DOCSLIB.ORG

The MKRN3 Gene

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The MKRN3 Gene A P ABREU and others MKRN3 deficiency causes CPP 54:3 R131–R139 Review A new pathway in the control of the initiation of puberty: the MKRN3 gene Ana Paula Abreu, Delanie B Macedo1, Vinicius N Brito1, Ursula B Kaiser and Ana Claudia Latronico1 Division of Endocrinology, Diabetes and Hypertension, Harvard Medical School, Brigham and Women’s Hospital, Correspondence Boston, Massachusetts, USA should be addressed 1Unidade de Endocrinologia do Desenvolvimento, Disciplina de Endocrinologia e Metabologia, Laborato´ rio de to A C Latronico Hormoˆ nios e Gene´ tica Molecular, LIM 42, Hospital das Clı´nicas, Faculdade de Medicina da Universidade Email de Sa˜ o Paulo, Avenida Dr Ene´ as de Carvalho Aguiar, 255, 78 andar, sala 7037, CEP: 05403-900, Sa˜ o Paulo, Brazil [email protected] Abstract Pubertal timing is influenced by complex interactions among genetic, nutritional, Key Words environmental, and socioeconomic factors. The role of MKRN3, an imprinted gene located " hypothalamus and in the Prader–Willi syndrome critical region (chromosome 15q11–13), in pubertal initiation neuroendocrinology was first described in 2013 after the identification of deleterious MKRN3 mutations in five " gonadotropins families with central precocious puberty (CPP) using whole-exome sequencing analysis. " mutations Since then, additional loss-of-function mutations of MKRN3 have been associated with the " secretion inherited premature sexual development phenotype in girls and boys from different ethnic groups. In all of these families, segregation analysis clearly demonstrated autosomal dominant inheritance with complete penetrance, but with exclusive paternal transmission, Journal of Molecular Endocrinology consistent with the monoallelic expression of MKRN3 (a maternally imprinted gene). Interestingly, the hypothalamic Mkrn3 mRNA expression pattern in mice correlated with a putative inhibitory input on puberty initiation. Indeed, the initiation of puberty depends on a decrease in factors that inhibit the release of GnRH combined with an increase in stimulatory factors. These recent human and animal findings suggest that MKRN3 plays an Journal of Molecular inhibitory role in the reproductive axis to represent a new pathway in pubertal regulation. Endocrinology (2015) 54, R131–R139 Introduction Puberty, a complex biological process involving sexual are superimposed upon substantial genetic control. maturation and accelerated linear growth, is initiated Similar timing of puberty shared by mothers and her when the pulsatile secretion of gonadotropin-releasing children, and within racial groups, suggests a genetic hormone (GnRH) increases after a quiescent period during component to the onset of puberty (Zacharias & Wurtman childhood. The regulation of puberty initiation remains 1969, Herman-Giddens et al. 1997). Substantial efforts as one of the great mysteries of human biology and it is have been made to identify genes that are responsible thought that a conjunction of factors plays a role to for the initiation of puberty (Ojeda & Lomniczi 2014). initiate puberty. The identification of these genes is critical for advancing Environmental and metabolic factors are important the understanding of the neuroendocrine regulation of regulators of pubertal development, but these influences puberty initiation. http://jme.endocrinology-journals.org Ñ 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-14-0315 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 04:54:59AM via free access Review A P ABREU and others MKRN3 deficiency causes CPP 54:3 R132 In an attempt to identify genes operating within the Prader–Willi syndrome (PWS) critical region and is neuroendocrine brain that ultimately regulate the repro- maternally imprinted (discussed later). Subsequently, we ductive axis, researchers have been studying patients with showed that mutations in MKRN3 are also the cause of CPP pubertal disorders. The hypothalamic–pituitary–gonadal in apparently sporadic cases (Macedo et al. 2014). These axis regulates puberty initiation and reproduction. GnRH findings were significant contributions to the field and is produced and secreted by the hypothalamus in a will advance the understanding of the pubertal process. pulsatile manner during the embryonic and neonatal We will review the genetic defects identified in patients phases of life. GnRH secretion is actively inhibited during with CPP and their clinical implications, and discuss herein infancy