Human Molecular Genetics Advance Access published online on March 3, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi094
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1 Institute of Human Genetics, Ludwig-Maximilians-University, Munich 80336, Germany; Department of Obstetrics and Gynaecology, Technical University, Munich 81675, Germany
* To whom correspondence should be addressed. The renin angiotensin system 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 (XMRE, OMIM #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 renin-angiotensin system in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.
Article
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
2 J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina 29646, USA
3 Institut National de la Santé et de la Recherche Médicale INSERM U36, Collège de France, Paris 75231, France
4 Institute of Human Genetics, Ludwig-Maximilians-University, Munich 80336, Germany
5 Spectrum Health, Grand Rapids, Michigan 49503, USA
6 Institute for Molecular Biotechnology, Jena 07745, Germany
7 J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina 29646, USA; Mailman Center Child Development, University of Miami School of Medicine, Miami, Florida 33101, USA
8 Department of Human Genetics, Ludwig-Maximilians-University, Goethestr. 29, Munich 80336, Germany; Department of Obstetrics and Gynaecology, Technical University, Munich 81675, Germany
Alfons Meindl, E-mail: alfons{at}pedgen.med.uni-muenchen.de
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