title: An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome.
abstract: 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.
authors.affiliation: University of Dundee, Ninewells Medical School, Dundee, UK. wmclean@hgmp.mrc.ac.uk
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hamill
authors.forename: Neil V
authors.initials: NV
authors.lastname: Whittock
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Coleman-Campbell
authors.forename: Jemima E
authors.initials: JE
authors.lastname: Mellerio
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Ashton
authors.forename: Patricia J H
authors.initials: PJ
authors.lastname: Dopping-Hepenstal
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Eady
authors.forename: Tanvir
authors.initials: T
authors.lastname: Jamil
authors.forename: Roderic  J
authors.initials: R
authors.lastname: Phillips
authors.forename: S Ghulam
authors.initials: SG
authors.lastname: Shabbir
authors.forename: Tahir S
authors.initials: TS
authors.lastname: Haroon
authors.forename: Khawar
authors.initials: K
authors.lastname: Khurshid
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Moore
authors.forename: Brian
authors.initials: B
authors.lastname: Page
authors.forename: Jonathan
authors.initials: J
authors.lastname: Darling
authors.forename: David J
authors.initials: DJ
authors.lastname: Atherton
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: Van Steensel
authors.forename: Colin S
authors.initials: CS
authors.lastname: Munro
authors.forename: Frances J D
authors.initials: FJ
authors.lastname: Smith
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Phillips
mesh_terms: D002887:Chromosomes, Human, Pair 18; D002908:Chronic Disease; D018388:Codon, Terminator; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D004820:Epidermolysis Bullosa / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005190:Family; D016368:Frameshift Mutation; D005602:France / Q000208:ethnology; D008040:Genetic Linkage; D006097:Granulation Tissue / Q000473:pathology*; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D007797:Laminin / Q000737:chemistry / Q000235:genetics*; D008126:Lod Score; D010154:Pakistan; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary; D013577:Syndrome; D006113:United Kingdom / Q000208:ethnology
chemical_list: D018388:Codon, Terminator; D007797:Laminin; D020033:Protein Isoforms; C095567:laminin alpha 3; D004247:DNA