and puberty begins with the reactivation of its the possible role of MKRN3 within the reproductive axis. secretion. GnRH deficiency results in hypogonadotropic hypogonadism, in which patients fail to develop puberty Loss-of-function mutations of MKRN3 cause and are usually infertile. Conversely, early reactivation of familial CPP GnRH secretion results in central precocious puberty (CPP). While several genes have been detected in asso- TheroleofMKRN3 in pubertal initiation was first ciation with GnRH deficiency and have contributed to the described in 2013 after a comprehensive genetic study current knowledge of GnRH regulation (Bianco & Kaiser of several families with CPP (Abreu et al. 2013). In this 2009, Semple & Topaloglu 2010), genes linked to CPP study, the authors investigated 40 members of 15 families have until recently only been identified subsequent to with CPP from different ethnic groups (12 Brazilian, their association with hypogonadotropic hypogonadism, two American, and one Belgian families), and applying such as KISS1 and KISS1R. However, only rare genetic whole-exome sequencing four deleterious MKRN3 defects in KISS1 and its receptor have been identified in mutations – three frameshift and a missense mutation patients with CPP (Teles et al. 2008, Silveira et al. 2010). (Fig. 1) – were detected in five of these families (33%). Both The advances in sequencing methods permitted the sexes were equally affected by MKRN3 mutations (eight detection of new genes implicated in the neuroendocrine girls and seven boys) (Table 1). regulation of puberty. Using exome sequencing analysis More recently, Macedo et al. (2014) studied 215 and studying familial cases of CPP, genetic defects in a unrelated children (207 girls and eight boys) with CPP gene with no previous link to the hypothalamic–pituitary– from three different University Medical Centers and gonadal axis, Makorin ring finger 3 (MKRN3), were identified five novel heterozygous mutations in eight identified as the cause of premature sexual development unrelated Brazilian girls, including four frameshift Journal of Molecular Endocrinology in one-third of the families (Abreu et al. 2013). MKRN3 variants and one missense variant (Fig. 1 and Table 1). is located on the long arm of chromosome 15 in the No family history of premature sexual development was Pro161Argfs*10 Pro161Argfs*16 Ala162Glyfs*14 Glu256Glyfs*36 Arg365Ser Phe417Ile MKRN type Ring Finger Cys-His C3HC4 H C C C C C C C C C Zn Zn C H Zn Zn Zn C C C H Zn C H C H C H C C 1 95 122 238 265 266 293 311 365 394 423 507 aa Glu111* Arg213Glyfs*73 Cys340Gly Tyr391* His420Gln Gln226Thrfs*6 Figure 1 MKRN3 protein structure and mutations identified in patients with central correspond to the amino acid positions in the protein. Blue mutation labels precocious puberty. Zn, zinc; H, histidine; C, cysteine. The three C3H zinc and arrows indicate the location of frameshift mutations; red mutation finger motifs are shown in red, the C3HC4 RING finger motif is in blue, labels and arrows indicate the location of the missense mutations. and the MKRN-specific Cys–His domain is shown in green. The numbers http://jme.endocrinology-journals.org Ñ 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-14-0315 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 04:54:59AM via free access Journal of Molecular Endocrinology http://jme.endocrinology-journals.org DOI: 10.1530/JME-14-0315 Printed in Great Britain Review Table 1 MKRN3 mutations identified in children with CPP. (Gonadarche or testicular enlargement. Breast/Genital development according to Tanner stage and bone age assessed at the time of diagnosis) Characteristics at time of diagnosis MKRN3 mutation Breast/Genital Family Patient Initial clinical manifestation Age development Bone age number Origin number Sex (age in years) (years) Tanner stage (years) DNA Protein References 1 USA I F Thelarche (5.7) 6.5 2 7.7 637delC Arg213Glyfs*73 Abreu et al. (2013) II M Gonadarche (8.0) 8.7 3 11 637delC Arg213Glyfs*73 III F Thelarche (6.5) 6.7 2 7.8 637delC Arg213Glyfs*73 A P ABREU Ñ 2 Brazil I F Thelarche (6.2) 7.0 3 7.0 1171_1172insA Tyr391* Abreu et al. (2013) 2015 Society for Endocrinology II F Thelarche (5.7) 6.0 3 6.0 1171_1172insA Tyr391* 3 Brazil I M Gonadarche and pubarche (5.9) 8.1 3 10 475_476insC Ala162Glyfs*14 Abreu et al. (2013) and others II M Gonadarche and pubarche 9.7 3 9.7 475_476insC Ala162Glyfs*14 unknown 4 USA I M Gonadarche and pubarche (8.5) 8.8 3 11 475_476insC Ala162Glyfs*14 Abreu et al. (2013) II F Thelarche (5.0) 6.5 2 8.3 