Ultrastructural study of the decapitated sperm defect in an infertile man

Perotti, M.E.; Giarola, A; Gioria, M

doi:10.1530/jrf.0.0630543

Cited by 85 publications

(67 citation statements)

References 17 publications

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“…Therefore, our descriptive data in humans, added to the previously published data in mice, suggest a potential causative role for ODF1 deficiency in human infertility. Other reports exists on human sperm that present as decapitated or, in the words of the authors, have "loose tails and head" (36). In one such report, a 36-year-old infertile man with normal WHO semen parameters (35-46 ϫ 10 6 sperm/ml, 60% motility), displayed decapitated heads, even though the tails were structurally normal (36).…”

Section: Discussionmentioning

confidence: 95%

“…Other reports exists on human sperm that present as decapitated or, in the words of the authors, have "loose tails and head" (36). In one such report, a 36-year-old infertile man with normal WHO semen parameters (35-46 ϫ 10 6 sperm/ml, 60% motility), displayed decapitated heads, even though the tails were structurally normal (36). Interestingly, electron micrographs showed many of the sperm cells displayed an underdeveloped or rudimentary connecting piece (36) or a failure in the implantation fossa to differentiate, giving rise to sperm with loose heads.…”

Section: Discussionmentioning

confidence: 97%

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Deficiency in Outer Dense Fiber 1 Is a Marker and Potential Driver of Idiopathic Male Infertility

Hetherington

Schneider‐Futschik

Scott

et al. 2016

Molecular & Cellular Proteomics

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Globally, ϳ1 in 15 men of reproductive age are infertile, yet the precise mechanisms underlying their gamete failure are unknown. Although a semen analysis is performed to determine fertilizing potential, the diagnostic suitability of this analysis has been questioned in several reports, as many men, classified as infertile according to their semen analysis, subsequently turn out to be fertile. Herein, we have used a quantitative (phospho)-proteomic analysis, using enrichment on titanium dioxide followed by ion-trap mass spectrometry (LC-MS/MS), to compare the semen of infertile versus fertile males. One protein, namely outer dense fiber 1 (ODF1), was dramatically reduced in infertile males. Using specific antibodies, we then screened the gametes of a cohort of suspected infertile men and demonstrated a reduction in the amount of ODF1 compared with fertile controls. Stress treatment of sperm deficient in ODF1 caused the head to decapitate, suggesting why these gametes fail to initiate fertilization. Interestingly, electron micrographs of ODF1-deficient spermatozoa revealed an abnormal connecting piece, indicating several developmental defects with both the implantation plate and the thin laminated fibers. In some cases, the implantation plate appeared to be reduced in size or was overburdened by granular material near the connecting piece. Hence, a strong reduction ODF1 is a marker of idiopathic male infertility and a potential driver of this condition. Molecular & Cellular Proteomics 15: 10.1074/ mcp.M116.060343, 3685-3693, 2016.Globally, in excess of 80 million people suffer from infertility (1), with ϳ1 in every seven couples so affected (2). In at least half of these cases, a defect in one or more aspects of sperm function appears to be the cause (2). Understanding the contribution of each partner to a couple's infertility is critical in determining how this situation can be optimally addressed. In the case of the male, a semen analysis focusing on sperm motility, concentration, and morphology is often performed to determine the fertilizing potential. A set of guidelines for evaluating semen quality was originally published by the World Health Organization (WHO) in 1980 (3). However, so inadequate were these criteria in predicting infertility that revised values had to be released in 1987, 1992, 1999, and again in 2010 (4). Although a semen analysis is the best predictive test we have to date, it clearly falls short of a true diagnosis (5, 6). Indeed, several studies have shown that men with sperm numbers (7-9), morphology (8, 10), and motility (11-17) below the thresholds outlined by the WHO can be fertile. Furthermore, there are many instances of men with normal sperm parameters that are infertile (13, 18 -20). Thus, these traditional diagnostic tests are limited in the information they generate and are poor predictors of male-factor infertility.In order to define the cause of male infertility, attempts have been made to identify changes in the proteomic composition of normal and infertile spermatozoa (20...

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 97%

Deficiency in Outer Dense Fiber 1 Is a Marker and Potential Driver of Idiopathic Male Infertility

Hetherington

Schneider‐Futschik

Scott

et al. 2016

Molecular & Cellular Proteomics

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“…Among all reported human cases of acephalic spermatozoa, only several displayed acephalic spermatozoa with full penetrance (∼100% headless), with the rest displaying various percentages of acephalic spermatozoa (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Similarly, mice lacking Odf1 or Oaz3 also display acephalic spermatozoa with partial penetrance (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous cases of acephalic spermatozoa have been reported in teratozoospermic patients (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In these patients, the major anomaly lies in headless spermatozoa in the ejaculate, and the headless spermatozoa were initially called "pinhead sperm" because the investigators mistakenly regarded the retained cytoplasmic droplets, which are usually attached to the midprincipal piece junction of the flagella, as the heads of reduced size (8,13,14).…”

