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

Hum Mol Genet. 2005 Apr 15;14(8):1019-27. doi: 10.1093/hmg/ddi094. Epub 2005 Mar 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Enhancer Elements, Genetic
  • Epilepsy / genetics*
  • Epilepsy / metabolism
  • Exons
  • Female
  • Humans
  • Male
  • Mental Retardation, X-Linked / genetics*
  • Mental Retardation, X-Linked / metabolism
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Renin-Angiotensin System / genetics
  • Renin-Angiotensin System / physiology
  • Vacuolar Proton-Translocating ATPases / genetics*
  • Vacuolar Proton-Translocating ATPases / metabolism


  • ATP6AP2 protein, human
  • Receptors, Cell Surface
  • Vacuolar Proton-Translocating ATPases

Associated data

  • GENBANK/AC092473
  • GENBANK/BI599385