475_476insC Ala162Glyfs*14 5 Belgium I F Thelarche (6.2) 6.4 2 9.4a 1095GOT Arg365Ser Abreu et al. (2013) II M Gonadarche and pubarche 9.7 3 12 1095GOT Arg365Ser unknown III F Thelarche and pubarche (5.4) 5.7 2 8.5 1095GOT Arg365Ser 6 Brazil I F Thelarche and pubarche (6.4) 7.8 3 11 482delC Pro161Argfs*10 Macedo et al. (2014) MKRN3 deficiency causes CPP Published by Bioscientifica Ltd. 7 Brazil I F Thelarche (5.4) 6.1 3 8.8 482_483insC Pro161Argfs*16 Macedo et al. (2014) 8 Brazil I F Thelarche (6.0) 7.9 4 11 482_483insC Pro161Argfs*16 Macedo et al. (2014) 9 Brazil I F Thelarche (3.0) and pubarche (6.0) 6.7 3 8.8 482delC Pro161Argfs*10 Macedo et al. (2014) 10 Brazil I F Thelarche (4.0) 6.8 4 12 675_676insA Gln226Thrfs*6 Macedo et al. (2014) 11 Brazil I F Thelarche and pubarche (6.0) 6.6 3 7.8 766_767delA Glu256Glyfs*36 Macedo et al.
Load more

Recommended publications
  • Protein Interaction Network of Alternatively Spliced Isoforms from Brain Links Genetic Risk Factors for Autism
    ARTICLE Received 24 Aug 2013 | Accepted 14 Mar 2014 | Published 11 Apr 2014 DOI: 10.1038/ncomms4650 OPEN Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism Roser Corominas1,*, Xinping Yang2,3,*, Guan Ning Lin1,*, Shuli Kang1,*, Yun Shen2,3, Lila Ghamsari2,3,w, Martin Broly2,3, Maria Rodriguez2,3, Stanley Tam2,3, Shelly A. Trigg2,3,w, Changyu Fan2,3, Song Yi2,3, Murat Tasan4, Irma Lemmens5, Xingyan Kuang6, Nan Zhao6, Dheeraj Malhotra7, Jacob J. Michaelson7,w, Vladimir Vacic8, Michael A. Calderwood2,3, Frederick P. Roth2,3,4, Jan Tavernier5, Steve Horvath9, Kourosh Salehi-Ashtiani2,3,w, Dmitry Korkin6, Jonathan Sebat7, David E. Hill2,3, Tong Hao2,3, Marc Vidal2,3 & Lilia M. Iakoucheva1 Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of genetic loci. The convergence of ASD variants have been investigated using various approaches, including protein interactions extracted from the published literature. However, these datasets are frequently incomplete, carry biases and are limited to interactions of a single splicing isoform, which may not be expressed in the disease-relevant tissue. Here we introduce a new interactome mapping approach by experimentally identifying interactions between brain-expressed alternatively spliced variants of ASD risk factors. The Autism Spliceform Interaction Network reveals that almost half of the detected interactions and about 30% of the newly identified interacting partners represent contribution from splicing variants, emphasizing the importance of isoform networks. Isoform interactions greatly contribute to establishing direct physical connections between proteins from the de novo autism CNVs. Our findings demonstrate the critical role of spliceform networks for translating genetic knowledge into a better understanding of human diseases.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Egfr Activates a Taz-Driven Oncogenic Program in Glioblastoma
    EGFR ACTIVATES A TAZ-DRIVEN ONCOGENIC PROGRAM IN GLIOBLASTOMA by Minling Gao A thesis submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March 2020 ©2020 Minling Gao All rights reserved Abstract Hyperactivated EGFR signaling is associated with about 45% of Glioblastoma (GBM), the most aggressive and lethal primary brain tumor in humans. However, the oncogenic transcriptional events driven by EGFR are still incompletely understood. We studied the role of the transcription factor TAZ to better understand master transcriptional regulators in mediating the EGFR signaling pathway in GBM. The transcriptional coactivator with PDZ- binding motif (TAZ) and its paralog gene, the Yes-associated protein (YAP) are two transcriptional co-activators that play important roles in multiple cancer types and are regulated in a context-dependent manner by various upstream signaling pathways, e.g. the Hippo, WNT and GPCR signaling. In GBM cells, TAZ functions as an oncogene that drives mesenchymal transition and radioresistance. This thesis intends to broaden our understanding of EGFR signaling and TAZ regulation in GBM. In patient-derived GBM cell models, EGF induced TAZ and its known gene targets through EGFR and downstream tyrosine kinases (ERK1/2 and STAT3). In GBM cells with EGFRvIII, an EGF-independent and constitutively active mutation, TAZ showed EGF- independent hyperactivation when compared to EGFRvIII-negative cells. These results revealed a novel EGFR-TAZ signaling axis in GBM cells. The second contribution of this thesis is that we performed next-generation sequencing to establish the first genome-wide map of EGF-induced TAZ target genes.
