title: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5.
abstract: Lissencephaly comprises a heterogeneous group of developmental brain disorders of varying severity, involving abnormal cortical gyration. We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Using microarray-based homozygosity mapping in the reported family, combined with whole exome sequencing in one affected infant, we identified a homozygous splice site mutation g.IVS8+1G>A in cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162SfsX19). The mutation co-segregated with the disease phenotype in all 29 study participants (4 patients and 25 healthy relatives), and was not identified in 200 ethnically matched control chromosomes. The p.V162SfsX19 mutation causes lack of endogenous CDK5 expression in affected dermal fibroblasts and brain tissue at the mRNA and protein levels, consistent with nonsense-mediated mRNA decay. Functional analysis of the p.V162SfsX19 mutation, using a yeast complementation assay, showed loss-of-function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family.
authors.affiliation: Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel, danmag@tx.technion.ac.il.
authors.forename: Daniella
authors.initials: D
authors.lastname: Magen
authors.forename: Ayala
authors.initials: A
authors.lastname: Ofir
authors.forename: Liron
authors.initials: L
authors.lastname: Berger
authors.forename: Dorit
authors.initials: D
authors.lastname: Goldsher
authors.forename: Ayelet
authors.initials: A
authors.lastname: Eran
authors.forename: Nasser
authors.initials: N
authors.lastname: Katib
authors.forename: Nassser
authors.initials: N
authors.lastname: Katib
authors.forename: Yousif
authors.initials: Y
authors.lastname: Nijem
authors.forename: Euvgeni
authors.initials: E
authors.lastname: Vlodavsky
authors.forename: Shay
authors.initials: S
authors.lastname: Tzur
authors.forename: Shay
authors.initials: S
authors.lastname: Zur
authors.forename: Doron M
authors.initials: DM
authors.lastname: Behar
authors.forename: Yakov
authors.initials: Y
authors.lastname: Fellig
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D002531:Cerebellum / Q000002:abnormalities* / Q000201:enzymology; D003241:Consanguinity; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000201:enzymology / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D054082:Lissencephaly / Q000201:enzymology / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009421:Nervous System Malformations / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree
chemical_list: D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human