductive Biomedicine Re-
search Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
Emails: kamranghaedi@royaninstitute.org, mh.nasr-esfahani@royaninstitute.org Royan Institute
International Journal of Fertility and Sterility
Vol 12, No 4, Jan-Mar 2019, Pages: 273-277
Introduction
Fertilization is a multifactorial process for fusion of
gametes to initiate development of a new individual. For
successful fertilization to occur, each process needs to
take place in a coordinated manner. One of the main steps
of fertilization is acrosome reaction during which proteo-
lytic contents of acrosome is released to facilitate zona
binding and penetration to zona and the oocyte by sperm
(1). Structural and functional anomalies of acrosome lead
to inability of sperm to penetrate oocyte, thereby resulting
in failed fertilization and infertility. Furthermore, differ-
ent studies show that when barriers of fertilization are by-
passed during intra-cytoplasmic insemination, in certain
cases with acrosome anomalies, the ability of sperm to
induce fertilization is still diminished due to inability of
the oocyte to induce activation (2-4).
7RWDODEVHQFHRIDFURVRPHZDV¿UVWUHSRUWHGE\6FKLUUHQ
et al. (5) which manifested by round head spermatozoa ap-
pearance. This syndrome has termed “globozoospermia”
with a prevalence of 0.1% among infertile male popula-
tion and two subtypes: complete (type-I: 100% spermato-
zoa are round head) or partial (type-II: over 50% sperma-
tozoa are round head). Further genetic pedigree analysis
revealed genetic basis with possible autosomal recessive
inheritance is responsible for incidence of this syndrome
(6). Individuals with globozoospermia commonly show
no mental and physical abnormities, and generally have
normal karyotype with no micro-deletion in chromosome
Y (7). However, sperm cells of the affected persons are
acrosome-less, and incapable of penetrating in zona pel-
lucida (ZP). Considering the importance of acrosome in
fertilization and oocyte activation, this review aimed to
describe the genetic and molecular aspects of globozoo-
spermia.
*HQHWLFDVSHFWVRIJORER]RRVSHUPLD
Literature survey shows different approaches were tak-
en by various researchers to detect genetic and molecular
basses of globozoospermia. These approaches include:
i. Purposefully designed knockout mice for a variety of
genes including: Hrb, Zpbp1, Hsp90b1, Vps54, SAMP32
(SPACA1), ii. Knockout mice approach for different pur-
pose which later exhibited globozoospermia manifesta-
tion. The target genes were as: Csnk2a2, GOPC, Gba2,
PICK1, iii. Whole-genome scan analysis which were car-
ried out using SNP-array approach on the genome of glo-
bozoospermia and the genes associated with this syndrome.
7KHVHJHQHV LGHQWL¿HUV DUH SPATA16 and DPY19L2, and
iv. Assessment of protein localization associate with acro-
some biogenesis such as: SPGL4, Calicin.
Among the 13 genes involved in globozoospermia, they
were mostly related to Golgi network, acrosome formation,
sperm head shaping (anchorage of acrosome to nucleus)
and zona binding. Only, four genes have been so far de-
Int J Fertil Steril, Vol 12, No 4, Jan- Mar 2019
274
tected in individuals presenting globozoospermia including
DPY19L2, SPATA16, PICK1 and Calicin (6-10). It is im-
portant to note that in addition to genetic defects, deregula-
tion of proteins (up or down regulation) can also result in
the onset of globozoospermia. To further elucidate the role
of these 13 genes, below section provides the cellular and
molecular mechanisms in acrosome biogenesis.
$FURVRPHELRJHQHVLV
Acrosome structure is divided into two segments, an-
terior and equatorial segments. The former segment con-
tains enzymes that are released during acrosome reaction
while the latter segment is predominantly involved in
sperm-oocyte fusion. Biogenesis of acrosome begins dur-
ing meiosis and continues through early stages of spermi-
ogenesis which is divided into four steps including golgi,
cap, acrosomal and maturation phases (Fig.1A) (11). In
golgi phase, pro-acrosomal granules (PAGs) derived from
endoplasmic reticulum (ER) are transported to golgi sacs
through anterograde pathway. Subsequently, PAGs are
transported toward sperm nucleus where they bind to an
actin-keratin containing cytoskeletal plate termed “acro-
plaxome”. In cap phase, PAGs fuse with each other to
form a structure known as “acrosomal cap”. In acrosomal
phase, cap begins to spread over anterior part of nucleus to
form an acrosome like structure. In maturation phase, fol-
lowing condensation and elongation of nucleus with the
help of manchette, the equatorial segment of acrosome is
shaped. At this stage, the acrosome is surrounded by two
distinct membranes known as “inner” and “outer” acroso-
mal membranes. Inner acrosomal membrane locates in vi-
cinity of nuclear membrane, tightly anchors the acrosome
to the nuclear envelop through cytoskeletal components
known as “perinuclear theca” (Fig.1B, C) (12).
