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Human Molecular Genetics, 2002, Vol. 11, No. 7 833-840
© 2002 Oxford University Press

Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1)

Takahiro Hamada1,3, W. H. Irwin McLean4, Michele Ramsay5, Gabrielle H. S. Ashton1, Arti Nanda6, Trefor Jenkins5, Isobel Edelstein5, Andrew P. South1, Oliver Bleck1, Vesarat Wessagowit1, Rajeev Mallipeddi1, Guy E. Orchard2, Hong Wan1, Patricia J. C. Dopping-Hepenstal1, Jemima E. Mellerio1, Neil V. Whittock4, Colin S. Munro7, Maurice A. M. van Steensel8, Peter M. Steijlen8, Jian Ni9, Lurong Zhang10, Takashi Hashimoto3, Robin A. J. Eady1 and John A. McGrath1,+

1Department of Cell and Molecular Pathology and 2Department of Dermatopathology, 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, 3Department of Dermatology, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan, 4Epithelial Genetics Group, Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK, 5Department of Human Genetics, National Health Laboratory Service and School of Pathology, University of the Witwatersrand, PO Box 1038, Johannesburg 2000, South Africa, 6Asad Al-Hamad Dermatology Center, PO Box 6759, 22078 Salmiya, Kuwait, 7Department of Dermatology, South Glasgow University Hospitals NHS Trust, Southern General Hospital, Glasgow G51 4TF, UK, 8Department of Dermatology, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands, 9Human Genome Sciences, 9410 Key West Avenue, Rockville, MD 20850, USA and 10Department of Oncology, Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20007, USA

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 ~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.

+ To whom correspondence should be addressed. Tel: +44 20 79289292; Fax: +44 20 79228175; Email: john.mcgrath@kcl.ac.uk


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