Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript

Diane M. Dunn, Tomoaki Ishigami, James Pankow, Andrew Von Niederhausern, Jonathan Alder, Steven Hunt, Mark F. Leppert, Jean Marc Lalouel, Robert B. Weiss

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)665-676
Number of pages12
JournalJournal of Human Genetics
Volume47
Issue number12
DOIs
Publication statusPublished - 2002
Externally publishedYes

Fingerprint

RNA Splice Sites
Protein Isoforms
Blood Pressure
Exons
Sodium
Genes
Epithelial Sodium Channels
Orthostatic Hypotension
Genetic Linkage
Nephrons
Genetic Polymorphisms
Ligases
Ubiquitin
Introns
Nucleotides
Chromosomes
Epithelial Cells
Phenotype
Kidney
Lipids

Keywords

  • Aberrant splicing
  • Common variants
  • Hypertension
  • Kidney
  • NEDD4L

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Dunn, D. M., Ishigami, T., Pankow, J., Von Niederhausern, A., Alder, J., Hunt, S., ... Weiss, R. B. (2002). Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript. Journal of Human Genetics, 47(12), 665-676. https://doi.org/10.1007/s100380200102

Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript. / Dunn, Diane M.; Ishigami, Tomoaki; Pankow, James; Von Niederhausern, Andrew; Alder, Jonathan; Hunt, Steven; Leppert, Mark F.; Lalouel, Jean Marc; Weiss, Robert B.

In: Journal of Human Genetics, Vol. 47, No. 12, 2002, p. 665-676.

Research output: Contribution to journalArticle

Dunn, DM, Ishigami, T, Pankow, J, Von Niederhausern, A, Alder, J, Hunt, S, Leppert, MF, Lalouel, JM & Weiss, RB 2002, 'Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript', Journal of Human Genetics, vol. 47, no. 12, pp. 665-676. https://doi.org/10.1007/s100380200102
Dunn, Diane M. ; Ishigami, Tomoaki ; Pankow, James ; Von Niederhausern, Andrew ; Alder, Jonathan ; Hunt, Steven ; Leppert, Mark F. ; Lalouel, Jean Marc ; Weiss, Robert B. / Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript. In: Journal of Human Genetics. 2002 ; Vol. 47, No. 12. pp. 665-676.
@article{346d8d994e774f7492d4c55ab1b05a6a,
title = "Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript",
abstract = "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.",
keywords = "Aberrant splicing, Common variants, Hypertension, Kidney, NEDD4L",
author = "Dunn, {Diane M.} and Tomoaki Ishigami and James Pankow and {Von Niederhausern}, Andrew and Jonathan Alder and Steven Hunt and Leppert, {Mark F.} and Lalouel, {Jean Marc} and Weiss, {Robert B.}",
year = "2002",
doi = "10.1007/s100380200102",
language = "English",
volume = "47",
pages = "665--676",
journal = "Journal of Human Genetics",
issn = "1434-5161",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript

AU - Dunn, Diane M.

AU - Ishigami, Tomoaki

AU - Pankow, James

AU - Von Niederhausern, Andrew

AU - Alder, Jonathan

AU - Hunt, Steven

AU - Leppert, Mark F.

AU - Lalouel, Jean Marc

AU - Weiss, Robert B.

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - Aberrant splicing

KW - Common variants

KW - Hypertension

KW - Kidney

KW - NEDD4L

UR - http://www.scopus.com/inward/record.url?scp=0036947482&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036947482&partnerID=8YFLogxK

U2 - 10.1007/s100380200102

DO - 10.1007/s100380200102

M3 - Article

VL - 47

SP - 665

EP - 676

JO - Journal of Human Genetics

JF - Journal of Human Genetics

SN - 1434-5161

IS - 12

ER -