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
J Ramser, FE Abidi, CA Burckle, C Lenski… - Human molecular …, 2005 - academic.oup.com
J Ramser, FE Abidi, CA Burckle, C Lenski, H Toriello, G Wen, HA Lubs, S Engert…
Human molecular genetics, 2005•academic.oup.comThe 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 …
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 …
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.
Oxford University Press