GPR56 spans 45 kb and consists of 14 exons, encoding an orphan G protein-coupled receptor(GPCR) which was constituted by 693 amino acids[7, 11]. The G protein-coupled receptor belongs to the adhesion G protein-coupled receptor family, which has an N- and a C-terminal fragmental and a G Protein-Coupled Receptor proteolytic site. In central nervous system, GPR56 plays an important role in the normal development of the cerebral cortex and cerebellar morphogenesis. In the peripheral nervous system, CPR56 can regulate the formation and maintenance of myelin sheath. Therefore, the normal expression of the GPR56 is essential for the function of nervous system. We have already known that the mutations of GPR56 were related to BFPP. The patient’s clinical manifestations were overall developmental delay, seizures, and MRI shows symmetrical polygyria (the frontal parietal area is the most serious part), ventricular enlargement, bilateral white matter changes, and 28 pathogenic GPR56 mutations related to the BFPP phenotype have been reported[11, 14]. All the individuals inherited in an autosomal recessive mode and almost all missense mutations showed similar clinical symptoms, indicating that the similar phenotype might be caused by the same mechanism, but the mechanism was not clear, which might involve GPR56 trafficking and surface reduction of receptor expression[15, 16, 17]. Knocking out the GPR56 did not affect the migration of neural progenitor cells, while overexpressing GPR56 could inhibit the migration of neural progenitor cells. This mechanism might be through the reorganization of cerebral cortex actin to change cell morphology to regulate neural progenitor cell behavior. We know that premature stop of neuronal migration could cause LIS, which might explain the mechanism of GPR56 mutations causing the LIS to some extent.
The development of brain is a delicate and complex physiological process, and the proper migration of neurons is one of the most critical steps. LIS is the brain dysplasia caused by the premature stop of neuron migration. The typical lissencephaly (type I LIS) is characterized by the thickened cerebral cortex (10–20 mm, normal 4 mm), and there are no other forms of brain developmental malformations, such as severe congenital microcephaly, corpus callosum hypoplasia, or cerebellar hypoplasia. And it can be observed under the microscope that the cerebral cortex is divided into 4 thick and dysplastic layers: molecular layer, superficial cellular layer, cell spare layer, and deeper cellular layer, while the normal cerebral cortex has 6 layers. Up to now, 20 genes have been considered to be related to LIS, many of which are microtubule genes. In a cohort study of 811 patients with LIS, the overall mutation frequency of the entire cohort was 81%, of which LIS1 accounted for 40%, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes account for 1% or less, and 19% of patients still have not found the cause, which indicates that other additional genes need to be discovered. In the past, there have been no reports about the GPR56-related LIS. Therefore, the relationship between LIS and GPR56 still needs further research.
There is no specific treatment method for LIS, mainly symptomatic treatment such as anti-epileptic treatment and rehabilitation training. Studies in animal models have shown that it might be possible to restart neuronal migration by re-expressing the missing genes after birth. Even if the degree of cortical deformity was partially improved, it could also be significantly beneficial by controlling seizures and reducing the clinical severity. Therefore, with all the advances in genetic testing and medical technology, the diagnosis and treatment of LIS will continue to improve and progress.