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confidence: 99%

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Yuan

Stratton

Bao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

116

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"Pinhead sperm," or "acephalic sperm," a type of human teratozoospermia, refers to the condition in which ejaculate contains mostly sperm flagella without heads. Family clustering and homogeneity of this syndrome suggests a genetic basis, but the causative genes remain largely unknown. Here we report that Spata6, an evolutionarily conserved testis-specific gene, encodes a protein required for formation of the segmented columns and the capitulum, two major structures of the sperm connecting piece essential for linking the developing flagellum to the head during late spermiogenesis. Inactivation of Spata6 in mice leads to acephalic spermatozoa and male sterility. Our proteomic analyses reveal that SPATA6 is involved in myosin-based microfilament transport through interaction with myosin subunits (e.g., MYL6).M ale gametes-spermatozoa-are produced in the testis through a process termed spermatogenesis, which can be divided into three phases: mitotic, meiotic, and haploid (1). In the mitotic phase, spermatogonial stem cells proliferate and differentiate into spermatogonia, which subsequently enter the meiotic phase and become spermatocytes. Spermatocytes undergo crossover, followed by two consecutive meiotic cell divisions to produce haploid spermatids. Spermatids then undergo a multistep differentiation process, also called spermiogenesis, to form spermatozoa. Severe disruptions in either the mitotic or the meiotic phase tend to cause azoospermia, whereas spermiogenic defects often lead to reduced sperm counts, aberrant sperm motility, and deformed spermatozoa, a condition termed oligoasthenoteratozoospermia (OAT) in humans (2, 3).OAT accounts for a significant proportion of male idiopathic infertility cases (2, 4). Numerous cases of acephalic spermatozoa have been reported in teratozoospermic patients (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In these patients, the major anomaly lies in headless spermatozoa in the ejaculate, and the headless spermatozoa were initially called "pinhead sperm" because the investigators mistakenly regarded the retained cytoplasmic droplets, which are usually attached to the midprincipal piece junction of the flagella, as the heads of reduced size (8,13,14). Extensive ultrastructral studies on humans and animals with acephalic spermatozoa suggest that this condition results from defects in formation of the connecting piece of spermatozoa during late spermiogenesis, including failure for the proximal centrioles to attach normally to the caudal portion of the sperm nuclei, leading to abnormal head-midpiece alignment, or a nuclear defect that interferes with formation of the implantation fossa, the normal lodging site for the sperm proximal centriole (16). Aberrant formation of the connecting piece leads to independent development of the sperm heads and flagella, and eventually these structures become separated within the seminiferous tubules or during their transition through the seminal tract as a consequence of increased instability of the head-midpiece junction (16,18)....

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“…Head-tail detachment is provoked by specific morphological defects affecting the tight insertion of the tail into the implantation fossa. Thus, decapitation occurred at the level of the proximal centriole, resulted from the dissociation between proximal and distal centrioles, originated from defects in the implantation fossa and the basal plate or might be due to dysfunctional sperm centrioles affecting migration and positioning of the tail (Perotti et al 1981, Baccetti et al 1984, Holstein et al 1986, Chemes et al 1987, Toyama et al 2000. ODF1 is restricted to spermatids and localised to the ODFs, capitulum and basal plate, thus implying that its function is required only in the germ cell and specifically in headtail coupling (Burmester & Hoyer-Fender 1996, Schalles et al 1998, Yang et al 2012.…”

Section: Discussionmentioning

confidence: 99%

Haplo-deficiency of ODF1/HSPB10 in mouse sperm causes relaxation of head-to-tail linkage

Yang¹,

Grzmil²,

Meinhardt³

et al. 2014

Reproduction

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The small heat shock protein ODF1/HSPB10 is essential for male fertility in mice. Targeted deletion of Odf1 resulted in acephalic sperm in homozygous mice of mixed background (C57BL/6J//129/Sv), whereas heterozygous animals are fully fertile. To further elucidate the function of ODF1, we generated incipient congenic mice with targeted deletion of Odf1 by successive backcrossing on the 129/Sv background. We observed that fecundity of heterozygous Odf1 C/K male mice was severely reduced over backcross generations. However, neither aberrant sperm parameters nor sperm anomalies could be observed. Ultra-structural analyses of sperm from incipient congenic heterozygous Odf1 C/K males of backcross generation N7 revealed no obvious pathological findings. However, we observed an enlargement of the distance between nuclear membrane and capitulum, indicating a weakening of the sperm head-to-tail coupling. Severe male subfertility provoked by haplo-deficiency of ODF1 is therefore most probably caused by impaired head-to-tail coupling that eventually might induce sperm decapitation on the specific conditions of in vivo fertilisation. As subfertility in haplo-deficient ODF1 male mice could not be diagnosed by semen analysis, it seems to be a paradigm for unexplained infertility that is a frequent diagnosis for male fertility impairment in humans.

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Ultrastructural study of the decapitated sperm defect in an infertile man

Cited by 85 publications

References 17 publications

Deficiency in Outer Dense Fiber 1 Is a Marker and Potential Driver of Idiopathic Male Infertility

Deficiency in Outer Dense Fiber 1 Is a Marker and Potential Driver of Idiopathic Male Infertility

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Haplo-deficiency of ODF1/HSPB10 in mouse sperm causes relaxation of head-to-tail linkage

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