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 Kozenko; Yalda Jamshidi; M Chiara Manzini; Mehran Beiraghi Toosi; Joseph G Gleeson

doi:10.1016/j.ajhg.2019.08.013

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

Am J Hum Genet. 2019 Oct 3;105(4):844-853. doi: 10.1016/j.ajhg.2019.08.013.

Authors

Sangmoon Lee¹, Dillon Y Chen¹, Maha S Zaki², Reza Maroofian³, Henry Houlden⁴, Nataliya Di Donato⁵, Dalia Abdin⁶, Heba Morsy⁷, Ghayda M Mirzaa⁸, William B Dobyns⁹, Jennifer McEvoy-Venneri¹⁰, Valentina Stanley¹⁰, Kiely N James¹⁰, Grazia M S Mancini¹¹, Rachel Schot¹¹, Tugba Kalayci¹², Umut Altunoglu¹³, Ehsan Ghayoor Karimiani¹⁴, Lauren Brick¹⁵, Mariya Kozenko¹⁵, Yalda Jamshidi¹⁴, M Chiara Manzini¹⁶, Mehran Beiraghi Toosi¹⁷, Joseph G Gleeson¹⁸

Affiliations

¹ Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
² Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
³ Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's University, London SW17 0RE, UK; Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
⁴ Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
⁵ Institute for Clinical Genetics, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
⁶ Institute for Clinical Genetics, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany; Human Cytogenetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
⁷ Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt.
⁸ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle Children's Research Institute, Seattle WA, 98101, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
⁹ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle Children's Research Institute, Seattle WA, 98101, USA; Department of Neurology, University of Washington, Seattle Children's Research Institute, Seattle WA, 98101, USA.
¹⁰ Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, CA 92093, USA.
¹¹ Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands.
¹² Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands; Department of Medical Genetics, Istanbul University, Istanbul Faculty of Medicine, Istanbul 34093, Turkey.
¹³ Department of Medical Genetics, Istanbul University, Istanbul Faculty of Medicine, Istanbul 34093, Turkey.
¹⁴ Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's University, London SW17 0RE, UK.
¹⁵ Department of Genetics, McMaster Children's Hospital, Hamilton, Ontario L8S 4L8, Canada.
¹⁶ Child Health Institute of New Jersey, Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
¹⁷ Department of Pediatric Neurology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad 7HRJ+HQ, Iran.
¹⁸ Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA. Electronic address: [email protected].

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.

Keywords: APC2; agyria; band heterotopia; epilepsy; intellectual disability; lissencephaly; neuronal migration; pachygyria.

Publication types

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

MeSH terms

Alleles*
Classical Lissencephalies and Subcortical Band Heterotopias / genetics*
Cytoskeletal Proteins / genetics*
Developmental Disabilities / genetics*
Female
Humans
Lissencephaly / genetics*
Male
Pedigree

Substances

APC2 protein, human
Cytoskeletal Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding