Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2.,Nature Communications

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Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2.
Nature Communications ( IF 14.7 ) Pub Date : 2019-10-29 , DOI: 10.1038/s41467-019-12671-y
Mark A Corbett ₁ , Thessa Kroes ₁ , Liana Veneziano ₂ , Mark F Bennett _{3,

4,

5} , Rahel Florian ₆ , Amy L Schneider ₅ , Antonietta Coppola ₇ , Laura Licchetta _{8,

9} , Silvana Franceschetti _{10,

11} , Antonio Suppa _{12,

13} , Aaron Wenger ₁₄ , Davide Mei ₁₅ , Manuela Pendziwiat ₁₆ , Sabine Kaya ₆ , Massimo Delledonne ₁₇ , Rachel Straussberg _{18,

19} , Luciano Xumerle ₂₀ , Brigid Regan ₅ , Douglas Crompton _{5,

21} , Anne-Fleur van Rootselaar ₂₂ , Anthony Correll ₂₃ , Rachael Catford ₂₃ , Francesca Bisulli _{8,

9} , Shreyasee Chakraborty ₁₄ , Sara Baldassari ₈ , Paolo Tinuper _{8,

9} , Kirston Barton ₂₄ , Shaun Carswell ₂₄ , Martin Smith _{24,

25} , Alfredo Berardelli _{12,

13} , Renee Carroll ₁ , Alison Gardner ₁ , Kathryn L Friend ₂₃ , Ilan Blatt ₂₆ , Michele Iacomino ₂₇ , Carlo Di Bonaventura ₁₂ , Salvatore Striano ₂₈ , Julien Buratti ₂₉ , Boris Keren ₂₉ , Caroline Nava ₃₀ , Sylvie Forlani ₃₀ , Gabrielle Rudolf _{31,

32,

33,

34,

35} , Edouard Hirsch ₃₄ , Eric Leguern _{29,

30} , Pierre Labauge ₃₆ , Simona Balestrini _{37,

38} , Josemir W Sander _{37,

38} , Zaid Afawi ₁₉ , Ingo Helbig _{16,

39} , Hiroyuki Ishiura ₄₀ , Shoji Tsuji _{40,

41,

42} , Sanjay M Sisodiya _{37,

38} , Giorgio Casari ₄₃ , Lynette G Sadleir ₄₄ , Riaan van Coller ₄₅ , Marina A J Tijssen ₄₆ , Karl Martin Klein _{47,

48,

49} , Arn M J M van den Maagdenberg ₅₀ , Federico Zara ₂₇ , Renzo Guerrini ₁₅ , Samuel F Berkovic ₅ , Tommaso Pippucci ₅₁ , Laura Canafoglia _{10,

11} , Melanie Bahlo _{3,

4} , Pasquale Striano _{52,

53} , Ingrid E Scheffer _{5,

54} , Francesco Brancati _{2,

55,

56} , Christel Depienne _{6,

31,

35} , Jozef Gecz _{1,

57}

Affiliation

Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, 5005, SA, Australia.
Institute of Translational Pharmacology, National Research Council, Rome, Italy.
Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, VIC, Australia.
Department of Medical Biology, the University of Melbourne, Melbourne, 3010, VIC, Australia.
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, 3084, VIC, Australia.
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy.
IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Neurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE, London, UK.
Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università, 30, 00185, Rome, Italy.
IRCCS Neuromed, Pozzilli, IS, Italy.
Pacific Biosciences, Menlo Park, CA, USA.
Neuroscience and Neurogenetics Department, Meyer Children's Hospital, Florence, Italy.
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.
Department of Biotechnology, University of Verona, Strada le Grazie 15, 37134, Verona, Italy.
Institute of Pediatric Neurology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
Tel Aviv University Medical School, 69978, Tel Aviv, Israel.
Personal Genomics, Strada le Grazie 15, 37134, Verona, Italy.
Department of Neurology, Northern Health, Melbourne, VIC, Australia.
Amsterdam UMC, University of Amsterdam, Department of Neurology and Clinical Neurophysiology, Amsterdam Neuroscience, Amsterdam, The Netherlands.
Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research, Darlinghurst, NSW, 2010, Australia.
St-Vincent's Clinical School, Faulty of Medicine, UNSW Sydney, Darlinghurst, NSW, 2010, Australia.
Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel.
Laboratory of Neurogenetics, IRCCS Istituto "G. Gaslini", Genova, Italy.
Department of Neurology, Federico II University, Napoli, Italy.
AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
INSERM, U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France.
Université de Strasbourg, Illkirch, France.
Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
Centre National de la Recherche Scientifique, U7104, Illkirch, France.
MS Unit, Montpellier University Hospital, Montpellier, France.
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK.
Division of Neurology Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Neurology, the University of Tokyo Hospital, Tokyo, Japan.
Medical Genome Center, the University of Tokyo Hospital, Tokyo, Japan.
International University of Health and Welfare, Chiba, Japan.
TIGEM - Telethon Institute of Genetics and Medicine, Naples, and San Raffaele University, Milan, Italy.
Department of Paediatrics and Child Health, University of Otago, Wellington, Wellington, New Zealand.
University of Pretoria, Pretoria, South Africa.
Department of Neurology, University of Groningen, Groningen, The Netherlands.
Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt am Main, Frankfurt, Germany.
Department of Neurology, Epilepsy Center Hessen, Philipps University, Marburg, Marburg, Germany.
Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Departments of Human Genetics & Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Bologna, Italy.
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "G. Gaslini", Genova, Italy.
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy.
Royal Children's Hospital, Murdoch Children's Research Institute and Florey Institute, Melbourne, VIC, Australia.
Medical Genetics, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy.
South Australian Health and Medical Research Institute, Adelaide, 5000, SA, Australia.

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.

中文翻译：

与 2 号染色体相关的家族性成人肌阵挛性癫痫 STARD7 中内含子 ATTTC 重复扩增。

家族性成人肌阵挛性癫痫 (FAME) 的特点是皮质肌阵挛性震颤，通常从二十岁开始，以及明显的肌阵挛或全身强直阵挛性癫痫发作。2、3、5 和 8 号染色体 (chr) 上的 FAME 涉及四个独立位点。通过全基因组测序和重复引物 PCR，我们提供了证据表明 chr2 连锁的 FAME (FAME2) 是由 ATTTC 五聚体的扩增引起的在 STARD7 的第一个内含子内。ATTTC 扩展分离了 158/158 个通常受 FAME 影响的个体，这些个体来自 22 个谱系，其中包括之前报告的 16 个在全球范围内招募的家族。来自患者的成纤维细胞的 RNA 测序显示，AUUUU 或 AUUUC 重复序列没有积累，并且 STARD7 基因表达不受影响。这些数据与 FAME 中涉及的具有相似突变的其他基因相结合，表明 ATTTC 扩展可能会导致这种疾病，无论所涉及的基因组位点如何。

更新日期：2019-10-29

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