Revertant mosaicism

Partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation

Thomas N. Darling, Carole Yee, Johann W. Bauer, Helmut Hintner, Kim B. Yancey

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Generalized atrophic benign epidermolysis bullosa is an autosomal recessive subepidermal blistering disease typified by null mutations in COL17A1. In 1 large kindred, affected individuals were homozygous for a 2-bp deletion in COL17A1, 4003delTC, which resulted in a downstream premature termination codon, nonsense-mediated mRNA decay, and abrogation of type XVII collagen synthesis. Interestingly, 1 of these patients, although phenotypically identical to her affected siblings showed focal expression of type XVII collagen in epidermal basement membrane in a pattern suggestive of revertant mosaicism. When studies of randomly obtained epidermal, oromucosal, and peripheral blood cells failed to identify the genetic basis of this apparent mosaicism, microscopic subpopulations of potentially revertant epidermal cells (i.e., those overlying basement membrane containing type XVII collagen) were selectively isolated using laser capture microdissection. Analysis of DNA and RNA from these cells revealed a second mutation, 4080insGG, on 1 allele of COL17A1. This 2-bp insertion corrected the reading frame just proximal to the premature termination codon, countered nonsense- mediated mRNA decay, and allowed protein production by patient keratinocytes in vivo and in vitro. These studies elucidate the molecular basis of a novel form of revertant mosaicism in humans.

Original languageEnglish (US)
Pages (from-to)1371-1377
Number of pages7
JournalJournal of Clinical Investigation
Volume103
Issue number10
StatePublished - May 1999

Fingerprint

Mosaicism
Germ-Line Mutation
Nonsense Mediated mRNA Decay
Nonsense Codon
Basement Membrane
Mutation
Junctional Epidermolysis Bullosa
Laser Capture Microdissection
Reading Frames
Keratinocytes
Siblings
Blood Cells
Alleles
RNA
DNA
collagen type XVII
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Revertant mosaicism : Partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation. / Darling, Thomas N.; Yee, Carole; Bauer, Johann W.; Hintner, Helmut; Yancey, Kim B.

In: Journal of Clinical Investigation, Vol. 103, No. 10, 05.1999, p. 1371-1377.

Research output: Contribution to journalArticle

Darling, Thomas N. ; Yee, Carole ; Bauer, Johann W. ; Hintner, Helmut ; Yancey, Kim B. / Revertant mosaicism : Partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation. In: Journal of Clinical Investigation. 1999 ; Vol. 103, No. 10. pp. 1371-1377.
@article{9640fd7c79b74e92a01c272aef9f99bb,
title = "Revertant mosaicism: Partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation",
abstract = "Generalized atrophic benign epidermolysis bullosa is an autosomal recessive subepidermal blistering disease typified by null mutations in COL17A1. In 1 large kindred, affected individuals were homozygous for a 2-bp deletion in COL17A1, 4003delTC, which resulted in a downstream premature termination codon, nonsense-mediated mRNA decay, and abrogation of type XVII collagen synthesis. Interestingly, 1 of these patients, although phenotypically identical to her affected siblings showed focal expression of type XVII collagen in epidermal basement membrane in a pattern suggestive of revertant mosaicism. When studies of randomly obtained epidermal, oromucosal, and peripheral blood cells failed to identify the genetic basis of this apparent mosaicism, microscopic subpopulations of potentially revertant epidermal cells (i.e., those overlying basement membrane containing type XVII collagen) were selectively isolated using laser capture microdissection. Analysis of DNA and RNA from these cells revealed a second mutation, 4080insGG, on 1 allele of COL17A1. This 2-bp insertion corrected the reading frame just proximal to the premature termination codon, countered nonsense- mediated mRNA decay, and allowed protein production by patient keratinocytes in vivo and in vitro. These studies elucidate the molecular basis of a novel form of revertant mosaicism in humans.",
author = "Darling, {Thomas N.} and Carole Yee and Bauer, {Johann W.} and Helmut Hintner and Yancey, {Kim B.}",
year = "1999",
month = "5",
language = "English (US)",
volume = "103",
pages = "1371--1377",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",

}

TY - JOUR

T1 - Revertant mosaicism

T2 - Partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation

AU - Darling, Thomas N.

AU - Yee, Carole

AU - Bauer, Johann W.

AU - Hintner, Helmut

AU - Yancey, Kim B.

PY - 1999/5

Y1 - 1999/5

N2 - Generalized atrophic benign epidermolysis bullosa is an autosomal recessive subepidermal blistering disease typified by null mutations in COL17A1. In 1 large kindred, affected individuals were homozygous for a 2-bp deletion in COL17A1, 4003delTC, which resulted in a downstream premature termination codon, nonsense-mediated mRNA decay, and abrogation of type XVII collagen synthesis. Interestingly, 1 of these patients, although phenotypically identical to her affected siblings showed focal expression of type XVII collagen in epidermal basement membrane in a pattern suggestive of revertant mosaicism. When studies of randomly obtained epidermal, oromucosal, and peripheral blood cells failed to identify the genetic basis of this apparent mosaicism, microscopic subpopulations of potentially revertant epidermal cells (i.e., those overlying basement membrane containing type XVII collagen) were selectively isolated using laser capture microdissection. Analysis of DNA and RNA from these cells revealed a second mutation, 4080insGG, on 1 allele of COL17A1. This 2-bp insertion corrected the reading frame just proximal to the premature termination codon, countered nonsense- mediated mRNA decay, and allowed protein production by patient keratinocytes in vivo and in vitro. These studies elucidate the molecular basis of a novel form of revertant mosaicism in humans.

AB - Generalized atrophic benign epidermolysis bullosa is an autosomal recessive subepidermal blistering disease typified by null mutations in COL17A1. In 1 large kindred, affected individuals were homozygous for a 2-bp deletion in COL17A1, 4003delTC, which resulted in a downstream premature termination codon, nonsense-mediated mRNA decay, and abrogation of type XVII collagen synthesis. Interestingly, 1 of these patients, although phenotypically identical to her affected siblings showed focal expression of type XVII collagen in epidermal basement membrane in a pattern suggestive of revertant mosaicism. When studies of randomly obtained epidermal, oromucosal, and peripheral blood cells failed to identify the genetic basis of this apparent mosaicism, microscopic subpopulations of potentially revertant epidermal cells (i.e., those overlying basement membrane containing type XVII collagen) were selectively isolated using laser capture microdissection. Analysis of DNA and RNA from these cells revealed a second mutation, 4080insGG, on 1 allele of COL17A1. This 2-bp insertion corrected the reading frame just proximal to the premature termination codon, countered nonsense- mediated mRNA decay, and allowed protein production by patient keratinocytes in vivo and in vitro. These studies elucidate the molecular basis of a novel form of revertant mosaicism in humans.

UR - http://www.scopus.com/inward/record.url?scp=0032740890&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032740890&partnerID=8YFLogxK

M3 - Article

VL - 103

SP - 1371

EP - 1377

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 10

ER -