title: Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1).
abstract: Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease (OMIM 247100) is a rare, autosomal recessive disorder typified by generalized thickening of skin, mucosae and certain viscera. Classical features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane. The aetiology of LP is currently unknown. Using DNA from three affected siblings in a consanguineous Saudi Arabian family we performed genome-wide linkage and mapped the disorder to 1q21 (marker D1S498) with a two-point LOD score of 3.45 at theta = 0. A further 28 affected individuals from five other unrelated consanguineous family groups from different geographical regions also showed complete linkage and resulted in a maximum two-point LOD score of 21.85 at theta = 0. Using available markers in the interval between D1S442 and D1S305, the observed recombinants placed the gene in a 2.3 cM critical interval between D1S2344 and D1S2343 (Marshfield genetic map) corresponding to an approximately 6.5 Mb region on the UCSC physical map. Using a candidate gene approach (comparison of control versus LP gene expression in cultured fibroblasts) and subsequent direct sequencing of genomic DNA, we identified six different homozygous loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). Although the precise function of ECM1 is not known, our findings provide the first clinical indication of its relevance to skin adhesion, epidermal differentiation, wound healing, scarring, angiogenesis/angiopathy and basement membrane physiology, as well as defining the molecular basis of this inherited disorder.
authors.affiliation: Department of Cell and Molecular Pathology, St John's Institute of Dermatology, The Guy's, King's College and St Thomas' Hospitals' Medical School, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hamada
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.forename: Michele
authors.initials: M
authors.lastname: Ramsay
authors.forename: Gabrielle H S
authors.initials: GH
authors.lastname: Ashton
authors.forename: Arti
authors.initials: A
authors.lastname: Nanda
authors.forename: Trefor
authors.initials: T
authors.lastname: Jenkins
authors.forename: Isobel
authors.initials: I
authors.lastname: Edelstein
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
authors.forename: Oliver
authors.initials: O
authors.lastname: Bleck
authors.forename: Vesarat
authors.initials: V
authors.lastname: Wessagowit
authors.forename: Rajeev
authors.initials: R
authors.lastname: Mallipeddi
authors.forename: Guy E
authors.initials: GE
authors.lastname: Orchard
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.forename: Patricia J C
authors.initials: PJ
authors.lastname: Dopping-Hepenstal
authors.forename: Jemima E
authors.initials: JE
authors.lastname: Mellerio
authors.forename: Neil V
authors.initials: NV
authors.lastname: Whittock
authors.forename: Colin S
authors.initials: CS
authors.lastname: Munro
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Steijlen
authors.forename: Jian
authors.initials: J
authors.lastname: Ni
authors.forename: Lurong
authors.initials: L
authors.lastname: Zhang
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Eady
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D001808:Blood Vessels / Q000473:pathology / Q000648:ultrastructure; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D006801:Humans; D008065:Lipoid Proteinosis of Urbach and Wiethe / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013019:South Africa
chemical_list: C490607:ECM1 protein, human; D016326:Extracellular Matrix Proteins