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

ABSTRACT: Background: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. Methods: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. Results: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. Conclusion: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.

SUBMITTER: Deng X

PROVIDER: S-EPMC7537572 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Deletion of <i>FUNDC2</i> and <i>CMC4</i> on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men.

Deng Xinxian X Fang He H Pathak Asha A Zou Angela M AM Neufeld-Kaiser Whitney W Malouf Emily A EA Failor Richard A RA Hisama Fuki M FM Liu Yajuan J YJ

Frontiers in genetics 20200922

<h4>Background</h4>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.<h4>Methods</h4>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 fami ...[more]

PMID: 33193636

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Project description:Abstract Background Hypergonadotropic hypogonadism can be caused by congenital or acquired causes. These can range from chromosomal abnormalities, enzymatic defects or mutations that cause gonadotropin resistance, trauma, chemotherapy, infections etc. It is uncommon in females other than in Turner syndrome and not all the genetic etiologies are known. Clinical Case A 15 10/12 year old female with primary amenorrhea and absent pubertal development presented with FSH and LH levels of 35.24 mIU/mL and 14.38 mIU/mL, respectively and non-pubertal estradiol levels of 4 pg/mL consistent with hypergonadotropic hypogonadism. Her evaluation showed a normal 46,XX female karyotype and no evidence of hyperandrogenism or thyroid dysfunction. Ultrasound showed no evidence of ovaries and a rudimentary uterus measuring 0.9 cm×1.4 cm×1.2 cm with a delayed bone age of 12 years. Family history was positive for mother having delayed puberty with menarche at 16.5 years of age. Patient was started on hormone replacement therapy with transdermal estrogen. Four months after treatment she developed breast buds and vaginal discharge. After 1.5 years, the uterus measurements were 5.7 cm x3.7 cm x2.2 cm although no ovarian tissue or follicles were identified on MRI. Her biochemical profile also showed decreases in FSH (3.48 mIU/mL) and LH (0.99 mIU/mL) and an increase in estradiol (38pg/mL). Exome sequencing was performed and revealed biallelic missense variants c.766C>T, p.(Pro256Ser) and c.1036G>C p.(Gly346Arg) in exon 2 of the INHA (NM_002191) gene. Both variants are rare in the human population, seen in a heterozygous state with a global allele frequency (gnomADv2.1) of 0 and 0.00002790 (rs780833794), respectively, and predicted to be damaging by bioinformatic tools. INHA, a member of the transforming growth factor-β (TGF-β) superfamily, encodes the alpha subunit of glycoprotein hormones inhibin A and B. Studies in animal models indicate that inhibin A negatively regulates follicle stimulating hormone (FSH) secretion by suppressing FSHR expression and plays a crucial role in ovarian steroid hormone production, follicular development, proliferation and apoptosis of granulosa cells, and oocyte maturation. Heterozygous pathogenic variants in the INHA gene have been reported in patients with primary ovarian insufficiency (POI) and secondary amenorrhea1, while our patient with biallelic variants in INHA is affected by gonadal dysgenesis, primary amenorrhea, absence of puberty, a more severe POI phenotype. Conclusion To our knowledge, this is the first case of biallelic mutations in INHA gene leading to a severe phenotype (gonadal dysgenesis, primary amenorrhea and absence of puberty) compared to heterozygous mutations that lead to POI with secondary amenorrhea. 1References: Marozzi A, Porta C, et al. 2002. Mutation analysis of the inhibin alpha gene in a cohort of Italian women affected by ovarian failure. Human Reproduction Vol. 17 No.7 1741-1745 Presentation: Monday, June 13, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Dataset Information

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

Publications

Deletion of <i>FUNDC2</i> and <i>CMC4</i> on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men.

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