    [Show full text]
  • Genetic Testing in Inherited Endocrine Disorders
    Eggermann et al. Orphanet Journal of Rare Diseases (2020) 15:144 https://doi.org/10.1186/s13023-020-01420-w REVIEW Open Access Genetic testing in inherited endocrine disorders: joint position paper of the European reference network on rare endocrine conditions (Endo-ERN) Thomas Eggermann1* , Miriam Elbracht1, Ingo Kurth1, Anders Juul2,3, Trine Holm Johannsen2,3, Irène Netchine4, George Mastorakos5, Gudmundur Johannsson6, Thomas J. Musholt7, Martin Zenker8, Dirk Prawitt9, Alberto M. Pereira10, Olaf Hiort11 and on behalf of the European Reference Network on Rare Endocrine Conditions (ENDO-ERN Abstract Background: With the development of molecular high-throughput assays (i.e. next generation sequencing), the knowledge on the contribution of genetic and epigenetic alterations to the etiology of inherited endocrine disorders has massively expanded. However, the rapid implementation of these new molecular tools in the diagnostic settings makes the interpretation of diagnostic data increasingly complex. Main body: This joint paper of the ENDO-ERN members aims to overview chances, challenges, limitations and relevance of comprehensive genetic diagnostic testing in rare endocrine conditions in order to achieve an early molecular diagnosis. This early diagnosis of a genetically based endocrine disorder contributes to a precise management and helps the patients and their families in their self-determined planning of life. Furthermore, the identification of a causative (epi)genetic alteration allows an accurate prognosis of recurrence risks for family planning as the basis of genetic counselling. Asymptomatic carriers of pathogenic variants can be identified, and prenatal testing might be offered, where appropriate. Conclusions: The decision on genetic testing in the diagnostic workup of endocrine disorders should be based on their appropriateness to reliably detect the disease-causing and –modifying mutation, their informational value, and cost-effectiveness.
    [Show full text]
  • Enrichment Analyses of Diseases and Pathways Associated With
    www.nature.com/scientificreports OPEN Enrichment analyses of diseases and pathways associated with precocious puberty using PrecocityDB Mridula Sharma1,2, Indra Kundu1,2, Ram Shankar Barai1, Sameeksha Bhaye1, Karishma Desai1, Khushal Pokar1 & Susan Idicula‑Thomas1* Precocious puberty (PP) is an important endocrine disorder afecting children globally. Several genes, SNPs and comorbidities are reported to be associated with PP; however, this data is scattered across scientifc literature and has not been systematically collated and analysed. In this study, we present PrecocityDB as the frst manually curated online database on genes and their ontology terms, SNPs, and pathways associated with PP. A tool for visualizing SNP coordinates and allelic variation on each chromosome, for genes associated with PP is also incorporated in PrecocityDB. Pathway enrichment analysis of PP‑associated genes revealed that endocrine and cancer‑related pathways are highly enriched. Disease enrichment analysis indicated that individuals with PP seem to be highly likely to sufer from reproductive and metabolic disorders such as PCOS, hypogonadism, and insulin resistance. PrecocityDB is a useful resource for identifcation of comorbid conditions and disease risks due to shared genes in PP. PrecocityDB is freely accessible at http://www.preco city.bicni rrh.res.in. The database source code and content can be downloaded through GitHub (https ://githu b.com/bic‑nirrh/ precocity ). Disease-centric databases signifcantly contribute to advancement of health research as they ofer curated and well-annotated data amenable for further analysis. While many of the diseases such as cancers, autism, Alzhei- mers, PCOS and endometriosis have dedicated databases, it would be worthwhile to include more diseases in this list.
