title: 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.
authors.affiliation: 1Institute of Human Genetics, Ludwig-Maximilians-University, Munich 80336, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Ramser
authors.forename: Fatima E
authors.initials: FE
authors.lastname: Abidi
authors.forename: Celine A
authors.initials: CA
authors.lastname: Burckle
authors.forename: Claus
authors.initials: C
authors.lastname: Lenski
authors.forename: Helga
authors.initials: H
authors.lastname: Toriello
authors.forename: Gaiping
authors.initials: G
authors.lastname: Wen
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Lubs
authors.forename: Stefanie
authors.initials: S
authors.lastname: Engert
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Genevieve
authors.initials: G
authors.lastname: Nguyen
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D004742:Enhancer Elements, Genetic; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D000093342:Prorenin Receptor
chemical_list: D011956:Receptors, Cell Surface; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor