MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.,Brain

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MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.
Brain ( IF 10.6 ) Pub Date : 2019-01-01 , DOI: 10.1093/brain/awz379
Christopher C Y Mak ₁ , Dan Doherty _{2,

3} , Angela E Lin ₄ , Nancy Vegas _{5,

6} , Megan T Cho ₇ , Géraldine Viot ₈ , Clémantine Dimartino _{5,

6} , James D Weisfeld-Adams ₉ , Davor Lessel ₁₀ , Shelagh Joss ₁₁ , Chumei Li ₁₂ , Claudia Gonzaga-Jauregui ₁₃ , Yuri A Zarate ₁₄ , Nadja Ehmke ₁₅ , Denise Horn ₁₅ , Caitlin Troyer ₁₆ , Sarina G Kant ₁₇ , Youngha Lee ₁₈ , Gisele E Ishak _{3,

19} , Gordon Leung ₁ , Amanda Barone Pritchard ₂₀ , Sandra Yang ₇ , Eric G Bend _{21,

22} , Francesca Filippini _{5,

6} , Chelsea Roadhouse ₁₂ , Nicolas Lebrun ₂₃ , Michele G Mehaffey ₂ , Pierre-Marie Martin _{24,

25} , Benjamin Apple ₉ , Francisca Millan ₇ , Oliver Puk ₂₆ , Mariette J V Hoffer ₁₇ , Lindsay B Henderson ₇ , Ruth McGowan ₁₁ , Ingrid M Wentzensen ₇ , Steven Pei ₁ , Farah R Zahir ₂₇ , Mullin Yu ₁ , William T Gibson ₂₇ , Ann Seman ₂₈ , Marcie Steeves ₄ , Jill R Murrell ₂₉ , Sabine Luettgen ₁₀ , Elizabeth Francisco ₃₀ , Tim M Strom _{31,

32} , Louise Amlie-Wolf ₃₃ , Angela M Kaindl _{34,

35} , William G Wilson ₁₆ , Sara Halbach ₃₆ , Lina Basel-Salmon _{37,

38,

39,

40} , Noa Lev-El ₃₇ , Jonas Denecke ₄₁ , Lisenka E L M Vissers ₄₂ , Kelly Radtke ₄₃ , Jamel Chelly _{44,

45,

46} , Elaine Zackai _{20,

47} , Jan M Friedman ₂₇ , Michael J Bamshad _{2,

48,

49} , Deborah A Nickerson _{48,

49} , , Russell R Reid ₅₀ , Koenraad Devriendt ₅₁ , Jong-Hee Chae ₅₂ , Elliot Stolerman ₂₁ , Carey McDougall ₂₀ , Zöe Powis ₄₃ , Thierry Bienvenu _{23,

53} , Tiong Y Tan ₅₄ , Naama Orenstein _{38,

39} , William B Dobyns _{2,

3,

55} , Joseph T Shieh _{24,

25} , Murim Choi _{18,

52} , Darrel Waggoner ₃₆ , Karen W Gripp ₃₃ , Michael J Parker ₅₆ , Joan Stoler ₂₈ , Stanislas Lyonnet _{5,

6,

57} , Valérie Cormier-Daire _{6,

57,

58} , David Viskochil ₅₉ , Trevor L Hoffman ₆₀ , Jeanne Amiel _{5,

6,

57} , Brian H Y Chung ₁ , Christopher T Gordon _{5,

6}

Affiliation

Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
Department of Pediatrics, University of Washington, Seattle, WA, USA.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Medical Genetics, MassGeneral Hospital for Children, Boston, MA, USA.
Laboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
GeneDx, Gaithersburg, MD, USA.
Gynécologie Obstétrique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre (HUPC), Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado-Denver School of Medicine, Aurora, CO, USA.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow, UK.
McMaster University Medical Center, Hamilton, Ontario, Canada.
Regeneron Genetics Center, Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA.
Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Pediatrics and Medical Genetics, University of Virginia Health System, Charlottesville, VA, USA.
Department of Clinical Genetics, Leiden University Medical Center, RC Leiden, The Netherlands.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Radiology, University of Washington, Seattle, WA, USA.
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Greenwood Genetic Center, Greenwood, SC, USA.
PreventionGenetics, Marshfield, WI, USA.
Institut Cochin, INSERM U1016, CNRS UMR, Paris Descartes University, Paris, France.
Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Praxis für Humangenetik Tübingen, Tübingen, Germany.
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
eviCore healthcare, Bluffton, SC, USA.
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Institute of Human Genetics, Technische Universität München, Munich, Germany.
Division of Medical Genetics, A I duPont Hospital for Children/Nemours, Wilmington, DE, USA.
Charité - Universitätsmedizin Berlin, Institute of Neuroanatomy and Cell Biology, Department of Pediatric Neurology and Center for Chronically Sick Children, Berlin, Germany.
Berlin Institute of Health (BIH), Berlin, Germany.
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Felsenstein Medical Research Center, Petach Tikva, Israel.
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, HB Nijmegen, The Netherlands.
Clinical Genomics Department, Ambry Genetics, Aliso Viejo, CA, USA.
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France.
Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France.
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
University of Washington Center for Mendelian Genomics, Seattle, WA, USA.
Department of Surgery, Section of Plastic Surgery, University of Chicago, Chicago, IL, USA.
Department of Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
Laboratoire de Génétique et Biologie Moléculaires, Hôpital Cochin, HUPC, AP-HP, 75014 Paris, France.
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, 3052, Australia.
Department of Neurology, University of Washington, Seattle, WA, USA.
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield S10 2TH, UK.
Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
Division of Medical Genetics, University of Utah, Salt Lake City, UT, USA.
Southern California Kaiser Permanente Medical Group, Anaheim, CA, USA.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

中文翻译：

MN1 C端截断综合征是一种新型的神经发育和颅面部疾病，伴有部分菱形脑突触。

MN1编码与其他蛋白质没有同源性的转录共调节子，以前与急性髓细胞性白血病和上颚发展有关。在具有可变神经发育异常和非特异性面部特征的个体中，已经报道了包含MN1的大缺失。我们在23名具有惊人相似的畸形面部特征，尤其是中面发育不全和严重语言表达迟缓的智力残疾的人群中，发现了MN1中的从头截短突变簇。影像学显示非典型形式的菱形脑突触，这是一种独特的脑畸形，其特征是在8/10个个体中，小脑mis部部分或全部消失，小脑半球融合。菱形脑突触没有先前确定的遗传或环境原因。其他常见的特征包括周围神经周围的多微球菌症，异常的后斜突和持续的三叉神经动脉。MN1仅由两个外显子编码。所有突变，包括在8/21先证者中观察到的复发变异p.Arg1295 *，均落在外显子的末端外显子或3'端极端区域，因此预计会导致无义介导的mRNA衰变逃逸。在来自三个个体的成纤维细胞中证实了这一点。我们建议这里描述的条件，MN1 C端截断（MCTT）综合征，不是由于MN1单倍体功能不全，而是由于主要作用于C端截短的MN1蛋白。我们的数据表明，MN1在人类颅面和大脑发育中起着至关重要的作用，

更新日期：2019-12-31

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