Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Medical Genetics
Published in: BMC Medical Genetics 1/2019

Open Access 01-12-2019 | Arterial Occlusive Disease | Research article

Evidence for long noncoding RNA GAS5 up-regulationin patients with Klinefelter syndrome

Authors: Michele Salemi, Rossella Cannarella, Rosita A. Condorelli, Laura Cimino, Federico Ridolfo, Giorgio Giurato, Corrado Romano, Sandro La Vignera, Aldo E. Calogero

Published in: BMC Medical Genetics | Issue 1/2019

Login to get access

Abstract

Background

Klinefelter syndrome (KS) is characterized by the presence of at least one supernumerary X chromosome. KS typical symptoms include tall stature, gynecomastia, hypogonadism and azoospermia. KS patients show a higher risk of developing metabolic and cardiovascular diseases, inflammatory and autoimmune disorders, osteoporosis and cancer. Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) has been shown to be involved in several biologic processes, including inflammatory and autoimmune diseases, vascular endothelial cells apoptosis and atherosclerosis, as well as cellular growth and proliferation, cellular development and cell-to-cell signaling and interaction. The lncRNA GAS5 expression profile in KS patients has never been evaluated so far.

Methods

To accomplish this, GAS5 mRNA levels were evaluated by Next Generation Sequencing (NGS) technology and qRT-PCR assay in 10 patients with KS and 10 age-matched controls.

Results

NGS results showed a significantly lncRNAGAS5up-regulation by 5.171-fold in patients with KS. Theresults of qRT-PCR confirmed the NGS data.

Conclusions

These findings showed the occurrence of lncRNA GAS5 over-expression in KS patients. Whether this lncRNA is involved in the pathogenesis of inflammation and autoimmune diseases, atherogenesis or germ cell depletion in KS patients is not known. Further studies are needed.
Literature
1.
Morris JK, Alberman E, Scott C, Jacobs P. Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet. 2008;16:163–70.CrossRef
2.
Klinefelter HF, Reifenstein EC, Albright F. Syndrome characterized by gynaecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle stimulating hormone. J Clin Endocrinol Metab. 1942;2:615–27.CrossRef
3.
Maiburg M, Repping S, Giltay J. The genetic origin of Klinefelter syndrome and its effect on spermatogenesis. Fertil Steril. 2012;98:253–60.CrossRef
4.
Wikstrom AM, Dunkel L. Klinefelter syndrome. Best Pract Res Clin Endocrinol Metab. 2011;25:239–50.CrossRef
5.
Frühmesser A, Kotzot D. Chromosomal variants in klinefelter syndrome. Sex Dev. 2011;5(3):109–23.CrossRef
6.
Aksglaede L, Link K, Giwercman A, Jørgensen N, Skakkebaek NE, Juul A. 47, XXY Klinefelter syndrome: clinical characteristics and age-specific recommendations for medical management. Am J Med Genet C Semin Med Genet. 2013;163C:55–63.CrossRef
7.
De Sanctis V, Ciccone S. Fertility preservation in adolescents with Klinefelter’s syndrome. Pediatr Endocrinol Rev Suppl 2010;1:178–181.
8.
Groth KA, Skakkebæk A, Høst C, Gravholt CH, review BAC. Klinefelter syndrome--a clinical update. J Clin Endocrinol Metab. 2013;98:20–30.CrossRef
9.
Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Mosekilde L, Bennett P, Laurberg P, Frystyk J, Flyvbjerg A, Christiansen JS, Gravholt CH. The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care. 2006;29:1591–8.CrossRef
10.
van den Bergh JP, Hermus AR, Spruyt AI, Sweep CG, Corstens FH, Smals AG. Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter's syndrome after long-term testosterone substitution. Osteoporos Int. 2001;12(1):55–62.CrossRef
11.
Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT, EMAS Group. Identification of lateonset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123–35.CrossRef
12.
Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms. J Clin Endocrinol Metab. 2004;89(8):3813–7.CrossRef
13.
Cimino L, Salemi M, Cannarella R, Condorelli RA, Giurato G, Marchese G, La Vignera S, Calogero AE. Decreased miRNA expression in Klinefelter syndrome. Sci Rep. 2017;7:16672.CrossRef
14.
Gu J, Wang Y, Wang X, Zhou D, Shao C, Zhou M, He Z. Downregulation of lncRNA GAS5 confers tamoxifen resistance by activating miR-222 in breast cancer. Cancer Lett. 2018;pii: S0304–3835(18):30447–6.
15.
Li M, Xie Z, Wang P, Li J, Liu W, Tang S, Liu Z, Wu X, Wu Y, Shen H. The long noncoding RNA GAS5 negatively regulates the adipogenic differentiation of MSCs by modulating the miR-18a/CTGF axis as a ceRNA. Cell Death Dis. 2018;9(5):554.CrossRef
16.
Mourtada-Maarabouni M, Hedge VL, Kirkham L, Farzaneh F, Williams GT. Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5). J Cell Sci. 2008;121:939–46.CrossRef
17.
Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene. 2009;28:195–208.CrossRef
18.
Schneider C, King RM, Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell. 1988;54:787–93.CrossRef
19.
Renganathan A, Kresoja-Rakic J, Echeverry N, Ziltener G, Vrugt B, Opitz I, Stahel RA, Felley-Bosco E. GAS5 long non-coding RNA in malignant pleural mesothelioma. Mol Cancer. 2014;13:119.CrossRef
20.
Pickard MR, Mourtada-Maarabouni M, Williams GT. Long non-coding RNA GAS5regulates apoptosis in prostate cancer cell lines. Biochim Biophys Acta. 2013;1832:1613–23.CrossRef
21.
Yacqub-Usman K, Pickard MR, Williams GT. Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells. Prostate. 2015;75:693–705.CrossRef
22.
Wang J, Gong X, Tian GG, Hou C, Zhu X, Pei X, Wang Y, Wu J. Long noncoding RNA growth arrest-specific 5 promotes proliferation and survival of female germline stem cells in vitro. Gene. 2018;653:14–21.CrossRef
23.
Chen L, Yang W, Guo Y, Chen W, Zheng P, Zeng J, Tong W. Exosomal lncRNA GAS5 regulates the apoptosis of macrophages and vascular endothelial cells in atherosclerosis. PLoS One. 2017;12(9):e0185406.CrossRef
24.
Mayama T, Marr AK, Kino T. Differential expression of glucocorticoid receptor noncoding RNA repressor Gas5 in autoimmune and inflammatory diseases. Horm Metab Res. 2016;48(8):550–7.CrossRef
25.
Salemi M, Cimino L, Marino M, Cannarella R, Condorelli RA, Romano C, LaVignera S, Calogero AE. Next generation sequencing expression profiling of mitochondrial subunits in men with Klinefelter syndrome. Int J Med Sci. 2018;15:31–5.CrossRef
