Polymicrogyria is a heterogeneous term used to describe a type of cortical malformation that is characterized by numerous (poly) small (micro) gyri overfolded upon one another [1
]. Bilateral frontoparietal polymicrogyria is a recently defined autosomal recessive brain malformation [2
]. The affected individuals present with severe neurological impairment. The affected cortex has an irregular surface and appears to comprise of an excessive number of small gyri, resulting in a scalloped appearance of the cortical-white matter junction, a shared feature with polymicrogyria. The observed cortical abnormality extends diffusely across the frontal and parietal lobes with a decreasing anterior-to-posterior gradient of severity. There are associated myelination defects, with areas of abnormal signal in the cerebral white matter, and cerebellar cortical dysplasia, as well as mild hypoplasia of the pons and cerebellar vermis. The radiological features seen in bilateral frontoparietal polymicrogyria show many similarities to those seen in conditions with cobblestone complex, such as muscle-eye-brain disease, Fukuyama’s congenital muscular dystrophy, and Walker-Warburg syndrome [4
]. The causative gene of bilateral frontoparietal polymicrogyria is GPR56 [5
]. Further histological study in mice with deletion of the Gpr56
gene as well as post-mortem human brain specimen harboring GPR56 mutation confirmed that the histopathology of bilateral frontoparietal polymicrogyria is indeed a cobblestone-like cortical malformation [7
GPR56 is an orphan G protein-coupled receptor that belongs to the family of adhesion G protein-coupled receptors [9
]. GPR56 mRNA is selectively expressed in hematopoietic stem cells and neural progenitors, suggesting a role in multipotent cell identity and tissue development [10
]. In the developing mouse brain, GPR56 mRNA is detected in the embryonic ventricular zone, the site for neural progenitor cells [5
]. Like other adhesion G protein-coupled receptors family members, GPR56 has a very long N-terminal stalk and seven transmembrane domains. The GPR56 protein undergoes G protein-coupled receptor proteolytic site mediated autoproteolytic process, resulting in an N- and a C-terminal fragment, named GPR56N
has been found to be associated with GPR56C
as well as secreted into the cultured media of GPR56-expressing cells [12
is a plasma membrane-bound fragment [12
]. The biological consequence of GPR56 protein cleavage and the functional interaction of GPR56N
remain largely unknown.
Here we report a novel GPR56 mutation E496K found in a bilateral frontoparietal polymicrogyria patient. Further biochemical analysis indicates this mutation affects the cell surface expression of GPR56C.