Deletion of FUNDC2 and CMC4 on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men

Frontiers in Genetics

卷:11

Angela M. Zou¹  Whitney Neufeld-Kaiser²  He Fang²  Xinxian Deng²  Yajuan J. Liu²  Fuki M. Hisama³  Emily A. Malouf³  Richard A. Failor⁴  Asha Pathak⁵ 

[1] Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States;

[2] Department of Pathology, University of Washington, Seattle, WA, United States;

[3] Division of Medical Genetics, University of Washington, Seattle, WA, United States;

[4] Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, United States;

[5] The Polyclinic, Seattle, WA, United States;

关键词: CMC4;    FUNDC2;    hypergonadotropic hypogonadism;    Sertoli cell barrier;    apoptosis;    Xq28 deletion;   

DOI  :  10.3389/fgene.2020.557341

来源: DOAJ

【 摘 要 】

BackgroundHypergonadotropic 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.MethodsHere, 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.ResultsOur 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.ConclusionCompared 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.

【 授权许可】

Unknown