A Human Homologue of the Drosophila melanogaster diaphanous Gene Is Disrupted in a Patient with Premature Ovarian Failure: Evidence for Conserved Function in Oogenesis and Implications for Human Sterility

Bione, Silvia; Sala, Cinzia; Manzini, M. Chiara; Arrigo, Giulia; Zuffardi, Orsetta; Banfi, Sandro; Borsani, Giuseppe; Jonveaux, Philippe; Philippe, Christophe; Zuccotti, Maurizio; Ballabio, Andrea; Toniolo, Daniela

doi:10.1086/301761

Cited by 244 publications

(160 citation statements)

References 26 publications

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“…The upstream diaphanous (DIAPH) genes accelerate actin nucleation and suppress actin depolymerization. Of interest, disruption of the DIAPH2 coding region was found in a POI family (31), whereas genome-wide association studies identified DIAPH2 (32) and DIAPH3 (33) as candidate genes in regulating follicle reserve and menopause (Fig. S7).…”

Section: Discussionmentioning

confidence: 99%

Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment

Kawamura

Cheng

Suzuki³

et al. 2013

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

722

685

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Primary ovarian insufficiency (POI) and polycystic ovarian syndrome are ovarian diseases causing infertility. Although there is no effective treatment for POI, therapies for polycystic ovarian syndrome include ovarian wedge resection or laser drilling to induce follicle growth. Underlying mechanisms for these disruptive procedures are unclear. Here, we explored the role of the conserved Hippo signaling pathway that serves to maintain optimal size across organs and species. We found that fragmentation of murine ovaries promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth, and the generation of mature oocytes. In addition to elucidating mechanisms underlying follicle growth elicited by ovarian damage, we further demonstrated additive follicle growth when ovarian fragmentation was combined with Akt stimulator treatments. We then extended results to treatment of infertility in POI patients via disruption of Hippo signaling by fragmenting ovaries followed by Akt stimulator treatment and autografting. We successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. The ovarian fragmentation-in vitro activation approach is not only valuable for treating infertility of POI patients but could also be useful for middle-aged infertile women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve.

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Section: Discussionmentioning

confidence: 99%

Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment

Kawamura

Cheng

Suzuki³

et al. 2013

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

722

685

View full text Add to dashboard Cite

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“…Cytogenetic studies have suggested that the long arm of the X chromosome is mainly involved in defects of ovulation [Bione et al 1998]. To the best of our knowledge five genes were disrupted as a result of interruption by an X;autosome translocation near our critical region have been observed.…”

Section: Resultsmentioning

confidence: 96%

“…To the best of our knowledge five genes were disrupted as a result of interruption by an X;autosome translocation near our critical region have been observed. [Cremers et al 1990], and DIAPH2 (MIM * 300108) in Xq22 [Bione et al 1998]. However, most of the breakpoints mapped in the Xq region described in POF patients are intergenic [Mumm et al 2001;Prueitt et al 2002].…”

Section: Resultsmentioning

confidence: 99%

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Disruption ofHDXgene in premature ovarian failure

Ökten

Güneş

Onat

et al. 2013

Systems Biology in Reproductive Medicine

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We present a case of a 19-year-old phenotypically normal girl with premature ovarian failure. Cytogenetic analysis using G banding and fluorescence in situ hybridization (FISH) from cultured peripheral blood lymphocytes of the patient and the family revealed a de novo X;15 translocation and the imbalance to be 46,X,t(X;15)(Xpter → Xq21::15q11 → 15qter;15pter → 15q11::Xq21 → Xqter).ish (CEPX+, wep15+, ISNRPN+, PML+, D15S10+, wcp15-, SNRRN-, PML-) [20]. The X chromosome inactivation (XCI) assay revealed a completely skewed XCI pattern in which selective pressure favors an active maternal allele. The Affymetrix 2.7 M cytogenetics whole-Genome array confirmed the chromosomal imbalance and identified disruption of the HDX gene at Xq21, the translocation breakpoint.

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“…Identification of deletions and translocations in POF1 and POF2 regions has suggested several POF-candidate genes, such as [36][37][38], although very few mutations have actually been detected in these loci [39,40].…”

Section: Candidate Genes On the X Chromosomementioning

confidence: 99%

Insight into the Genomics of Premature Ovarian Failure

Stigliani¹

2013

J Mol Genet Med

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Primary Ovarian Failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles. It causes infertility in ~1% of women <40 years of age and it has important health consequences for affected patients. POF is a heterogeneous disease, which can develop as a result of a broad variety of pathogenic mechanisms including genetic, autoimmune and iatrogenic causes. However, the mechanisms that cause ovarian dysfunction are poorly understood. Focus on genetic component of the disease has revealed the existence of several causal genetic defects, thus indicating that in addition to some monogenic forms, POF may frequently be a multifactorial disease involving several gene abnormalities and chromosome aberrations. Moreover, most recent studies have highlighted that epigenetic mechanisms may give an additional contribution to POF pathogenesis. This review gives a picture of the state of the art of the complex genetic and epigenetic defects associated with POF, being it clear that a deep comprehension of the molecular etiology of POF may in future early identify those women with higher risk of POF.

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A Human Homologue of the Drosophila melanogaster diaphanous Gene Is Disrupted in a Patient with Premature Ovarian Failure: Evidence for Conserved Function in Oogenesis and Implications for Human Sterility

Cited by 244 publications

References 26 publications

Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment

Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment

Disruption ofHDXgene in premature ovarian failure

Insight into the Genomics of Premature Ovarian Failure

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