Human Molecular Genetics Advance Access originally published online on March 3, 2005
Human Molecular Genetics 2005 14(8):1019-1027; doi:10.1093/hmg/ddi094
© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
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
Juliane Ramser1,7,
Fatima E. Abidi2,
Celine A. Burckle3,
Claus Lenski1,
Helga Toriello4,
Gaiping Wen5,
Herbert A. Lubs2,6,
Stefanie Engert1,
Roger E. Stevenson2,
Alfons Meindl1,7,*,
Charles E. Schwartz2 and
Genevieve Nguyen3
1Institute of Human Genetics, Ludwig-Maximilians-University, Munich 80336, Germany,
2J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA,
3Institut National de la Santé et de la Recherche Médicale INSERM U36, Collège de France, Paris 75231, France,
4Spectrum Health, Grand Rapids, MI 49503, USA,
5Institute for Molecular Biotechnology, Jena 07745, Germany,
6Mailman Center Child Development, University of Miami School of Medicine, Miami, FL 33101, USA and
7Department of Obstetrics and Gynaecology, Technical University, Munich 81675, Germany
* To whom correspondence should be addressed at: Institute of Human Genetics, Ludwig-Maximilians-University, Goethestr. 29, Munich 80336, Germany. Tel: +49 8941402429; Fax: +49 8941404831; Email: alfons{at}pedgen.med.uni-muenchen.de
Received December 20, 2004; Revised February 16, 2005; Accepted February 23, 2005
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.
NM_005765, BI599385 and AC092473
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