Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly

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. (Copyright © 2020 Elsevier Inc. All rights reserved.)Genet Med. 2018 Nov;20(11):1354-1364. (PMID: 29671837); Nature. 2009 Sep 10;461(7261):272-6. (PMID: 19684571); EMBO J. 2011 Apr 20;30(8):1520-35. (PMID: 21399614); J Cell Sci. 2015 Oct 15;128(20):3837. (PMID: 26471995); Nat Commun. 2018 Jun 27;9(1):2498. (PMID: 29950674); Nature. 2016 Aug 17;536(7616):285-91. (PMID: 27535533); N Engl J Med. 2018 Apr 26;378(17):1646-1648. (PMID: 29694806); J Cell Biol. 2004 Jun 7;165(5):709-21. (PMID: 15173193); Am J Med Genet A. 2017 Jun;173(6):1473-1488. (PMID: 28440899); Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886); Nucleic Acids Res. 2009 May;37(9):e67. (PMID: 19339519); Nat Genet. 2019 Jan;51(1):88-95. (PMID: 30531870); Genome Res. 2013 May;23(5):843-54. (PMID: 23382536); Nat Genet. 2011 May;43(5):491-8. (PMID: 21478889); Nature. 2017 Feb 23;542(7642):433-438. (PMID: 28135719); Neuropediatrics. 2003 Jun;34(3):146-8. (PMID: 12910438); Wiley Interdiscip Rev Dev Biol. 2013 Mar-Apr;2(2):229-45. (PMID: 23495356). Linking ISSN: 08966273. Subset: MEDLINE; Grant Information: P50 HD103524 United States HD NICHD NIH HHS; R01 NS069605 United States NS NINDS NIH HHS; UM1 HG006493 United States HG NHGRI NIH HHS Date of Electronic Publication: 2020 Feb 24. ; Original Imprints: Publication: [Cambridge, Mass. : Cell Press, c1988- <br />