Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly

University of Washington Center for Mendelian Genomics

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)237-245.e8
JournalNeuron
Volume106
Issue number2
DOIs
StatePublished - Apr 22 2020

Bibliographical note

Funding Information:
N.D. has served on scientific advisory boards for Sarepta, Biomarin, and Avexis. I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, and Xenon Pharmaceuticals; editorial boards of the Annals of Neurology, Neurology, and Epileptic Disorders; may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has received speaker honoraria from GlaxoSmithKline, Athena Diagnostics, UCB, BioMarin, and Eisai; and has received funding for travel from Athena Diagnostics, UCB, Biocodex, GlaxoSmithKline, Biomarin, and Eisai. H.C.M. is a member of scientific advisory boards for Lennox Gastaut Syndrome Foundation, Dravet Syndrome Foundation, and SPARK. K.R. has served on advisory boards for UCB, Eisai, Liva Nova, and Novartis; has received research funding from UCB, Jansen-Cilag, Novartis, Zogenix, Liva Nova, Eisai, and AFT Pharmaceuticals; and received speaker honoraria from UCB and Biomarin. All other authors declare no competing interests.

Funding Information:
We thank the patients and their families for participating in this study. We thank Dr. Sarah Barton for assistance with MRI image processing. This work was supported by the University of Washington Birth Defects Research Laboratory ( NIH 5R24HD000836 ) and the University of Washington Intellectual and Developmental Disabilities Research Center (IDDRC; NIH U54HD083091 ) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Sequencing was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.M.M. received support from the American Epilepsy Society . H.C.M. received support from the National Institutes of Health (NIH R01 NS069605 ). M.-H.T. received support from Chang Gung Medical Foundation (CGMF grant CMRPG8G0252 ), Whole-Genome Research Core Laboratory of Human Diseases at CGMF , and Ministry of Science and Technology (MOST grants 106-2314-B-182A-077 and 107-2314-B-182A-057-MY3 ), Taiwan. J.-W.T. received support from MOST ( 103-2628-B-010-002-MY3 , 106-2628-B-010-002-MY3 , 107-2633-B-009-003 , 107-2221-E-010-014 , 108-2638-B-010-001-MY2 , and 108-2321-B-010-011-MY2 ), the National Health Research Institute (NHRI), the Brain Research Center , NYMU through the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education, and NYMU School of Medicine ( 107F-M01-0502 ), Taiwan. W.-J.W. received support from MOST ( 108-2628-B-010-007 and 107-2313-B-010-001 ). G.M.M. received support from the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898 , Jordan’s Guardian Angels , and the Brotman Baty Institute . I.E.S. and S.F.B. were supported by National Health and Medical Research Council (NHMRC) of Australia (program grant 628952 , 2011–2015; 1091593 , 2016–2020); I.E.S. has a NHMRC Senior Practitioner Fellowship ( 1006110 , 2011–2015; 1104831 2016–2020). M.S.H. was supported by a NHMRC Career Development Fellowship ( 1063799 ) and project grant ( 1079058 ). R.J.L. is supported by a Melbourne Children’s Clinician Scientist Fellowship . Support was received from the Australian Genomics Health Alliance , funded by NHMRC grant 1113531 and the Australian Government’s Medical Research Future Fund .

Funding Information:
We thank the patients and their families for participating in this study. We thank Dr. Sarah Barton for assistance with MRI image processing. This work was supported by the University of Washington Birth Defects Research Laboratory (NIH 5R24HD000836) and the University of Washington Intellectual and Developmental Disabilities Research Center (IDDRC; NIH U54HD083091) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Sequencing was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.M.M. received support from the American Epilepsy Society. H.C.M. received support from the National Institutes of Health (NIH R01 NS069605). M.-H.T. received support from Chang Gung Medical Foundation (CGMF grant CMRPG8G0252), Whole-Genome Research Core Laboratory of Human Diseases at CGMF, and Ministry of Science and Technology (MOST grants 106-2314-B-182A-077 and 107-2314-B-182A-057-MY3), Taiwan. J.-W.T. received support from MOST (103-2628-B-010-002-MY3, 106-2628-B-010-002-MY3, 107-2633-B-009-003, 107-2221-E-010-014, 108-2638-B-010-001-MY2, and 108-2321-B-010-011-MY2), the National Health Research Institute (NHRI), the Brain Research Center, NYMU through the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education, and NYMU School of Medicine (107F-M01-0502), Taiwan. W.-J.W. received support from MOST (108-2628-B-010-007 and 107-2313-B-010-001). G.M.M. received support from the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898, Jordan's Guardian Angels, and the Brotman Baty Institute. I.E.S. and S.F.B. were supported by National Health and Medical Research Council (NHMRC) of Australia (program grant 628952, 2011?2015; 1091593, 2016?2020); I.E.S. has a NHMRC Senior Practitioner Fellowship (1006110, 2011?2015; 1104831 2016?2020). M.S.H. was supported by a NHMRC Career Development Fellowship (1063799) and project grant (1079058). R.J.L. is supported by a Melbourne Children's Clinician Scientist Fellowship. Support was received from the Australian Genomics Health Alliance, funded by NHMRC grant 1113531 and the Australian Government's Medical Research Future Fund. M.-H.T. A.M.M. J.-W.T. and H.C.M. designed the study. M.-H.T. A.M.M. E.P.A.F. M.G.M. W.-L.F. S.-C.S. W.-H.C. P.J.L. UWCMG, J.A.D. and M.S.H. supported the sequencing and variant interpretation. M.-H.T. B.E.P. L.A.J. G.S. N.D. G.M.M. R.J.L. K.R. S.F.B. I.E.S. W.B.D. Y.-C.C. and H.C.M. collected and analyzed the clinical data and/or provided patients? samples. J.-W.T, W.-J.W. Y.-N.K. K.-C.Y. N.H.C. and M.-F.W. performed the CEP85L functional analysis. M.-H.T. A.M.M. J.-W.T. and H.C.M. wrote the manuscript, with contributions from W.-J.W. S.F.B. and I.E.S. All authors contributed to and critically reviewed the manuscript. N.D. has served on scientific advisory boards for Sarepta, Biomarin, and Avexis. I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, and Xenon Pharmaceuticals; editorial boards of the Annals of Neurology, Neurology, and Epileptic Disorders; may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has received speaker honoraria from GlaxoSmithKline, Athena Diagnostics, UCB, BioMarin, and Eisai; and has received funding for travel from Athena Diagnostics, UCB, Biocodex, GlaxoSmithKline, Biomarin, and Eisai. H.C.M. is a member of scientific advisory boards for Lennox Gastaut Syndrome Foundation, Dravet Syndrome Foundation, and SPARK. K.R. has served on advisory boards for UCB, Eisai, Liva Nova, and Novartis; has received research funding from UCB, Jansen-Cilag, Novartis, Zogenix, Liva Nova, Eisai, and AFT Pharmaceuticals; and received speaker honoraria from UCB and Biomarin. All other authors declare no competing interests.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • CEP85L
  • centrosome
  • lissencephaly
  • pachygyria
  • posterior predominant
  • subcortical band heterotopia

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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