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.
Highlights
Interstitial deletion of 12q21 has been reported in four cases since 1999 [1,2,3,4]
The L27 domain mediates heterodimerization with several membrane-associated guanylate kinase (MAGUK) proteins – including calcium/calmodulin-dependent serine protein kinase (CASK), protein associated with LIN-7 (Pals), synapse-associated protein 97 (SAP97), and PSD95/93 – which form the core of the protein complexes that mediate synaptic development, plasticity, and functionality [8]
Using array comparative genomic hybridization (CGH) analysis, we identified a deletion at 12q21.2–q21.33, which is the narrowest deletion found in a patient with 12q21-deletion syndrome to date
Summary
Common clinical features of this deletion include: intellectual disability (ID), low-set ears, sparse hair, prominent forehead, hyper- or hypo-telorism, minor cardiac abnormalities, and cutaneous findings, such as hyperkeratotic papular eruption and atopic dermatitis. These phenotypes resemble those in cardiofaciocutaneous (CFC) syndrome, which is characterized by a distinctive facial appearance, heart defects, and ID [5]. Outside of the RAS-MAPK pathway, many genes that are related to synaptic function and plasticity have been reported as responsible for ID [6,7]. The PDZ domain (corresponding to the first letters of PSD-95, Discs-large, and ZO-1) binds with many proteins, which are essential for neuronal cell polarity, cell adhesion, and cell signaling [9]
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