The (pro)renin receptor [(P)RR] plays a pivotal role in the renin-angiotensin system. Experimental models emphasize the role of (P)RR in organ damage associated with hypertension and diabetes. However, a mutation of the (P)RR gene, resulting in frame deletion of exon 4 [⌬4-(P)RR] is associated with X-linked mental retardation (XLMR) and epilepsy pointing to a novel role of (P)RR in brain development and cognitive function. We have studied (P)RR expression in mouse brain, as well as the effect of transfection of ⌬4-(P)RR on neuronal differentiation of rat neuroendocrine PC-12 cells induced by nerve growth factor (NGF). In situ hybridization showed a wide distribution of (P)RR, including in key regions involved in the regulation of blood pressure and body fluid homeostasis. In mouse neurons, the receptor is on the plasma membrane and in synaptic vesicles, and stimulation by renin provokes ERK1/2 phosphorylation. In PC-12 cells, (P)RR localized mainly in the Golgi and in endoplasmic reticulum and redistributed to neurite projections during NGF-induced differentiation. In contrast, ⌬4-(P)RR remained cytosolic and inhibited NGF-induced neuronal differentiation and ERK1/2 activation. Cotransfection of PC-12 cells with (P)RR and ⌬4-(P)RR cDNA resulted in altered localization of (P)RR and inhibited (P)RR redistribution to neurite projections upon NGF stimulation. Furthermore, (P)RR dimerized with itself and with ⌬4-(P)RR, suggesting that the XLMR and epilepsy phenotype resulted from a dominant-negative effect of ⌬4-(P)RR, which coexists with normal transcript in affected males. In conclusion, our results show that (P)RR is expressed in mouse brain and suggest that the XLMR and epilepsy phenotype might result from a dominant-negative effect of the ⌬4-(P)RR protein.brain (P)RR expression; functional (P)RR; X-linked mental retardation THE CLASSICAL RENIN-ANGIOTENSIN system (RAS) is an intravascular enzymatic cascade that generates ANG II, considered the biologically active peptide, and plays a major role in the control of blood pressure, as well as fluid and salt balance. A receptor for renin and its proenzyme form, prorenin, called (pro)renin receptor [(P)RR] was recently cloned (20). The binding of renin and of prorenin results in increased angiotensin generation at the cell surface. Activation of (P)RR results in the activation of the MAP kinases ERK1/2 pathway and in upregulation of profibrotic genes, independently of ANG II generation (9, 10, 13, 21). These biochemical characteristics have generated a special interest in potential nonhemodynamic functions of renin ad prorenin. The receptor is abundantly expressed in adult human (20) and rat (14) organs, including the brain. Although overexpression of (P)RR is associated with a renal (15) and cardiovascular phenotype (3), it is surprising that alterations in the (P)RR gene, ATP6ap2 point to an essential role of (P)RR in cell survival and development of the central nervous system. In zebra fish, (P)RR/ATP6AP2 is expressed at a very early stage of development (www.zfin.o...

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X-Linked intellectual disability accounts for a significant fraction of males with cognitive impairment. Many of these males present with a non-syndromic phenotype and presently mutations in 17 X-linked genes are associated with these patients. Mutations in IL1RAPL1 have been found in multiple families with non-syndromic X-linked intellectual disability. All of the published mutations predict loss of function of the protein. We have identified an additional two families with deletions of a portion of the gene that give rise to cognitive impairment, as well as some behavioral problems and mild dysmorphism. Our clinical findings better delineate the phenotypic spectrum associated with IL1RAPL1 mutations.