title: LIN7A depletion disrupts cerebral cortex development, contributing to intellectual disability in 12q21-deletion syndrome.
abstract: Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID), low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH) analysis using the Agilent Human Genome CGH 180K array was performed with the genomic DNA from a two-year-old Japanese boy with these symptoms, as well as hypoplasia of the corpus callosum. Consequently, a 14 Mb deletion at 12q21.2-q21.33 (nt. 77 203 574-91 264 613 bp), which includes 72 genes, was detected. Of these, we focused on LIN7A, which encodes a scaffold protein that is important for synaptic function, as a possible responsible gene for ID, and we analyzed its role in cerebral cortex development. Western blotting analyses revealed that Lin-7A is expressed on embryonic day (E) 13.5, and gradually increases in the mouse brain during the embryonic stage. Biochemical fractionation resulted in the enrichment of Lin-7A in the presynaptic fraction. Suppression of Lin-7A expression by RNAi, using in utero electroporation on E14.5, delayed neuronal migration on postnatal day (P) 2, and Lin-7A-deficient neurons remained in the lower zone of the cortical plate and the intermediate zone. In addition, when Lin-7A was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed; development of these neurons was disrupted such that one half did not extend into the contralateral hemisphere after leaving the corpus callosum. Taken together, LIN7A is a candidate gene responsible for 12q21-deletion syndrome, and abnormal neuronal migration and interhemispheric axon development may contribute to ID and corpus callosum hypoplasia, respectively.
authors.affiliation: Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Mizuno
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Nanako
authors.initials: N
authors.lastname: Hamada
authors.affiliation: Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
authors.forename: Eriko F
authors.initials: EF
authors.lastname: Jimbo
authors.affiliation: Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
authors.forename: Mariko Y
authors.initials: MY
authors.lastname: Momoi
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Nagata
authors.affiliation: Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yamagata
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D019556:COS Cells; D002453:Cell Cycle / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002522:Chlorocebus aethiops; D002872:Chromosome Deletion; D002881:Chromosomes, Human, Pair 12; D055028:Comparative Genomic Hybridization; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007621:Karyotyping; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D033921:Vesicular Transport Proteins
chemical_list: C486532:LIN7A protein, human; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins