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MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism

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Abstract

Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.

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Authors and Affiliations

  1. 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary

    Vince Kornél Grolmusz, Annamária Kövesdi, Kinga Németh, Katalin Balogh, Anna Szentpéteri, Beatrix Sármán, Anikó Somogyi, Miklós Tóth, Péter Igaz & Károly Rácz

  2. “Lendület” Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis University, Szentkirályi utca 46, Budapest, H-1088, Hungary

    Vince Kornél Grolmusz & Attila Patócs

  3. 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, 1091, Hungary

    Katalin Borka, Csaba Dékány & András Kiss

  4. 1st Department of Medicine, University of Szeged, Korányi fasor 8-10, Szeged, 6720, Hungary

    Éva Csajbók & Zsuzsanna Valkusz

  5. Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary

    Károly Rácz & Attila Patócs

  6. Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary

    Attila Patócs

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  1. Vince Kornél Grolmusz
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  2. Katalin Borka
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  3. Annamária Kövesdi
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  4. Kinga Németh
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  5. Katalin Balogh
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Contributions

A.P. conceived the study. V.K.G., K.B., K.R., and A.P. designed research. V.K.G. and A.P. performed in silico analysis. K.Ba., B.S., A.S., É.Cs., Zs.V., M.T., P.I., and K.R. evaluated patients. V.K.G., A.Kö., K.N., K.Ba., and A.P. performed genetic screening. K.B., C.D., and A.K. performed immunohistochemistry and histopathologically analyzed samples. V.K.G. and A.Sz. performed qPCR measurements. V.K.G., K.B., and A.P. analyzed data. V.K.G., K.B., K.R., and A.P. wrote the manuscript. The authors would like to thank Ms. Mariann Benkő for the excellent technical assistance.

Corresponding author

Correspondence to Attila Patócs.

Ethics declarations

The study was approved by the Scientific and Research Committee of the Medical Research Council of Hungary (ETT-TUKEB 4457/2012/EKU). Written informed consent was acquired from all patients undergoing genetic testing.

Funding

The authors acknowledge the financial support of the Hungarian Academy of Sciences (“Lendulet” grant awarded to Attila Patócs) and of the Hungarian Scientific Research Grant (OTKA, PD100648 to Attila Patocs).

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Figure 1

Chromatogram of novel MEN1 mutations. Chromatograms of novel heterozygous mutations and wild type sequences of c.168delC (Panel A) and c.1160delA (Panel B). (GIF 283 kb)

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Grolmusz, V.K., Borka, K., Kövesdi, A. et al. MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism. Virchows Arch 471, 401–411 (2017). https://doi.org/10.1007/s00428-017-2158-3

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