Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay

Sangmoon Lee, Dillon Y. Chen, Maha S. Zaki, Reza Maroofian, Henry Houlden, Nataliya Di Donato, Dalia Abdin, Heba Morsy, Ghayda M. Mirzaa, William B. Dobyns, Jennifer McEvoy-Venneri, Valentina Stanley, Kiely N. James, Grazia M.S. Mancini, Rachel Schot, Tugba Kalayci, Umut Altunoglu, Ehsan Ghayoor Karimiani, Lauren Brick, Mariya KozenkoYalda Jamshidi, M. Chiara Manzini, Mehran Beiraghi Toosi, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, “ribbon-like” heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

Original languageEnglish (US)
Pages (from-to)844-853
Number of pages10
JournalAmerican Journal of Human Genetics
Volume105
Issue number4
DOIs
StatePublished - Oct 3 2019
Externally publishedYes

Bibliographical note

Funding Information:
We thank the children and their families for their contributions to this study. This work was supported by National Institutes of Health grants U01 MH108898, R01 NS048453, R01 NS098004, the Simons Foundation Autism Research Initiative (SFARI), the Howard Hughes Medical Institute (J.G.G.), Qatar National Research Foundation 6-1463 (J.G.G.), and the March of Dimes 6-FY14-422 (M.C.M.). G.M.S.M. is supported by the ZonMW TOP grant 91217045. N.D.D. U.A. W.B.D. G.M.M. G.M.S.M. and M.S.Z. are members of the European Network on Brain Malformations (Neuro-MIG, European Cooperation in Science and Technology [COST] Action CA16118). T.K. was supported by COST Action CA16118 (STSM grant #41344). G.M.M. is supported by National Institutes of Health grant K08NS092898 and Jordan's Guardian Angels. Data on one family was collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). This research was conducted as part of the University College London Queen Square Genomics group, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. We thank the Rady Children's Institute for Genomic Medicine, the Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur), the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and Murat Gunel) for sequencing support, and the Matchmaker Exchange. We acknowledge M. Gerstein, S. Mane, A.B. Ekici, S. Uebe, E.S. Cauley, and the University of California, San Diego Institute for Genomic Medicine Genetics Center for sequencing support and analysis, the Yale Biomedical High-Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics, and the Yale Center for Human Genetics.

Funding Information:
We thank the children and their families for their contributions to this study. This work was supported by National Institutes of Health grants U01 MH108898 , R01 NS048453 , R01 NS098004 , the Simons Foundation Autism Research Initiative (SFARI), the Howard Hughes Medical Institute (J.G.G.), Qatar National Research Foundation 6-1463 (J.G.G.), and the March of Dimes 6-FY14-422 (M.C.M.). G.M.S.M. is supported by the ZonMW TOP grant 91217045 . N.D.D., U.A., W.B.D., G.M.M., G.M.S.M., and M.S.Z. are members of the European Network on Brain Malformations (Neuro-MIG, European Cooperation in Science and Technology [COST] Action CA16118). T.K. was supported by COST Action CA16118 (STSM grant # 41344 ). G.M.M. is supported by National Institutes of Health grant K08NS092898 and Jordan’s Guardian Angels . Data on one family was collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding ( WT093205 MA and WT104033AIA ). This research was conducted as part of the University College London Queen Square Genomics group, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre . We thank the Rady Children’s Institute for Genomic Medicine , the Broad Institute ( U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur), the Yale Center for Mendelian Disorders ( U54HG006504 to R. Lifton and Murat Gunel) for sequencing support, and the Matchmaker Exchange. We acknowledge M. Gerstein, S. Mane, A.B. Ekici, S. Uebe, E.S. Cauley, and the University of California, San Diego Institute for Genomic Medicine Genetics Center for sequencing support and analysis, the Yale Biomedical High-Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics, and the Yale Center for Human Genetics.

Publisher Copyright:
© 2019 American Society of Human Genetics

Keywords

  • APC2
  • agyria
  • band heterotopia
  • epilepsy
  • intellectual disability
  • lissencephaly
  • neuronal migration
  • pachygyria

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