Daniel L Polla1,2, Mohammad Ali Farazi Fard3, Zahra Tabatabaei3, Parham Habibzadeh3, Olga A Levchenko4, Pooneh Nikuei5, Periklis Makrythanasis6,7, Mureed Hussain1, Sandra von Hardenberg8, Sirous Zeinali9, Mohammad-Sadegh Fallah10, Janneke H M Schuurs-Hoeijmakers1, Mohsin Shahzad11,12,13, Fareeha Fatima14, Neelam Fatima14, Laura Donker Kaat15, Hennie T Bruggenwirth15, Leah R Fleming16, John Condie17, Rafal Ploski18, Agnieszka Pollak18, Jacek Pilch19, Nina A Demina4, Alena L Chukhrova4, Vasilina S Sergeeva4, Hanka Venselaar20, Amira T Masri21, Hanan Hamamy6, Federico A Santoni6,22, Katrin Linda1, Zubair M Ahmed11, Nael Nadif Kasri1, Arjan P M de Brouwer1, Anke K Bergmann8, Sven Hethey23, Majid Yavarian3, Muhammad Ansar6,24, Saima Riazuddin11, Sheikh Riazuddin12,13, Mohammad Silawi3, Gaia Ruggeri25, Filomena Pirozzi25, Ebrahim Eftekhar5, Afsaneh Taghipour Sheshdeh3, Shima Bahramjahan3, Ghayda M Mirzaa25,26,27, Alexander V Lavrov4, Stylianos E Antonarakis6,28, Mohammad Ali Faghihi3,29, Hans van Bokhoven30. 1. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. 2. CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil. 3. Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Fars, Iran. 4. Research Centre for Medical Genetics, Moscow, Russia. 5. Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. 6. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. 7. Biomedical Research Foundation Academy of Athens, Athens, Greece. 8. Department of Human Genetics, Hannover Medical School, Hanover, Germany. 9. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. 10. Department of Medical Genetics, Kawsar Human Genetics Research Center, Tehran, Iran. 11. Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA. 12. Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan. 13. Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical Research Center, University of Health Sciences, Lahore, Pakistan. 14. Center for Excellence in Molecular Biology, University of Punjab, Lahore, Pakistan. 15. Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. 16. St. Luke's Children's Genetics and Metabolic Clinic, Boise, ID, USA. 17. St Luke's Pediatric Neurology Clinic, Boise, ID, USA. 18. Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland. 19. Department of Pediatric Neurology, Medical University of Silesia, Katowice, Poland. 20. Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 21. Faculty of Medicine, Pediatric Department Division of Child Neurology, The University of Jordan, Amman, Jordan. 22. Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne, Switzerland. 23. Department of Neuropediatrics, Children's and Youth Hospital Auf der Bult, Hanover, Germany. 24. Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland. 25. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. 26. Department of Pediatrics, University of Washington, Seattle, WA, USA. 27. Brotman Baty Institute for Precision Medicine, Seattle, WA, USA. 28. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland. 29. Department of Psychiatry & Behavioral Sciences, Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA. 30. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. Hans.vanbokhoven@radboudumc.nl.
Abstract
PURPOSE: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. METHODS: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. RESULTS: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. CONCLUSION: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.
PURPOSE: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. METHODS: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. RESULTS: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. CONCLUSION: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.
Authors: Hanan Hamamy; Stylianos E Antonarakis; Luigi Luca Cavalli-Sforza; Samia Temtamy; Giovanni Romeo; Leo P Ten Kate; Robin L Bennett; Alison Shaw; Andre Megarbane; Cornelia van Duijn; Heli Bathija; Siv Fokstuen; Eric Engel; Joel Zlotogora; Emmanouil Dermitzakis; Armand Bottani; Sophie Dahoun; Michael A Morris; Steve Arsenault; Mona S Aglan; Mubasshir Ajaz; Ayad Alkalamchi; Dhekra Alnaqeb; Mohamed K Alwasiyah; Nawfal Anwer; Rawan Awwad; Melissa Bonnefin; Peter Corry; Lorraine Gwanmesia; Gulshan A Karbani; Maryam Mostafavi; Tommaso Pippucci; Emmanuelle Ranza-Boscardin; Bruno Reversade; Saghira M Sharif; Marieke E Teeuw; Alan H Bittles Journal: Genet Med Date: 2011-09 Impact factor: 8.822
Authors: Tomasz Wrzesiński; Malgorzata Szelag; Wojciech A Cieślikowski; Agnieszka Ida; Rachel Giles; Elżbieta Zodro; Joanna Szumska; Joanna Poźniak; Zbigniew Kwias; Hans A R Bluyssen; Joanna Wesoly Journal: BMC Cancer Date: 2015-07-14 Impact factor: 4.430
Authors: Joseph P Yuan; Weizhong Zeng; Michael R Dorwart; Young-Jin Choi; Paul F Worley; Shmuel Muallem Journal: Nat Cell Biol Date: 2009-02-01 Impact factor: 28.824
Authors: Sara El-Gebali; Jaina Mistry; Alex Bateman; Sean R Eddy; Aurélien Luciani; Simon C Potter; Matloob Qureshi; Lorna J Richardson; Gustavo A Salazar; Alfredo Smart; Erik L L Sonnhammer; Layla Hirsh; Lisanna Paladin; Damiano Piovesan; Silvio C E Tosatto; Robert D Finn Journal: Nucleic Acids Res Date: 2019-01-08 Impact factor: 16.971