Linked Life Data

12522688

Source:http://linkedlifedata.com/resource/pubmed/id/12522688

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2003-1-10
pubmed:abstractText
The ubiquitin ligase NEDD4L is a candidate gene for essential hypertension on both functional and genetic grounds. By targeting the epithelial sodium channel (ENaC) for degradation, NEDD4L is a significant determinant of sodium reabsorption in the distal nephron. Genetic linkage has been reported to a region of chromosome 18q harboring the gene, with phenotypes that include a rare orthostatic hypotension disorder, essential hypertension, and postural change in systolic blood pressure. A systematic search for genetic polymorphisms by resequencing exons and intron boundaries in 48 Caucasians yielded 38 variants. Among these, variant 13 is common, with either G (70%) or A (30%) as the last nucleotide of a putative exon 1. This mutation could affect the generation of a previously unrecognized splice isoform. In subsequent experiments, (1) we confirmed the presence of this putative isoform in both kidney and adrenals; (2) we established that variant 13-A leads to the systematic use of an alternative splice site, generating a transcript encoding a nonfunctional protein; and (3) we demonstrated differences in tissue-specific expression of the novel isoform relative to its previously reported counterpart. Variant 13-A precludes the formation of a transcript encoding a full-length Ca2+-dependent lipid-binding (C2) domain with very high evolutionary conservation among NEDD4L orthologs. A similar C2 domain in the paralogous NEDD4 gene plays a significant role in the transfer of its product to the apical membrane of epithelial cells. Differential function of NEDD4L isoforms could prove significant in blood pressure regulation through an effect on ENaC-dependent sodium reabsorption.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1434-5161
pubmed:author
pubmed:issnType
Print
pubmed:volume
47
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
665-76
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:12522688-Alternative Splicing, pubmed-meshheading:12522688-Amino Acid Sequence, pubmed-meshheading:12522688-Calcium-Binding Proteins, pubmed-meshheading:12522688-Chromosomes, Human, Pair 18, pubmed-meshheading:12522688-Endosomal Sorting Complexes Required for Transport, pubmed-meshheading:12522688-Exons, pubmed-meshheading:12522688-Frameshift Mutation, pubmed-meshheading:12522688-Humans, pubmed-meshheading:12522688-Hypertension, pubmed-meshheading:12522688-Introns, pubmed-meshheading:12522688-Kidney, pubmed-meshheading:12522688-Ligases, pubmed-meshheading:12522688-Molecular Sequence Data, pubmed-meshheading:12522688-Polymorphism, Genetic, pubmed-meshheading:12522688-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:12522688-Sequence Analysis, DNA, pubmed-meshheading:12522688-Sequence Homology, Amino Acid, pubmed-meshheading:12522688-Tissue Distribution, pubmed-meshheading:12522688-Ubiquitin-Protein Ligases
pubmed:year
2002
pubmed:articleTitle
Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript.
pubmed:affiliation
Department of Human Genetics, Rm 308 BPRB, 20 South 2030 East, University of Utah, Salt Lake City, UT 84112, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.