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Genetic bases of severe junctional epidermolysis bullosa presenting spontaneous amelioration with aging

Genetic bases of severe junctional epidermolysis bullosa presenting spontaneous amelioration with... Change of the clinical picture with aging is noted in some patients suffering from junctional epidermolysis bullosa (JEB), an inherited blistering disorder caused by extensive disadhesion of the epithelia. We have studied a patient born with severe JEB associated with absent expression of laminin 5. A remarkable reduction of the blistering tendency was observed with aging that correlated with a restored expression of immunoreactive laminin 5 molecules. Genetic analysis of the gene LAMB3 detected compound heterozygosity for the nonsense mutation R635X and a novel 2 bp deletion (1587delAG) resulting in a downstream premature termination codon. RT–PCR amplification of total RNA purified from skin biopsies demonstrated that the mutated β3 mRNAs underwent rapid decay shortly after birth, and that illegitimate splicing of the mRNA carrying mutation 1587delAG generated a new internally shortened β3 transcript with advancing age. Our genetic and biochemical data show that (i) the illegitimate splicing of the β3 pre-mRNA results in synthesis and secretion of a laminin 5 heterotrimer with an internally deleted β3 polypeptide, (ii) expression of the mutated β3 polypeptide is up-regulated in the basal keratinocytes with high proliferative potential, (iii) absence of the N-terminal region of the β3 rod domain II thought to stabilize the tertiary structure of the laminin 5 is not required for the assembly of the protein and (iv) the mutant laminin 5 retains its adhesive potential. Our results demonstrate that mRNA rescue may underlie the evolution of the clinical phenotype in inherited skin conditions. Received July 2, 2001; Revised and Accepted August 8, 2001. « Previous | Next Article » Table of Contents This Article Hum. Mol. Genet. (2001) 10 (21): 2453-2461. doi: 10.1093/hmg/10.21.2453 » Abstract Free Full Text (HTML) Free Full Text (PDF) Free Classifications Report Services Article metrics Alert me when cited Alert me if corrected Find similar articles Similar articles in Web of Science Similar articles in PubMed Add to my archive Download citation Request Permissions Citing Articles Load citing article information Citing articles via CrossRef Citing articles via Scopus Citing articles via Web of Science Citing articles via Google Scholar Google Scholar Articles by Gache, Y. Articles by Meneguzzi, G. Search for related content PubMed PubMed citation Articles by Gache, Y. Articles by Allegra, M. Articles by Bodemer, C. Articles by Pisani-Spadafora, A. Articles by de Prost, Y. Articles by Ortonne, J. P. Articles by Meneguzzi, G. Related Content Load related web page information Share Email this article CiteULike Delicious Facebook Google+ Mendeley Twitter What's this? Search this journal: Advanced » Current Issue November 15, 2015 24 (22) Alert me to new issues The Journal About this journal Rights & Permissions Dispatch date of the next issue This journal is a member of the Committee on Publication Ethics (COPE) We are mobile – find out more Journals Career Network Impact factor: 6.393 5-Yr impact factor: 6.850 Executive Editors Professor Kay Davies Professor Anthony Wynshaw-Boris Professor Joel Hirschhorn Dr Jeffrey Barrett View full editorial board For Authors Instructions to authors Online submission Submit Now! Self-archiving policy Open access options for authors - visit Oxford Open This journal enables compliance with the NIH Public Access Policy Alerting Services Email table of contents Email Advance Access CiteTrack XML RSS feed Corporate Services Advertising sales Reprints Supplements var taxonomies = ("SCI01140"); Most Most Read Genetics of obesity and the prediction of risk for health Non-coding RNA Telomerase and cancer Ion channel diseases Down syndrome--recent progress and future prospects » View all Most Read articles Most Cited The DNA methyltransferases of mammals Nonsense-Mediated mRNA Decay in Health and Disease Mutation of human short tandem repeats Prediction of deleterious human alleles Isolation of a Candidate Human Telomerase Catalytic Subunit Gene, Which Reveals Complex Splicing Patterns in Different Cell Types » View all Most Cited articles Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. 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Genetic bases of severe junctional epidermolysis bullosa presenting spontaneous amelioration with aging

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References (50)

Publisher
Oxford University Press
Copyright
Copyright © 2015 Oxford University Press
ISSN
0964-6906
eISSN
1460-2083
DOI
10.1093/hmg/10.21.2453
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Abstract

