DPY19L2 Deletion as a Major Cause of Globozoospermia

Koscinski, Isabelle; ElInati, Elias; Fossard, Camille; Redin, Claire; Muller, Jean; Calle, Juan Velez de la; Schmitt, Françoise; Khelifa, Mariem Ben; Ray, Pierre F.; Kilani, Zaid; Barratt, Christopher L.R.; Viville, Stéphane

doi:10.1016/j.ajhg.2011.01.018

Cited by 169 publications

(71 citation statements)

References 29 publications

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“…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 ] .…”

Section: Introductionmentioning

confidence: 99%

A Homozygous Deletion of the DPY19L2 Gene is a Cause of Globozoospermia in Men From the Republic of Macedonia

Noveski

Madjunkova

Maleva

et al. 2013

Balkan Journal of Medical Genetics

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Globozoospermia is a rare but severe teratozoospermia, characterized by ejaculates consisting completely of round-headed spermatozoa that lack an acrosome or, in partial globozoospermia, containing a variable proportion (20.0–90.0%) of acrosomeless spermatozoa. Men that are affected with total globozoospermia are infertile, and even the application of intracytoplasmic sperm injection (ICSI) has met with disappointingly low success rates. In humans, several case reports of globozoospermia have demonstrated that two or more siblings were affected in each family, which suggested a genetic component to this disease. Currently, three genes are known to be associated with total globozoospermia in humans, SPATA16 , PICK1 and DPY19L2 genes. Mutations in SPATA16 and PICK1 are rare causes of globozoospermia, found in only one patient each. Several studies have suggested that DPY19L2 mutations are the major cause of globozoospermia in patients from different ethnic origins and different geographic regions. The most common DPY19L2 mutation is the 200 kb deletion arising from a nonallelic homologous recombination (NAHR) between the flanking low copy repeats (LCRs). Here we describe the presence of a homozygous deletion of the DPY19L2 gene in two infertile Macedonian patients with 100.0% round headed spermatozoa, thus suggesting that this deletion represents a major cause of globozoospermia among Macedonian men.

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Section: Introductionmentioning

confidence: 99%

A Homozygous Deletion of the DPY19L2 Gene is a Cause of Globozoospermia in Men From the Republic of Macedonia

Noveski

Madjunkova

Maleva

et al. 2013

Balkan Journal of Medical Genetics

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“…Among these members, Dpy19L2 is the most well-studied gene, since DPY19L2 is a causative gene responsible for human globozoospermia, which is a severe and rare male infertility disorder [22,23,32]. Interestingly, Dpy19L2 is found only in mammals, whereas three Dpy19L members ( Dpy19L1 , Dpy19L3 and Dpy19L4 ) are in other vertebrates [21].…”

Section: Discussionmentioning

confidence: 99%

“…The mammalian Dpy-19-like (Dpy19L) gene family consists of four members ( Dpy19L1 to Dpy19L4 ), and the members have 9−11 putative transmembrane domains [21]. Recently, a DPY19L2 deletion has been found to cause human globozoospermia, which is a severe male infertility disorder resulting from round-headed spermatozoa [22,23]. In accord with these observations, Dpy19L2 knockout male mice are sterile caused by aberrant spermiogenesis [19].…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum-Localized Transmembrane Protein Dpy19L1 Is Required for Neurite Outgrowth

et al. 2016

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The endoplasmic reticulum (ER), including the nuclear envelope, is a continuous and intricate membrane-bound organelle responsible for various cellular functions. In neurons, the ER network is found in cell bodies, axons, and dendrites. Recent studies indicate the involvement of the ER network in neuronal development, such as neuronal migration and axonal outgrowth. However, the regulation of neural development by ER-localized proteins is not fully understood. We previously reported that the multi-transmembrane protein Dpy19L1 is required for neuronal migration in the developing mouse cerebral cortex. A Dpy19L family member, Dpy19L2, which is a causative gene for human Globozoospermia, is suggested to act as an anchor of the acrosome to the nuclear envelope. In this study, we found that the patterns of exogenous Dpy19L1 were partially coincident with the ER, including the nuclear envelope in COS-7 cells at the level of the light microscope. The reticular distribution of Dpy19L1 was disrupted by microtubule depolymerization that induces retraction of the ER. Furthermore, Dpy19L1 showed a similar distribution pattern with a ER marker protein in embryonic mouse cortical neurons. Finally, we showed that Dpy19L1 knockdown mediated by siRNA resulted in decreased neurite outgrowth in cultured neurons. These results indicate that transmembrane protein Dpy19L1 is localized to the ER membrane and regulates neurite extension during development.

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“…Similarly, causative mutations for globozoospermia have been identified in humans, including those in SPATA16 [14], DPY19L2 [15,16], and PICK1 [10]. …”

Section: Introductionmentioning

confidence: 99%

Decreased Expression of KIFC1 in Human Testes with Globozoospermic Defects

Zhi

Chen

et al. 2016

Genes

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Globozoospermia is a rare (prevalence of <0.1%) but severe male infertility condition. In our previous study, we found that robust KIFC1 immunostaining was detected in the human elongating/elongated spermatids during human acrosomogenesis. However, the relationship between the decreased expression of KIFC1 and human globozoospermia remains largely unknown. Testicular biopsies of 30 globozoospermia and 30 obstructive azoospermia patients who underwent infertility evaluation and treatment were utilized in this study. Reverse transcriptase polymerase chain reaction (RT-PCR), Western blots, immunohistochemistry, an in vivo model, and intratesticular injection of small inhibitory RNA (siRNA) against the Kifc1 gene were employed, and sperm abnormalities were evaluated by hematoxylin and eosin (H&E) staining and immunocytochemistry. We revealed that the testicular level of KIFC1 mRNA in globozoospermia was significantly reduced compared with that in obstructive azoospermia, and the KIFC1 protein was barely detectable in testicular specimens in 30% (9 of 30) of patients with globozoospermia. Furthermore, knockdown of the Kifc1 gene in mice increased the percentage of sperm with globozoospermic defects (26.5%). Decreased KIFC1 expression was mainly observed in the testes of patients with globozoospermia at the spermatid stage, which may be useful for counseling and management of such patients.

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DPY19L2 Deletion as a Major Cause of Globozoospermia

Cited by 169 publications

References 29 publications

A Homozygous Deletion of the DPY19L2 Gene is a Cause of Globozoospermia in Men From the Republic of Macedonia

A Homozygous Deletion of the DPY19L2 Gene is a Cause of Globozoospermia in Men From the Republic of Macedonia

Endoplasmic Reticulum-Localized Transmembrane Protein Dpy19L1 Is Required for Neurite Outgrowth

Decreased Expression of KIFC1 in Human Testes with Globozoospermic Defects

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