An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome

Laryngo-onycho-cutaneous (LOC or Shabbir) syndrome (OMIM 245660) is an autosomal recessive epithelial disorder confined to the Punjabi Muslim population. The condition is characterized by cutaneous erosions, nail dystrophy and exuberant vascular granulation tissue in certain epithelia, especially co...

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Bibliographic Details
Published in:Human molecular genetics 2003-09, Vol.12 (18), p.2395-2409
Main Authors: McLean, W H Irwin, Irvine, Alan D, Hamill, Kevin J, Whittock, Neil V, Coleman-Campbell, Carrie M, Mellerio, Jemima E, Ashton, Gabrielle S, Dopping-Hepenstal, Patricia J H, Eady, Robin A J, Jamil, Tanvir, Phillips, Roderic J, Shabbir, S Ghulam, Haroon, Tahir S, Khurshid, Khawar, Moore, Jonathan E, Page, Brian, Darling, Jonathan, Atherton, David J, Van Steensel, Maurice A M, Munro, Colin S, Smith, Frances J D, McGrath, John A, Phillips, Rodney J
Format: Article
Language:English
Subjects:
Chromosomes, Human, Pair 18
Chronic Disease
Codon, Terminator
Consanguinity
DNA - genetics
Epidermolysis Bullosa - genetics
Epidermolysis Bullosa - pathology
Exons
Family
Frameshift Mutation
France - ethnology
Genetic Linkage
Granulation Tissue - pathology
Haplotypes
Homozygote
Humans
Keratinocytes - secretion
Laminin - chemistry
Laminin - genetics
Lod Score
Pakistan
Protein Biosynthesis
Protein Isoforms - chemistry
Protein Isoforms - genetics
Protein Structure, Tertiary
Syndrome
United Kingdom - ethnology
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Description
Summary:Laryngo-onycho-cutaneous (LOC or Shabbir) syndrome (OMIM 245660) is an autosomal recessive epithelial disorder confined to the Punjabi Muslim population. The condition is characterized by cutaneous erosions, nail dystrophy and exuberant vascular granulation tissue in certain epithelia, especially conjunctiva and larynx. Genome-wide homozygosity mapping localized the gene to a 2 Mb region on chromosome 18q11.2 with an LOD score of 19.8 at theta=0. This region includes the laminin alpha3 gene (LAMA3), in which loss-of-expression mutations cause the lethal skin blistering disorder Herlitz junctional epidermolysis bullosa. Detailed investigation showed that this gene possesses a further 38 exons (76 exons in total) spanning 318 kb of genomic DNA, and encodes three distinct proteins, designated laminin alpha3a, alpha3b1 and alpha3b2. The causative mutation in 15 families was a frameshift mutation 151insG predicting a stop codon 7 bp downstream in an exon that is specific to laminin alpha3a. This protein is secreted only by the basal keratinocytes of stratified epithelia, implying that LOC is caused by dysfunction of keratinocyte-mesenchymal communication. Surprisingly, the 151insG mutation does not result in nonsense-mediated mRNA decay due to rescue of the transcript by an alternative translation start site 6 exons downstream. The resultant N-terminal deletion of laminin alpha3a was confirmed by immunoprecipitation of secreted proteins from LOC keratinocytes. These studies show that the laminin alpha3a N-terminal domain is a key regulator of the granulation tissue response, with important implications not only in LOC but in a range of other clinical conditions associated with abnormal wound healing.
ISSN:0964-6906