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.

Role of an adaptor protein Lin‐7B in brain development: possible involvement in autism spectrum disorders

“…This result was similar to that of Lin‐7A silencing experiments (Matsumoto et al . ). Although the molecular mechanism(s) of Lin‐7 proteins in cell migration has not so far been analyzed, their regulatory roles in filopodia formation (Crespi et al .…”

“…Such recovery was also observed in the case of silencing of Lin‐7A, a possible causative gene for 12q21‐deletion syndrome which has ID as a major symptom (Matsumoto et al . ). Although it remains to be clarified whether and how neuronal migration delay is crucial for neurodevelopmental disorders including ASD, it is likely that the abnormal migration process per se causes impairment in neuronal network formation and functions.…”

“…Based on the results obtained in this study and those described recently (Matsumoto et al . ), neuronal migration defects might take place in a transient manner in Lin‐7A/B‐double knockout mice; these neurons may finally make it to their correct destination. In addition, axonal growth may also be delayed during brain development in Lin‐7A/B‐double knockout mice, as in the case of in utero electroporation‐based acute silencing experiments carried out in this study.…”

“…; Matsumoto et al . ). c.602+1G>C mutant cDNA, encoding hLin‐7B (p.S147VfsX30), was produced by PCR.…”

“…In addition, we recently proposed a pathophysiological role for Lin‐7A in a 12q21‐deletion syndrome with intellectual disability (ID) (Matsumoto et al . ).…”