    [Show full text]
  • Mutations in the Maternally Imprinted Gene MKRN3 Are Common in Familial Central Precocious Puberty
    D Simon and others MKRN3 mutations in central 174:1 1–8 Clinical Study precocious puberty Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty Dominique Simon1,2,3, Ibrahima Ba4, Nancy Mekhail1, Emmanuel Ecosse1, Anne Paulsen1, Delphine Zenaty1,2,3, Muriel Houang5, Monique Jesuran Perelroizen6, Gian-Paolo de Filippo7, Mariacarolina Salerno8, Gilbert Simonin9, Rachel Reynaud9, Jean-Claude Carel1,2,3, Juliane Le´ ger1,2,3 and Nicolas de Roux2,3,4 1AP-HP, Service d’Endocrinologie Diabe´ tologie Pe´ diatrique, Centre de Re´ fe´ rence des Maladies Endocriniennes Rares de la Croissance, Hoˆ pital Robert Debre´ , Paris F-75019, France, 2Universite´ Paris Diderot, Sorbonne Paris Cite´ F-75019, France, 3Institut National de la Sante´ et de la Recherche Me´ dicale (INSERM), Unite´ 1141, DHU Protect, Paris F-75019, France, 4AP-HP, INSERM U1141, Laboratoire de Biochimie, Hoˆ pital Robert Debre´ , 48 Boulevard Se´ rurier, Paris F-75019, France, 5AP-HP, Explorations Fonctionnelles Endocriniennes, Hoˆ pital Armand Trousseau, Paris F-75012, France, 6Centre d’Endocrinologie Pe´ diatrique, 14 Rue du Rempart St-Etienne, Toulouse F-31000, France, 7Pediatric Correspondence Endocrinology Unit, Gaetano Rummo Hospital, Benevento 82100, Italy, 8Pediatric Endocrinology Unit, Federico II should be addressed University, Naples 80131, Italy and 9Service de Pe´ diatrie Multidisciplinaire, Centre de Re´ fe´ rence des Maladies Rares to N de Roux d’Origine Hypophysaire, Assistance Publique-Hopitaux de Marseille (APHM), Hoˆ pital de la Timone, Aix-Marseille Email Universite´ , Marseille F-13385, France [email protected] Abstract Context and objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic– pituitary–gonadal axis in the absence of identifiable central lesions.
    [Show full text]
  • Mutations in the Maternally Imprinted Gene MKRN3 Are Common in Familial Central Precocious Puberty
    D Simon and others MKRN3 mutations in central 174:1 1–8 Clinical Study precocious puberty Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty Dominique Simon1,2,3, Ibrahima Ba4, Nancy Mekhail1, Emmanuel Ecosse1, Anne Paulsen1, Delphine Zenaty1,2,3, Muriel Houang5, Monique Jesuran Perelroizen6, Gian-Paolo de Filippo7, Mariacarolina Salerno8, Gilbert Simonin9, Rachel Reynaud9, Jean-Claude Carel1,2,3, Juliane Le´ ger1,2,3 and Nicolas de Roux2,3,4 1AP-HP, Service d’Endocrinologie Diabe´ tologie Pe´ diatrique, Centre de Re´ fe´ rence des Maladies Endocriniennes Rares de la Croissance, Hoˆ pital Robert Debre´ , Paris F-75019, France, 2Universite´ Paris Diderot, Sorbonne Paris Cite´ F-75019, France, 3Institut National de la Sante´ et de la Recherche Me´ dicale (INSERM), Unite´ 1141, DHU Protect, Paris F-75019, France, 4AP-HP, INSERM U1141, Laboratoire de Biochimie, Hoˆ pital Robert Debre´ , 48 Boulevard Se´ rurier, Paris F-75019, France, 5AP-HP, Explorations Fonctionnelles Endocriniennes, Hoˆ pital Armand Trousseau, Paris F-75012, France, 6Centre d’Endocrinologie Pe´ diatrique, 14 Rue du Rempart St-Etienne, Toulouse F-31000, France, 7Pediatric Correspondence Endocrinology Unit, Gaetano Rummo Hospital, Benevento 82100, Italy, 8Pediatric Endocrinology Unit, Federico II should be addressed University, Naples 80131, Italy and 9Service de Pe´ diatrie Multidisciplinaire, Centre de Re´ fe´ rence des Maladies Rares to N de Roux d’Origine Hypophysaire, Assistance Publique-Hopitaux de Marseille (APHM), Hoˆ pital de la Timone, Aix-Marseille Email Universite´ , Marseille F-13385, France [email protected] Abstract Context and objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic– pituitary–gonadal axis in the absence of identifiable central lesions.
