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Transcription factor FIGLA is mutated in patients with premature ovarian failure.

ABSTRACT: Premature Ovarian Failure (POF) is a genetically heterogenous disorder that leads to hypergonadotropic ovarian failure and infertility. We screened 100 Chinese women with POF for mutations in the oocyte-specific gene FIGLA and identified three variants in four women: missense mutation c.11C --> A (p.A4E) was found in two women; deletion c. 15-36 del (p.G6fsX66), resulting in a frameshift that leads to haploinsufficiency, was found in one woman; and deletion c.419-421 delACA (p.140 delN) was found in one. Functional analyses by the yeast two-hybrid assay demonstrated that the p.140 delN mutation disrupted FIGLA binding to the TCF3 helix-loop-helix (HLH) domain. Our findings show that a subset of Chinese women with sporadic, premature ovarian failure harbor mutations in FIGLA.

SUBMITTER: Zhao H

PROVIDER: S-EPMC2427265 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Transcription factor FIGLA is mutated in patients with premature ovarian failure.

Zhao Han H Chen Zi-Jiang ZJ Qin Yingying Y Shi Yuhua Y Wang Shan S Choi Youngsok Y Simpson Joe Leigh JL Rajkovic Aleksandar A

American journal of human genetics 20080522 6

Premature Ovarian Failure (POF) is a genetically heterogenous disorder that leads to hypergonadotropic ovarian failure and infertility. We screened 100 Chinese women with POF for mutations in the oocyte-specific gene FIGLA and identified three variants in four women: missense mutation c.11C --> A (p.A4E) was found in two women; deletion c. 15-36 del (p.G6fsX66), resulting in a frameshift that leads to haploinsufficiency, was found in one woman; and deletion c.419-421 delACA (p.140 delN) was foun ...[more]

PMID: 18499083

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Project description:BackgroundHuman amniotic epithelial cells (hAECs) exhibit a strong capability to restore ovarian function in chemotherapy-induced premature ovarian failure (POF). However, the therapeutic efficacy of hAECs is usually affected by the limited number and proliferative ability of grafted hAECs in target organs. The transplantation of stem cells encapsulated in sodium alginate-bioglass (SA-BG) composite hydrogel has recently been shown to be an effective strategy for tissue regeneration. The current study aims to investigate the therapeutic potential of hAECs or hAEC-derived conditioned medium (CM) encapsulated in SA-BG in mice with chemotherapy-induced POF.MethodsC57BL/6 mice were intraperitoneally injected with chemotherapy drugs to induce POF. hAECs or CM were harvested and encapsulated in SA-BG composite hydrogel, which were transplanted onto the injured ovaries of mice with POF. Follicle development, granulosa cell function, and ovarian angiogenesis were evaluated by morphological methods. To further elucidate the effect of SA-BG-encapsulated hAECs/CM on vascularization, the tube formation of human umbilical vein epithelial cells (hUVECs) was conducted in vitro. Cytokine array and ELISA were used to analyze and quantify the effects of bioactive components released by SA-BG on the secretion of angiogenic factors by hAECs.ResultsThe transplantation of SA-BG-encapsulated hAECs/CM restored follicle development, repaired granulosa cell function, and enhanced ovarian angiogenesis in POF mice. The further study showed that SA-BG significantly promoted the tube formation of hUVECs in vitro. Moreover, encapsulating hAECs could facilitate the effect of SA-BG on inducing the formation of the capillary tube in a paracrine manner. In addition, we found that SA-BG extracts significantly enhanced the viability of hAECs and stimulated the secretion of pro-angiogenic factors of hAECs. Notably, compared with SA-BG/CM, SA-BG/hAECs achieve better therapeutic effects, possibly because stimulation of BG enhanced the viability and paracrine capacity of hAECs.ConclusionsThe present study initially demonstrates that SA-BG-encapsulated hAECs or CM can exert a therapeutic effect on chemotherapy-induced POF mainly by protecting granulosa cell function and enhancing ovarian vascularization, which might provide a novel strategy for the delivery of hAECs for treating POF.

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Transcription factor FIGLA is mutated in patients with premature ovarian failure.

Publications

Transcription factor FIGLA is mutated in patients with premature ovarian failure.

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