Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder

Reham Khalaf-Nazzal, James Fasham, Katherine A. Inskeep, Lauren E. Blizzard, Joseph S. Leslie, Matthew N. Wakeling, Nishanka Ubeyratna, Tadahiro Mitani, Jennifer L. Griffith, Wisam Baker, Fida’ Al-Hijawi, Karen C. Keough, Alper Gezdirici, Loren Pena, Christine G. Spaeth, Peter D. Turnpenny, Joseph R. Walsh, Randall Ray, Amber Neilson, Evguenia KouranovaXiaoxia Cui, David T. Curiel, Davut Pehlivan, Zeynep Coban Akdemir, Jennifer E. Posey, James R. Lupski, William B. Dobyns, Rolf W. Stottmann, Andrew H. Crosby, Emma L. Baple

Research output: Contribution to journalArticlepeer-review

Abstract

Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.

Original languageEnglish (US)
Pages (from-to)2068-2079
Number of pages12
JournalAmerican Journal of Human Genetics
Volume109
Issue number11
DOIs
StatePublished - Nov 3 2022

Bibliographical note

Funding Information:
First and foremost, we are grateful to the families for taking part in this study and Landon’s League Foundation ( https://landonsleague.com/ ) for their ongoing support of our work. The study was supported by the following grants: NIDCR R01 DE027091 (R.W.S.); MRC G1002279 (A.H.C.), G1001931 (E.L.B.), Proximity to Discover and Confidence in Concept grants MC-PC-18047 , MC_PC_15054 , MC_PC_15047 (University of Exeter, E.L.B. and A.H.C.); Medical Research Foundation MRF-145-0006-DG-BAPL-C0788 (E.L.B. and A.H.C.). The iPSC72.3, CCHMC PSCF iPSC line used as a control in this study was generated by the Cincinnati Children’s Pluripotent Stem Cell Facility. This work was supported, in part, by US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) UM1 HG006542 to the Baylor Hopkins Center for Mendelian Genomics (BHCMG, J.R.L.). This research was funded in whole, or in part, by the Wellcome Trust ( GW4-CAT Fellowship 216279/Z/19/Z [J.F.]). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

Funding Information:
First and foremost, we are grateful to the families for taking part in this study and Landon's League Foundation (https://landonsleague.com/) for their ongoing support of our work. The study was supported by the following grants: NIDCR R01 DE027091 (R.W.S.); MRC G1002279 (A.H.C.), G1001931 (E.L.B.), Proximity to Discover and Confidence in Concept grants MC-PC-18047, MC_PC_15054, MC_PC_15047 (University of Exeter, E.L.B. and A.H.C.); Medical Research Foundation MRF-145-0006-DG-BAPL-C0788 (E.L.B. and A.H.C.). The iPSC72.3, CCHMC PSCF iPSC line used as a control in this study was generated by the Cincinnati Children's Pluripotent Stem Cell Facility. This work was supported, in part, by US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) UM1 HG006542 to the Baylor Hopkins Center for Mendelian Genomics (BHCMG, J.R.L.). This research was funded in whole, or in part, by the Wellcome Trust (GW4-CAT Fellowship 216279/Z/19/Z [J.F.]). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. E.L.B. A.H.C. R.W.S. and R.K.N. conceived and supervised the study. R.W.S. D.T.C. and X.C. supervised cellular work. E.L.B. J.F. W.B.D. R.K.N. J.L.G. K.C.K. A.G. L.P. C.G.S. P.D.T. R.R. T.M. D.P. Z.C.A. J.E.P. and J.R.L. collated and analyzed clinical and genomic data. R.N. J.F. J.S.L. N.U. T.M. J.E.P. and Z.C.A. performed genetic studies/analysis. K.I. L.B. and E.K. performed cell and mouse studies. E.L.B. A.H.C. and J.R.W. coordinated/managed collaborations. J.F. K.I. W.B.D. A.H.C. R.W.S. and E.L.B. wrote the initial draft of the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2022 The Authors

Keywords

  • agyria
  • autosomal recessive
  • lissencephaly
  • MARK2
  • neurodevelopmental disorder
  • pachygyria
  • patronin
  • tubulinopathy

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder'. Together they form a unique fingerprint.

Cite this