    [Show full text]
  • PWS Publications Apr to Jun 2020 PWS PAPERS of INTEREST
    PWS publications Apr to Jun 2020 PWS PAPERS OF INTEREST Listed below along with their abstracts are selected papers on PWS newly appearing in PubMed between 1st April and end of June 2020 in peer reviewed academic journals. All papers are initially listed without their summaries to give a quick overview, then for most of the papers the summaries are included later in the document. They are divided into specific categories: General PWS and families; Genetics, and brain imaging; Endocrine including GH; Sensory and physical; Behaviour; Cognition and mental health. Open access is indicated next to the link. This list has been compiled by Joyce Whittington and by members of the IPWSO Scientific Advisory Committee. If there are papers that you think should have been included please let Joyce Whittington know ([email protected] tel. +44 (0)1223 465266) PWS publications 1st Apr to 30th Jun 2020 Index General PWS and families Henningsen AA, Gissler M, Rasmussen S, Opdahl S, Wennerholm UB, Spangsmose AL, Tiitinen A, Bergh C, Romundstad LB, Laivuori H, Forman JL, Pinborg A, Lidegaard Ø. Imprinting disorders in children born after ART: a Nordic study from the CoNARTaS group. Hum Reprod. 2020 May 12. pii: deaa039. [Epub ahead of print] Mongkollarp N, Tim-Aroon T, Okascharoen C, Wichajarn K, Phosuwattanakul J, Chongviriyaphan N, Wattanasirichaigoon D. Growth charts for Thai children with Prader-Willi syndrome aged 0-18 years. Orphanet J Rare Dis. 2020 15:111. Srebnik N, Even Zohar NG, Salama A, Sela HY, Hirsch HJ, Gross-Tsur V, Eldar-Geva T. Recognizing the unique prenatal phenotype of Prader-Willi Syndrome (PWS) indicates the need for a diagnostic methylation test.
    [Show full text]
  • Conservation of Imprinting and Methylation of MKRN3, MAGEL2 and NDN Genes in Cattle
    animals Article Conservation of Imprinting and Methylation of MKRN3, MAGEL2 and NDN Genes in Cattle Junliang Li 1,†, Weina Chen 2,†, Dongjie Li 3, Shukai Gu 1, Xiaoqian Liu 1, Yanqiu Dong 1, Lanjie Jin 1, Cui Zhang 1,* and Shijie Li 1,* 1 College of Life Science, Agricultural University of Hebei, Baoding 071000, China; [email protected] (J.L.); [email protected] (S.G.); [email protected] (X.L.); [email protected] (Y.D.); [email protected] (L.J.) 2 Department of Traditional Chinese Medicine, Hebei University, Baoding 071000, China; [email protected] 3 College of Bioscience and Bioengineering, Hebei University of Science and Technology, Shijiazhuang 050081, China; [email protected] * Correspondence: [email protected] (C.Z.); [email protected] (S.L.) † These authors contributed equally to this work. Simple Summary: In mammals, imprinted genes play key roles in embryonic growth and postnatal behavior and their misregulation has been associated with several developmental syndrome and cancers. At present, more than 150 imprinted genes have been identified in humans and mice. Cattle is an economically important farm animal, but compared to humans and mice, few genes have been reported as imprinted in this species. MKRN3, MAGEL2 and NDN are three maternally imprinted genes in the human Prader-Willi and Angelman syndromes imprinted locus at 15q11-q13. In this study, we determined that the bovine MKRN3, MAGEL2 and NDN genes are three paternally Citation: Li, J.; Chen, W.; Li, D.; Gu, expressed gene, and their expression is regulated by the DNA methylation. This work could advance S.; Liu, X.; Dong, Y.; Jin, L.; Zhang, C.; the genomic imprinting by increasing the knowledge of imprinted genes in bovine and also facilitate Li, S.