2ULJLQDOO\DFURVRPHZDVGHVFULEHGDVDPRGL¿HGO\VR-
some while recent literatures suggest that in addition to
PAGs forming from Golgi network, early endosome (EE)
may also have a role in acrosomal biogenesis (Fig.1B).
Hence it is agreed that cargos originated from Golgi ap-
paratus are sorted to plasma membrane, subsequently are
recruited back into cytoplasm and incorporate into devel-
oping pro-acrosomes (13). During acrosomal biogenesis,
particular proteins are involved that their absence or de-
fect may result in globozoospermia.
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&VQND
&DVHLQNLQDVH,,Į SRO\SHSWLGH&VQNDZDVWKH ¿UVW
introduced protein whose gene was associated with glo-
bozoospermia. This protein is a kind of serine-threonine
kinase which relates to nuclear matrix. Multiple forms of
acrosome imperfection like complete lack of acrosome,
indented/detached acrosome from nucleus, and acrosomal
remnants were recognized in spermatozoa of Csnk2a2-
GH¿FLHQWPLFH,QRWKHUZRUGVPLFHODFNLQJWKHCsnk2a2
gene demonstrated aberrant development in both nucleus
and acrosome (14).
*%$
ȕ*OXFRVLGDVH*%$LVDJO\FROLSLGK\GURODVHUHVL-
GHQWLQ(5 DQGLWVUHODWLRQWR JORER]RRVSHUPLDZDV¿UVW
UHFRJQL]HGLQJO\FROLSLGVWRUDJHGLVHDVHGXHWRGH¿FLHQF\
of Gba2 in male mice with reduced fecundity. Glucosyl-
ceramides are normally transferred from developing germ
cells to Sertoli cells for subsequent breakdown. Loss of
the GBA2 results in accumulation of glucosylceramide
in Sertoli cells and disrupts transport of glycolipid from
germ cells which in turn interrupts normal Sertoli-germ
cell interactions. Therefore, this defect leads to formation
of abnormal sperm (Fig.1A, D). Unlike in mice, muta-
tional assessments for GBA2 in 3 unrelated families, orig-
inating from Britain, Canada, and Germany, have been
unfruitful to show an association with globozoospermia
in man (15).
63$7$
Spermatogenesis-associated 16 (SPATA16), also known
DV1<'63LVDKXPDQ WHVWLV VSHFL¿F SURWHLQ DQGLWV
ortholog encoding gene is expressed in mouse spermato-
cyte and spermatids. SPATA16 has a subcellular localiza-
tion in Golgi apparatus and pro-acrosmal vesicles being
transported to acrosome. Its function is sorting and modi-
¿FDWLRQ RI DFURVRPDO HQ]\PHV LQ *ROJL QHWZRUN
This protein also interacts with other proteins involved in
acrosomal biogenesis including GOPC and Hrb (Fig.1B).
SPATA16ZDVWKH¿UVWJHQHZKLFKZDVVKRZQWRFRQWULE-
ute to human globozoospermia with an autosomal domi-
nant pattern of inheritance (6).
+UE
Hrb, formerly known as human Rev-binding/interact-
ing protein (hRIP), is the cofactor of HIV-1 Rev protein,
involved in shuttling of proteins between nucleus and cy-
toplasm. Hrb interacts with proteins involved in nucleo-
F\WRSODVPLF WUDI¿FNLQJ %DVHG RQ WKHVH IXQFWLRQV
Hrb mice knockout model revealed that, Hrb is involved
in vesicle to vesicle docking, fusion of pro-acrosmal
vesicles with acrosome and thereby acrosomal biogen-
esis (Fig.1B). Therefore, its absence was associated with
JORER]RRVSHUPLD )XUWKHU DQDO\VLV RI Hrb-/- mice
revealed a second role for Hrb in formation of acroplax-
ome plague. Acroplaxome is encompassed by 3 proteins
including: F-actin, Sak57 (an ortholog of keratin5) and
myosin Va. In HrbGH¿FLHQWPLFHNHUDWLQ¿ODPHQWEXQ-
dle in acroplaxome is missing and the strength of acro-
some vesicle in binding to nucleus is reduced which its
outcome is manifested as globozoospermia (19).