26.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.CrossRef
27.
Anders S, Pyl PT, Huber W. HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.CrossRef
28.
Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;(5):511–5.
29.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001 Dec;25(4):402–8.CrossRef
30.
Salemi M, La Vignera S, Castiglione R, Condorelli RA, Cimino L, Bosco P, Romano C, Romano C, Calogero AE. Expression of STRBP mRNA in patients with cryptorchidism and Down's syndrome. J Endocrinol Investig. 2012;35:5–7.CrossRef
31.
Dong S, Qu X, Li W, Zhong X, Li P, Yang S, Chen X, Shao M, Zhang L. The long non-coding RNA, GAS5, enhances gefitinib-induced cell death in innate EGFR tyrosine kinase inhibitor-resistant lung adenocarcinoma cells with wide-type EGFR via downregulation of the IGF-1R expression. J Hematol Oncol. 2015;8:43.CrossRef
32.
Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP. Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal. 2010;3:ra8.PubMedPubMedCentral
33.
Pickard MR, Williams GT. Molecular and cellular mechanisms of action of tumour suppressor GAS5 LncRNA. Genes (Basel). 2015;6(3):484–99.CrossRef
34.
Lucafo M, De Iudicibus S, Di Silvestre A, Pelin M, Candussio L, Martelossi S, Tommasini A, Piscianz E, Ventura A, Decorti G. Long noncoding RNA GAS5: a novel marker involved in glucocorticoid response. Curr Mol Med. 2015;15(1):94–9.CrossRef
35.
Xing D, Liang JQ, Li Y, Lu J, Jia HB, Xu LY, Ma XL. Identification of long noncoding RNA associated with osteoarthritis in humans. Orthop Surg. 2014;6(4):288–93.CrossRef
36.
Lucafò M, Di Silvestre A, Romano M, Avian A, Antonelli R, Martelossi S, Naviglio S, Tommasini A, Stocco G, Ventura A, Decorti G, De Iudicibus S. Role of the long non-coding RNA growth arrest-specific 5 in glucocorticoid response in children with inflammatory bowel disease. Basic Clin Pharmacol Toxicol 2018;122(1):87–93.ù.
37.
Calogero AE, Giagulli VA, Mongioì LM, Triggiani V, Radicioni AF, Jannini EA, Pasquali D. Klinefelter ItaliaN group (KING). Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders. J Endocrinol Investig. 2017;40(7):705–12.CrossRef
38.
Cannarella R, Mattina T, Condorelli RA, Mongioì LM, Pandini G, La Vignera S, Calogero AE. Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function. Endocr Connect. 2017;6(7):528–39.CrossRef
39.
Cannarella R, Condorelli RA, La Vignera S, Calogero AE. Effects of the insulin-like growth factor system on testicular differentiation and function: a review of the literature. Andrology. 2018;6(1):3–9.CrossRef
40.
Pitetti JL, Calvel P, Romero Y, Conne B, Truong V, Papaioannou MD, Schaad O, Docquier M, Herrera PL, Wilhelm D, Nef S. Insulin and IGF1 receptors are essential for XX and XY gonadal differentiation and adrenal development in mice. PLoS Genet. 2013;9:e1003160.CrossRef
41.
Grootegoed JA, Siep M, Baarends WM. Molecular and cellular mechanisms inspermatogenesis. Baillieres Best Pract Res Clin Endocrinol Metab. 2000;14:331–43.CrossRef
42.
Print CG, Loveland KL. Germ cell suicide: new insights into apoptosis during spermatogenesis. BioEssays. 2000;22:423–30.CrossRef
43.
Koldemir O, Özgür E, Gezer U. Accumulation of GAS5 in exosomes is a marker of apoptosis induction. Biomed Rep. 2017;6(3):358–62.CrossRef
Metadata
Title
Evidence for long noncoding RNA GAS5 up-regulationin patients with Klinefelter syndrome
Authors
Michele Salemi
Rossella Cannarella
Rosita A. Condorelli
Laura Cimino
Federico Ridolfo
Giorgio Giurato
Corrado Romano
Sandro La Vignera
Aldo E. Calogero
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2019
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-018-0744-0

Other articles of this Issue 1/2019

BMC Medical Genetics 1/2019 Go to the issue

Research article

The association between interleukin-6 gene -174G/C single nucleotide polymorphism and sepsis: an updated meta-analysis with trial sequential analysis

Case report

De novo truncating variant in NSD2gene leading to atypical Wolf-Hirschhorn syndrome phenotype

Research article

The prevalence of CGG repeat expansion mutation in FMR1 gene in the northern Chinese women of reproductive age

Research article

Decoding of novel missense TSC2 gene variants using in-silico methods

Research article

HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia

Research article

A novel frameshift mutation in FRMD7 causes X-linked infantile nystagmus in a Chinese family