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.
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.
Ramser
Juliane
J
1Institute of Human Genetics, Ludwig-Maximilians-University, Munich 80336, Germany.
Abidi
Fatima E
FE
Burckle
Celine A
CA
Lenski
Claus
C
Toriello
Helga
H
Wen
Gaiping
G
Lubs
Herbert A
HA
Engert
Stefanie
S
Stevenson
Roger E
RE
Meindl
Alfons
A
Schwartz
Charles E
CE
Nguyen
Genevieve
G
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
D011956:Receptors, Cell Surface; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor