The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene

Abstract

WAGR syndrome is characterized by Wilm’s tumor, aniridia, genitourinary abnormalities and intellectual disabilities. WAGR is caused by a chromosomal deletion that includes the PAX6, WT1 and PRRG4 genes. PRRG4 is proposed to contribute to the autistic symptoms of WAGR syndrome, but the molecular function of PRRG4 genes remains unknown. The Drosophila commissureless (comm) gene encodes a short transmembrane protein characterized by PY motifs, features that are shared by the PRRG4 protein. Comm intercepts the Robo axon guidance receptor in the ER/Golgi and targets Robo for degradation, allowing commissural axons to cross the CNS midline. Expression of human Robo1 in the fly CNS increases midline crossing and this was enhanced by co-expression of PRRG4, but not CYYR, Shisa or the yeast Rcr genes. In cell culture experiments, PRRG4 could re-localize hRobo1 from the cell surface, suggesting that PRRG4 is a functional homologue of Comm. Comm is required for axon guidance and synapse formation in the fly, so PRRG4 could contribute to the autistic symptoms of WAGR by disturbing either of these processes in the developing human brain.

Structure and Function of Roundabout Receptors

“…However, a proline rich and Gla domain protein, PRRG4, containing the L/PPxY motifs found in Comm was recently shown to affect a hRobo1 expression phenotype in flies (Justice et al 2017). In addition, PRRG4 is able to re-localise hRobo1 from cell surfaces, which taken together strongly suggest it's a functional homologue of Comm (Justice et al 2017). The role of endocytosis in Slit-Robo signalling is further supported by Drosophila genetic experiments and complementary in vitro data (Chance and Bashaw 2015).…”

“…While Slit-Robo signalling is conserved in bilateral species, and endocytosis was shown to be important for Slit2 mediated collapse of Xenopus retinal growth cones (Piper et al 2006), no Comm proteins were identified in vertebrates. However, a proline rich and Gla domain protein, PRRG4, containing the L/PPxY motifs found in Comm was recently shown to affect a hRobo1 expression phenotype in flies (Justice et al 2017). In addition, PRRG4 is able to re-localise hRobo1 from cell surfaces, which taken together strongly suggest it's a functional homologue of Comm (Justice et al 2017).…”

“…After midline crossing Comm is downregulated to ensure newly synthesized Robo receptors can reach the cell surface for interaction with Slit to mediate repulsion. However, no functional Comm homologue was ever identified in vertebrates until the recent discovery of PRRG4 (Justice et al 2017). But Robo3 was shown to be important for commissural axon midline attraction by blocking Slit mediated Robo1 repulsion (Marillat et al 2004), suggesting Robo3 might play an attractive rather than repulsive role in midline crossing (Domyan et al 2013).…”

Clinical, molecular genetics and therapeutic aspects of syndromic obesity

“…Obesity or severe hyperphagia has also been described in a subgroup of these patients, in which case the condition is often called WAGRO . Secondary features often seen in WAGR patients are renal problems, cardiopulmonary defects and behavioral difficulties like autism . Due to the specific combination of manifestations, the differential diagnosis of WAGR is very limited.…”

“…[156][157][158][159][160][161][162] Secondary features often seen in WAGR patients are renal problems, cardiopulmonary defects and behavioral difficulties like autism. 160,163 Due to the specific combination of manifestations, the differential diagnosis of WAGR is very limited.…”