Deletion of FUNDC2 and CMC4 on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men.
Deletion of FUNDC2 and CMC4 on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men.
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DOI：
10.3389/fgene.2020.557341
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发表时间：
2020
影响因子：
3.7
通讯作者：
Liu YJ
中科院分区：
文献类型：
--
作者：
Deng X;Fang H;Pathak A;Zou AM;Neufeld-Kaiser W;Malouf EA;Failor RA;Hisama FM;Liu YJ
高促性腺激素低性腺功能减退症(HH)的特征是性激素水平降低，继发性促性腺激素水平升高，原因有先天性或获得性。导致HH的遗传因素尚未完全阐明。在这里，我们报告了一例男性HH患者的基因组和转录组数据分析，该患者患有遗传性Xq28缺失，有生长迟缓史。对这名患者及其未受影响的家庭成员进行了表达分析，并与正常对照组进行了比较，以确定由于该缺失而导致的基因失调。我们的患者Xq28缺失44,806个碱基，只包含两个基因，FundC2和CMC4。FundC2和CMC4在患者体内的表达完全取消。与对照组相比，患者差异表达基因(DIG)的基因本体论分析表明，患者显著上调的基因在支持细胞屏障(SCB)调节、细胞凋亡、炎症反应和促性腺激素释放调节中丰富。事实上，我们的患者有高水平的卵泡刺激素(FSH)，它调节支持细胞的增殖和精子发生。在他的母亲和妹妹中，他们是这种缺失的杂合子，X染色体失活(XCI)偏向于缺失的X，这表明了一种避免FSH失调的机制。与先前报道的大小可变的Xq28缺失的男性相比，我们的研究表明，FundC2和CMC4功能的丧失导致了细胞凋亡、炎症和FSH的失调，并足以导致Xq28相关的HH。
Hypergonadotropic hypogonadism (HH) is characterized by low sex steroid levels and secondarily elevated gonadotropin levels with either congenital or acquired etiology. Genetic factors leading to HH have yet to be fully elucidated. Here, we report on genome and transcriptome data analyses from a male patient with HH and history of growth delay who has an inherited deletion of chromosome Xq28. Expression analyses were done for this patient and his unaffected family members and compared to normal controls to identify dysregulated genes due to this deletion. Our patient’s Xq28 deletion is 44,806 bp and contains only two genes, FUNDC2 and CMC4. Expression of both FUNDC2 and CMC4 are completely abolished in the patient. Gene ontology analyses of differentially expressed genes (DEGs) in the patient in comparison to controls show that significantly up-regulated genes in the patient are enriched in Sertoli cell barrier (SCB) regulation, apoptosis, inflammatory response, and gonadotropin-releasing regulation. Indeed, our patient has an elevated follicle stimulating hormone (FSH) level, which regulates Sertoli cell proliferation and spermatogenesis. In his mother and sister, who are heterozygous for this deletion, X-chromosome inactivation (XCI) is skewed toward the deleted X, suggesting a mechanism to avoid FSH dysregulation. Compared to the previously reported men with variable sized Xq28 deletions, our study suggests that loss of function of FUNDC2 and CMC4 results in dysregulation of apoptosis, inflammation, and FSH, and is sufficient to cause Xq28-associated HH.