3,&.
Protein interacting with C kinase 1 (PICK1) was ini-
tially found in brain. It plays an important role in protein
WUDI¿FNLQJRIQHXURQV$OWKRXJKWKH3,&.PLFHZHUH
produced to study the brain function but these mice were
infertile. PICK1 like GOPC has a postsynaptic density 95,
discs large, and zonula occludens-1 (PDZ) domain which
*ORER]RRVSHUPLDDQG5HVSRQVLEOH*HQHV
Int J Fertil Steril, Vol 12, No 4, Jan- Mar 2019
275
LVLQYROYHGLQ 3$*WUDI¿FNLQJ)LJ%6R IDU RQH
mutation in this gene has been reported to be associated
with globozoospermia (9).
*23&
GOPC gene, encodes Golgi-associated PDZ and coiled-
coil motif containing protein (GOPC). GOPC protein has
5 domains including: one PDZ domain, two coiled-coil
motifs, and two conserved domains with unknown func-
tion (21). GOPC is involved in PAG transport from Golgi
network to acrosome and its absence (GOPC-/-) is as-
sociated with globozoospermia (Fig. 1B). In addition to
lack of acrosome, other deformities associated with this
defect, are lack of post-acrosomal sheath or peri-nuclear
theca (22) and coiled-coil tail (23).
=3%3
=3ELQGLQJ SURWHLQ =3%3RU6SRU ,DP DQG
its paralog, ZPBP2, were described as acrosomal proteins
in mice and human. ZPBP1-GH¿FLHQWPDOHPLFHDUHVWHU-
ile and present round-head spermatozoa due to disrupted
acrosome biogenesis. Zpbp1 is an intra-acrosomal protein
DQG =SESGH¿FLHQW VSHUPDWLGV GHPRQVWUDWH GHIHFWLYH
protein matrix assembly and results in fragmentation of
the abnormal acrosomes (Fig.1B) (24).
Considering candidate genes responsible for abnor-
mal sperm head morphology, heterozygous mutation in
ZPBP1 were described in patients with aforementioned
condition, however direct involvement of ZPBP1 in the
RQVHWRIVXFKFRQGLWLRQVUHPDLQVWREHFODUL¿HG
63$&$
Sperm acrosome associated 1 (SPACA1) or SAMP32
(sperm acrosomal membrane-associated protein 32) is a
WHVWLVVSHFL¿FWUDQVPHPEUDQHSURWHLQLQYROYHGLQVSHUP
egg interaction. During elongation stage of developing
spermatozoa, this protein is localized in inner acrosomal
membrane (Fig.1B) (26) and no role has been envisaged
in acrosome reaction (27). The role of this protein in glo-
bozoospermia was initially recognized when this protein
was absent in Gopc- and Zpbp1-disrupted mouse line.
However, later studies revealed that “disruption of Gopc
FDXVHG D VLJQL¿FDQW GHFUHDVH LQ 63$&$ DQG =3%3´
while “disruption of Zpbp1 caused loss of SPACA1where-
as GOPC was unaffected” and “disruption of Spaca1 did
not affect the amounts of GOPC and ZPBP1 in the testis”.
Thereby, suggesting that Spaca1 is likely downstream of
these two genes (27). Spaca1GH¿FLHQF\OHDGVWR IDLOXUH
of acrosome thinning, coinciding with instability/or loss
of acroplaxome and nuclear plate (27) and unlike most of
aforementioned proteins, it has no role in protein trans-
port in golgi network or in acrosome formation.
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Heat shock protein 90b1 (Hsp90b1), a member of heat
VKRFNSURWHLQIDPLO\LVD WHVWLV VSHFL¿F HQGRSODVPLF
chaperone involving in entire folding, activation and/or
degradation of ER proteins (Fig.1B). It was shown that
Hsp90b1- null sperm cells are round and not able to ferti-
lize the oocyte. Therefore, absence of this protein showed
DSRWHQWLDOUROHLQWKHLQFLGHQFHRIJORER]RRVSHUPLD
Recent study has hypothesized that phosphorylation
of Hsp90b1 along with other chaperon proteins during
sperm capacitation leads to the formation of ZP -recog-
nized protein complexes and/or the translocation of these
complexes to the surface of spermatozoa (29).
