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Human Molecular Genetics Advance Access originally published online on July 15, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 18 2395-2409
DOI: 10.1093/hmg/ddg234
© 2003 Oxford University Press

An unusual N-terminal deletion of the laminin {alpha}3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome

W. H. Irwin McLean1,*, Alan D. Irvine2, Kevin J. Hamill1, Neil V. Whittock1, Carrie M. Coleman-Campbell1, Jemima E. Mellerio3, Gabrielle S. Ashton3, Patricia J. H. Dopping-Hepenstal3, Robin A. J. Eady3, Tanvir Jamil4, Rodney J. Phillips5, S. Ghulam Shabbir6, Tahir S. Haroon6, Khawar Khurshid6, Jonathan E. Moore7, Brian Page7, Jonathan Darling8, David J. Atherton9, Maurice A. M. van Steensel10, Colin S. Munro11, Frances J. D. Smith1 and John A. McGrath3

1Epithelial Genetics Group, Human Genetics Unit, Department of Molecular and Cellular Pathology, University of Dundee, Ninewells Medical School, Dundee DD1 9SY, UK, 2Department of Paediatric Dermatology, Our Lady's Hospital for Sick Children, Dublin, Ireland, 3Genetic Skin Disease Group, St John's Institute of Dermatology, The Guy's, King's College and St Thomas' Hospitals' Medical School, St Thomas' Hospital, London, UK, 4Hasham M. Jamil Trust, Burnham Health Centre, Minniecroft Road, Burnham, Burkinghamshire SL1 7DE, UK, 5Department of Paediatrics, Royal Children's Hospital, Melbourne, Australia, 6Department of Dermatology, King Edward Medical College, Nila Gumbad, Lahore, Pakistan, 7Department of Ophthalmology, Royal Victoria Hospital, Belfast, UK, 8Department of Paediatrics, St James's University Hospital, Leeds, UK, 9Department of Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK, 10Department of Dermatology, University Hospital Maastricht, The Netherlands and 11Department of Dermatology, Southern General Hospital, Glasgow, UK

Received June 25, 2003; Accepted July 8, 2003

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 {alpha}3 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 {alpha}3a, {alpha}3b1 and {alpha}3b2. 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 {alpha}3a. 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 {alpha}3a was confirmed by immunoprecipitation of secreted proteins from LOC keratinocytes. These studies show that the laminin {alpha}3a 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.

* To whom correspondence should be addressed. Tel: +44 1382425618; Fax: +44 1382425619; Email: wmclean{at}hgmp.mrc.ac.uk


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