线粒体核糖体蛋白MRPS22的突变导致原发性卵巢功能不全

Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency

哺乳动物：人

细胞：内皮细胞；上皮细胞；间皮细胞，成纤维细胞

作者：Chen A, Tiosano D, Guran T, Baris HN, Bayram Y, Mory A, Shapiro-Kulnane L, Hodges CA, Coban Akdemir Z, Turan S, Jhangiani SN, van den Akker F, Hoppel CL, Salz HK, Lupski JR, Buchner DA
出版期刊：《Hum Mol Genet》 （2018）

Abstract：

Primary ovarian insufficiency (POI) is characterized by amenorrhea and loss or dysfunction of ovarian follicles prior to the age of 40. POI has been associated with autosomal recessive mutations in genes involving hormonal signaling and folliculogenesis, however the genetic etiology of POI most often remains unknown. Here we report MRPS22 homozygous missense variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) identified in four females from two independent consanguineous families as a novel genetic cause of POI in adolescents. Both missense mutations identified in MRPS22 are rare, occurred in highly evolutionarily conserved residues, and are predicted to be deleterious to protein function. In contrast to prior reports of mutations in MRPS22 associated with severe mitochondrial disease, the POI phenotype is far less severe. Consistent with this genotype - phenotype correlation, mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, suggesting a non-bioenergetic or tissue specific mitochondrial defect. Furthermore, we demonstrate in a Drosophila model that mRpS22 deficiency specifically in somatic cells of the ovary had no effect on fertility, whereas flies with mRpS22 deficiency specifically in germ cells were infertile and agametic, demonstrating a cell autonomous requirement for mRpS22 in germ cell development. These findings collectively identify that MRPS22, a component of the small mitochondrial ribosome subunit, is critical for ovarian development and may therefore provide insight into the pathophysiology and treatment of ovarian dysfunction.

文章摘要：

原发性卵巢功能不全 (POI) 的特征是在 40 岁之前闭经和卵巢卵泡丧失或功能障碍。POI 与涉及激素信号传导和卵泡发生的基因中的常染色体隐性突变有关，但 POI 的遗传病因通常仍然未知.在这里，我们报告了在来自两个独立近亲家庭的四名女性中发现的 MRPS22 纯合错义变异 c.404G>A (p.R135Q) 和 c.605G>A (p.R202H) 作为青少年 POI 的新遗传原因。在 MRPS22 中鉴定的两种错义突变都很罕见，发生在高度进化保守的残基中，并且预计对蛋白质功能有害。与先前报道的与严重线粒体疾病相关的 MRPS22 突变相比，POI 表型的严重程度要低得多。与这种基因型-表型相关性一致，在源自 POI 患者的成纤维细胞中未检测到氧化磷酸化或 rRNA 水平的线粒体缺陷，表明存在非生物能或组织特异性线粒体缺陷。此外，我们在果蝇模型中证明，mRpS22 特异性在卵巢体细胞中的缺乏对生育能力没有影响，而在生殖细胞中特异性缺乏 mRpS22 的果蝇是不育和无配子的，这表明在生殖细胞发育中对 mRpS22 的细胞自主需要。这些发现共同确定 MRPS22 是线粒体核糖体小亚基的一个组成部分，对卵巢发育至关重要，因此可能有助于深入了解卵巢功能障碍的病理生理学和治疗。

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