Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1).
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.
Hamada
Takahiro
T
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.
McLean
W H Irwin
WH
Ramsay
Michele
M
Ashton
Gabrielle H S
GH
Nanda
Arti
A
Jenkins
Trefor
T
Edelstein
Isobel
I
South
Andrew P
AP
Bleck
Oliver
O
Wessagowit
Vesarat
V
Mallipeddi
Rajeev
R
Orchard
Guy E
GE
Wan
Hong
H
Dopping-Hepenstal
Patricia J C
PJ
Mellerio
Jemima E
JE
Whittock
Neil V
NV
Munro
Colin S
CS
van Steensel
Maurice A M
MA
Steijlen
Peter M
PM
Ni
Jian
J
Zhang
Lurong
L
Hashimoto
Takashi
T
Eady
Robin A J
RA
McGrath
John A
JA
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
C490607:ECM1 protein, human; D016326:Extracellular Matrix Proteins