9SV
Vps54 is a protein apparently involved in tethering of
vesicles from endosomes to the trans-golgi sacs (13). This
is an alternative pathway in acrosome biogenesis as men-
tioned earlier. The role of this protein in acrosomal biogen-
esis was found when wobbler mouse with Vps54(L967Q)
mutation were found to cause sterility. The protein codi-
¿HG E\ WKH 9SV JHQH KDV DQ DFWLYH UROH LQ YHVLFXODU
UHWURJUDGHWUDI¿FNLQJDQGOLNH+UEJHQHDIIHFWVSURDFUR-
somal vesicle coalesces with acrosome (Fig.1B) (30).
63$*//
63$*/DQGLWVLVRIRUPDUHWHVWLVVSHFL¿FSURWHLQVEH-
long to SUN domain proteins. These transmembrane pro-
teins are located on inner nuclear membrane (INM). By
interacting with their partner on outer nuclear membrane
(ONM), known as KASH domain can anchor or create
linkage to nucleo- and cytoskeleton complex (LINC com-
plex) (Fig.1C) (31).
Different members of this anchoring system have been
discovered but their role in acrosomal biogenesis re-
mains to be determined. Among these proteins, absence of
SPAGL4/4L-2 has been associated with globozoospermia.
SPAG4L/4L-2 is localized on apical side of nuclear mem-
brane of developing spermatid and it may have a function
in docking of acrosome vesicle to nuclear membrane (31).
'3</
DPY19L2, similar to SPAGL4/4L-2, is a transmem-
EUDQHSURWHLQZLWKSUHGLFWHGGRPDLQVLQLQQHUQXFOH-
ar membrane. The expression of this protein is restricted
to testis and like SPAGL4 (or SUN5) is involved in an-
chorage of cytoskeleton to nuclear membrane (Fig.1C).
Therefore, its absence leads to instability and dissocia-
tion of the layered structure of acroplaxome, the nuclear/
acrosome bridging region. Thereby, its absence results in
formation of round head spermatozoa (32). ElInati et al.
(10) revealed that DPY19L2 gene has an inevitable re-
lationship with globozoospermia. They have shown that
DPY19L2 is one of the main genes responsible for globo-
zoospermia. In this regard, a wide spectrum of plausible
mutations for this gene has been detected in globozoo-
spermic individuals such as: deletion of the whole locus,
nonsense, missense, splicing mutations, partial deletion in
GLIIHUHQWUHJLRQVRIWKHJHQHHQFRPSDVVLQJH[RQV
15, 21 and intron 11 (10, 33-36).
Modarres et al.
Int J Fertil Steril, Vol 12, No 4, Jan- Mar 2019
276
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&DOLFLQ
Calicin is one of the subacrosomal cytoskeletal proteins
involved in acrosomal biogenesis which its absence re-
VXOWVLQJORER]RRVSHUPLD
7KHSURWHRPLFVRIURXQGKHDGVSHUPDWR]RD
Collectively, it is evident that numerous proteins are in-
volved in acrosomal biogenesis and the absence of each
protein may result in globozoospermia phenotype. One
approach to distinguish proteins associated with globo-
zoospermia is comparative proteomics between normo-
zoospermia and globozoospermia. The results of this
study have shown up/down regulation of several proteins
in affected subjects. Spermatozoa acrosome membrane-
associated protein 1 (SAMP1) and sperm protein associ-
ated with the nucleus on the X chromosome (SPANX) are
among the proteins that their expression was shown to be
down regulated (37). SAMP1 is a glycoprotein receptor
residing in inner nuclear membrane and its absence re-
VXOWV LQ PLVORFDOL]DWLRQ RI WKH 681 63$1; DOVR
acts as a nuclear envelope protein residing in post-acro-
somal perinuclear theca and is expected to be associated
with acrosome-nucleus binding and down regulation of
this protein in globozoospermia may be underlying cause
of the lack of acrosome (37).
Conclusion
Taken together, the results of this study suggest that
mutation, deletion of genes products associate with Golgi
apparatus, formation of acroplaxome or those associated
with neuclo-cytoskeleton involved in attachment of acro-
some with nucleus have a potential role in induction of
globozoospermia.
Acknowledgements
We would like to express our gratitude to staff of Royan
LQVWLWXWH7KHDXWKRUVGHFODUHGQRFRQÀLFWVRILQWHUHVW
Author's Contributions
P.M; Search and collection of articles, interpretation,
manuscript writing. M.T, K.G., M.H.N.-E.: Manuscript
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DQGDSSURYHGWKH¿QDOPDQXVFULSW
References
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2237.
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