2. Academic Validation
  3. Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly

Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly

  • Neuron. 2020 Apr 22;106(2):237-245.e8. doi: 10.1016/j.neuron.2020.01.027.
Meng-Han Tsai 1,  Alison M Muir 2,  Won-Jing Wang 3,  Yi-Ning Kang 4,  Kun-Chuan Yang 4,  Nian-Hsin Chao 4,  Mei-Feng Wu 3,  Ying-Chao Chang 5,  Brenda E Porter 6,  Laura A Jansen 7,  Guillaume Sebire 8,  Nicolas Deconinck 9,  Wen-Lang Fan 10,  Shih-Chi Su 11,  Wen-Hung Chung 12,  Edith P Almanza Fuerte 2,  Michele G Mehaffey 2,  University of Washington Center for Mendelian Genomics,  Ching-Ching Ng 13,  Chung-Kin Chan 13,  Kheng-Seang Lim 14,  Richard J Leventer 15,  Paul J Lockhart 15,  Kate Riney 16,  John A Damiano 17,  Michael S Hildebrand 17,  Ghayda M Mirzaa 18,  William B Dobyns 18,  Samuel F Berkovic 19,  Ingrid E Scheffer 20,  Jin-Wu Tsai 21,  Heather C Mefford 22
Affiliations

Affiliations

  • 1 Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 833, ROC; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan 33302, ROC.
  • 2 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • 3 Institute of Biochemistry and Molecular Biology, College of Life Science, National Yang-Ming University, Taipei, Taiwan, ROC.
  • 4 Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
  • 5 Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
  • 6 Department of Neurology, Stanford University School of Medicine, Palo Alto, CA, USA.
  • 7 Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
  • 8 Department of Pediatrics, McGill University, Montreal, QC, Canada.
  • 9 Department of Paediatric Neurology, Hôpital Universitaire des Enfants Reine Fabiola, HUDERF, Université Libre de Bruxelles (ULB), Brussels, Belgium.
  • 10 Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan, ROC.
  • 11 Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC.
  • 12 School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan 33302, ROC; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC; Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan, ROC.
  • 13 Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
  • 14 Division of Neurology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
  • 15 Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, VIC, Australia; Departments of Paediatrics and Neurology, The Royal Children's Hospital, The University of Melbourne, Melbourne 3052, VIC, Australia.
  • 16 Neurosciences Unit, Queensland Children's Hospital and School of Medicine, University of Queensland, Brisbane 4101, QLD, Australia.
  • 17 Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, VIC, Australia; Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne 3084, VIC, Australia.
  • 18 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
  • 19 Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne 3084, VIC, Australia.
  • 20 Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, VIC, Australia; Departments of Paediatrics and Neurology, The Royal Children's Hospital, The University of Melbourne, Melbourne 3052, VIC, Australia; Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne 3084, VIC, Australia; The Florey Institute of Neuroscience and Mental Health, Melbourne 3052, VIC, Australia.
  • 21 Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan, ROC; Department of Biological Science & Technology, National Chiao Tung University, Hsin-Chu 30010, Taiwan, ROC. Electronic address: tsaijw@ym.edu.tw.
  • 22 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA. Electronic address: hmefford@uw.edu.
PMID: 32097630 DOI: 10.1016/j.neuron.2020.01.027
Abstract

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

Keywords

CEP85L; centrosome; lissencephaly; pachygyria; posterior predominant; subcortical band heterotopia.

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