    [Show full text]
  • The Neurobiology of Mouse Models Syntenic to Human Chromosome 15Q
    J Neurodevelop Disord (2011) 3:270–281 DOI 10.1007/s11689-011-9088-1 The neurobiology of mouse models syntenic to human chromosome 15q Toru Takumi Received: 1 December 2010 /Accepted: 12 July 2011 /Published online: 26 July 2011 # Springer Science+Business Media, LLC 2011 Abstract Autism is a neurodevelopmental disorder that Autism manifests in childhood as social behavioral abnormalities, such as abnormal social interaction, impaired communication, Autism is a developmental brain disorder whose definition has and restricted interest or behavior. Of the known causes of been extended to autism spectrum disorders (ASDs), including autism, duplication of human chromosome 15q11–q13 is the non-pervasive development disorder and Asperger syndrome most frequently associated cytogenetic abnormality. Chromo- (Levitt and Campbell 2009). The prevalence of autism is some 15q11–q13 is also known to include imprinting genes. increasing and currently stands at one in every 150 In terms of neuroscience, it contains interesting genes such as individuals. Its influence on modern society is increasing, Necdin, Ube3a, and a cluster of GABAA subunits as well as especially in developed countries, where birthrates are low huge clusters of non-coding RNAs (small nucleolar RNAs, and the management of children with these disorders is a snoRNAs). Phenotypic analyses of mice genetically or serious social issue. However, the cause of autism and its chromosomally engineered for each gene or their clusters pathophysiology remain unknown and require further on a region of mouse chromosome seven syntenic to human research from a number of different approaches. Among the 15q11–q13 indicate that this region may be involved in neuropsychiatric diseases, autism is considered as an appro- social behavior, serotonin metabolism, and weight control.
    [Show full text]
  • Genetic Dissection Identifies Necdin As a Driver Gene in a Mouse Model
    ARTICLE https://doi.org/10.1038/s41467-021-24359-3 OPEN Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications Kota Tamada 1,2,3, Keita Fukumoto 1,2, Tsuyoshi Toya1,4, Nobuhiro Nakai 1,2,3, Janak R. Awasthi1,5, Shinji Tanaka6, Shigeo Okabe 6, François Spitz 7, Fumihito Saitow 8, Hidenori Suzuki 8 & ✉ Toru Takumi 1,2,3,5 Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy 1234567890():,; number variation (CNV) associated with autism spectrum disorder (ASD). Recently, pater- nally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory- inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome. 1 RIKEN Brain Science Institute, Wako, Saitama, Japan. 2 Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan. 3 Department of Physiology and Cell Biology, Kobe University School of Medicine, Chuo, Kobe, Japan.
    [Show full text]
  • MKRN3 Interacts with Several Proteins Implicated in Puberty Timing but Does Not Influence GNRH1 Expression
    ORIGINAL RESEARCH published: 08 February 2019 doi: 10.3389/fendo.2019.00048 MKRN3 Interacts With Several Proteins Implicated in Puberty Timing but Does Not Influence GNRH1 Expression Venkatram Yellapragada 1,2, Xiaonan Liu 3,4, Carina Lund 1,2, Johanna Känsäkoski 2, Kristiina Pulli 1,2, Sanna Vuoristo 5, Karolina Lundin 5, Timo Tuuri 5, Markku Varjosalo 3,4† and Taneli Raivio 1,2,6*† 1 Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland, 2 Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland, 3 Molecular Systems Biology Research Group, Institute of Biotechnology & HiLIFE, University of Helsinki, Helsinki, Finland, 4 Proteomics Unit, Institute of Biotechnology, University of Helsinki, Helsinki, Finland, 5 Department of Obstetrics and Gynecology, Helsinki University Hospital, HUH, Helsinki, Finland, 6 New Children’s Hospital, Pediatric Research Center, Helsinki University Hospital, HUH, Helsinki, Finland Edited by: Gustavo M. Somoza, Institute of Biotechnological Research Paternally-inherited loss-of-function mutations in makorin ring finger protein 3 gene (IIB-INTECH), Argentina (MKRN3) underlie central precocious puberty. To investigate the puberty-related Reviewed by: mechanism(s) of MKRN3 in humans, we generated two distinct bi-allelic MKRN3 Stephanie Constantin, knock-out human pluripotent stem cell lines, Del 1 and Del 2, and differentiated them National Institutes of Health (NIH), United States into GNRH1-expressing neurons. Both Del 1 and Del 2 clones could be differentiated into Marina Olga Fernandez, neuronal progenitors and GNRH1-expressing neurons, however, the relative expression Instituto de Biología y Medicina Experimental (IBYME), Argentina of GNRH1 did not differ from wild type cells (P = NS).
    [Show full text]