ORIGINAL ARTICLE MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism Vince Kornél Grolmusz 1,2 & Katalin Borka 3 & Annamária Kövesdi 1 & Kinga Németh 1 & Katalin Balogh 1 & Csaba Dékány 3 & András Kiss 3 & Anna Szentpéteri 1 & Beatrix Sármán 1 & Anikó Somogyi 1 & Éva Csajbók 4 & Zsuzsanna Valkusz 4 & Miklós Tóth 1 & Péter Igaz 1 & Károly Rácz 1,5 & Attila Patócs 2,5,6 Received: 31 October 2016 /Revised: 24 April 2017 /Accepted: 17 May 2017 # Springer-Verlag Berlin Heidelberg 2017 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 syn- drome 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 mu- tation 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 immunohis- tochemistry 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 oc- curred between menin-positive and menin-negative PHPT tis- sues. Menin deficiency is the consequence of a MEN1 muta- tion in most menin-negative PHPT tissues. Elevated expres- sion of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT. Keywords MEN1 . Mutation . microRNA . Primary hyperparathyroidism . Menin . Immunohistochemistry Introduction Primary hyperparathyroidism (PHPT) is the third most com- mon endocrine disorder [1], with prevalence rates ranging from 0.1 to 0.7% in different populations [2]. It occurs pre- dominantly in postmenopausal women [1, 3]. Autonomous hyperfunctioning of the parathyroid glands leads to parathy- roid hormone (PTH) overproduction and hypercalcemia, resulting in osteoporosis and nephrolithiasis [1]. Upon Electronic supplementary material The online version of this article (doi:10.1007/s00428-017-2158-3) contains supplementary material, which is available to authorized users. * Attila Patócs patocs.attila@med.semmelweis-univ.hu 1 2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest 1088, Hungary 2 BLendület^ Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis University, Szentkirályi utca 46, Budapest H-1088, Hungary 3 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest 1091, Hungary 4 1st Department of Medicine, University of Szeged, Korányi fasor 8-10, Szeged 6720, Hungary 5 Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis University, Szentkirályi utca 46, Budapest 1088, Hungary 6 Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, Budapest 1089, Hungary Virchows Arch DOI 10.1007/s00428-017-2158-3