Change of the clinical picture with aging is noted in some patients suffering from junctional epidermolysis bullosa (JEB), an inherited blistering disorder caused by extensive disadhesion of the epithelia. We have studied a patient born with severe JEB associated with absent expression of laminin 5. A remarkable reduction of the blistering tendency was observed with aging that correlated with a restored expression of immunoreactive laminin 5 molecules. Genetic analysis of the gene LAMB3 detected compound heterozygosity for the nonsense mutation R635X and a novel 2 bp deletion (1587delAG) resulting in a downstream premature termination codon. RT–PCR amplification of total RNA purified from skin biopsies demonstrated that the mutated β3 mRNAs underwent rapid decay shortly after birth, and that illegitimate splicing of the mRNA carrying mutation 1587delAG generated a new internally shortened β3 transcript with advancing age. Our genetic and biochemical data show that (i) the illegitimate splicing of the β3 pre-mRNA results in synthesis and secretion of a laminin 5 heterotrimer with an internally deleted β3 polypeptide, (ii) expression of the mutated β3 polypeptide is up-regulated in the basal keratinocytes with high proliferative potential, (iii) absence of the N-terminal region of the β3 rod domain II thought to stabilize the tertiary structure of the laminin 5 is not required for the assembly of the protein and (iv) the mutant laminin 5 retains its adhesive potential. Our results demonstrate that mRNA rescue may underlie the evolution of the clinical phenotype in inherited skin conditions. Received July 2, 2001; Revised and Accepted August 8, 2001. « Previous | Next Article » Table of Contents This Article Hum. Mol. Genet. (2001) 10 (21): 2453-2461. doi: 10.1093/hmg/10.21.2453 » Abstract Free Full Text (HTML) Free Full Text (PDF) Free Classifications Report Services Article metrics Alert me when cited Alert me if corrected Find similar articles Similar articles in Web of Science Similar articles in PubMed Add to my archive Download citation Request Permissions Citing Articles Load citing article information Citing articles via CrossRef Citing articles via Scopus Citing articles via Web of Science Citing articles via Google Scholar Google Scholar Articles by Gache, Y. Articles by Meneguzzi, G. Search for related content PubMed PubMed citation Articles by Gache, Y. Articles by Allegra, M. Articles by Bodemer, C. Articles by Pisani-Spadafora, A. Articles by de Prost, Y. Articles by Ortonne, J. P. Articles by Meneguzzi, G. Related Content Load related web page information Share Email this article CiteULike Delicious Facebook Google+ Mendeley Twitter What's this? Search this journal: Advanced » Current Issue November 15, 2015 24 (22) Alert me to new issues The Journal About this journal Rights & Permissions Dispatch date of the next issue This journal is a member of the Committee on Publication Ethics (COPE) We are mobile – find out more Journals Career Network Impact factor: 6.393 5-Yr impact factor: 6.850 Executive Editors Professor Kay Davies Professor Anthony Wynshaw-Boris Professor Joel Hirschhorn Dr Jeffrey Barrett View full editorial board For Authors Instructions to authors Online submission Submit Now! Self-archiving policy Open access options for authors - visit Oxford Open This journal enables compliance with the NIH Public Access Policy Alerting Services Email table of contents Email Advance Access CiteTrack XML RSS feed Corporate Services Advertising sales Reprints Supplements var taxonomies = ("SCI01140"); Most Most Read Genetics of obesity and the prediction of risk for health Non-coding RNA Telomerase and cancer Ion channel diseases Down syndrome--recent progress and future prospects » View all Most Read articles Most Cited The DNA methyltransferases of mammals Nonsense-Mediated mRNA Decay in Health and Disease Mutation of human short tandem repeats Prediction of deleterious human alleles Isolation of a Candidate Human Telomerase Catalytic Subunit Gene, Which Reveals Complex Splicing Patterns in Different Cell Types » View all Most Cited articles Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department. Online ISSN 1460-2083 - Print ISSN 0964-6906 Copyright © 2015 Oxford University Press Oxford Journals Oxford University Press Site Map Privacy Policy Cookie Policy Legal Notices Frequently Asked Questions Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan Academic & Professional books Children's & Schools Books Dictionaries & Reference Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks International Education Unit Law Medicine Music Online Products & Publishing Oxford Bibliographies Online Oxford Dictionaries Online Oxford English Dictionary Oxford Language Dictionaries Online Oxford Scholarship Online Reference Rights and Permissions Resources for Retailers & Wholesalers Resources for the Healthcare Industry Very Short Introductions World's Classics function fnc_onDomLoaded() { var query_context = getQueryContext(); PF_initOIUnderbar(query_context,":QS:default","","JRN"); PF_insertOIUnderbar(0); }; if (window.addEventListener) { window.addEventListener('load', fnc_onDomLoaded, false); } else if (window.attachEvent) { window.attachEvent('onload', fnc_onDomLoaded); } var gaJsHost = (("https:" == document.location.protocol) ? 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Journal

Human Molecular Genetics – Oxford University Press

Published: Oct 2, 2001

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