A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor

Abstract

The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C>T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

“…112 The (P)RR is essential along functional link with the v-H + -ATPase for cell survival and in early organ development. 87,111,115 In rodents, the receptor expression is ubiquitous and occurs early in development, 116 and in humans, (P)RR/ATP6ap2 mutation results in mental retardation and epilepsy 117 , and the lack of it may impair neurotransmission. 118 Thus, the (P)RR is slated to act in two ways: (a) as the receptor for renin and prorenin generates Ang-II and triggers the activation of the MAPKs extracellular signal-regulated kinase 1/2 signaling pathways resulting in hypertension, cardiac fibrosis and glomerulosclerosis, and (b) as a protein associated with the v-H + -ATPase, exerts v-H + -ATPase-associated functions essential to Wnt signaling.…”

Qualitative and quantitative analyses of (pro)renin receptor in the medium of cultured human umbilical vein endothelial cells

“…11 Mutation of the (P)RR gene is associated with X-linked mental retardation in humans. 12 We have reported the expression and purification of full-length rat (P)RR using a baculovirus expression system. 13,14 Purified rat (P)RR could bind to rat renin and its inactive form, prorenin.…”

Ontogeny of the (pro)renin receptor

“…The possibility that (P)RR may be important for brain development is supported by the findings that Xenopus embryos injected with (P)RR antisense morpholino oligonucleotides have small head size (25). Moreover, hypomorphic mutation in the (P)RR is causally linked to the absence of Erk1/2 phosphorylation and the development of X-linked mental retardation in humans (14). Although the role of the (P)RR in the developing or adult lung remains to be determined, relatively high expression levels of the pulmonary (P)RR protein throughout ontogeny support a novel role for (P)RR in lung morphogenesis.…”

“…Studies in zebrafish demonstrate that (P)RR mutations result in brain malformations and early embryonic lethality (13). Moreover, hypomorphic mutations in the (P)RR are causally linked to the development of X-linked mental retardation in humans (14). Given that the precise function of the (P)RR during kidney, lung, heart, and brain development is still emerging, we examined the spatiotemporal ontogeny of the (P)RR in the kidney, lung, heart, and brain in the mouse.…”