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.

Development of antigen-specific ELISA for circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus

“…The rationale for ECM1 as a target antigen in lichen sclerosus is supported by the recent identification of pathogenic mutations in the ECM1 gene in an inherited autosomal recessive skin disorder, lipoid proteinosis (OMIM 247100) (14). Histology of skin in this genetic condition shows considerable overlap with skin biopsy findings in lichen sclerosus, including disruption of basement membrane and hyaline (glassy) changes in the upper dermis (11,14,15). From a clinicopathologic perspective, disruption of ECM1 function by acquired autoantibodies or inherited gene mutations appears to contribute significantly to the disease pathology in lichen sclerosus or lipoid proteinosis, respectively.…”

Lipoid proteinosis of the larynx in siblings: exploring new modalities of treatment

“…There is an increase in type IV collagen with a decrease in type I collagen. The defect is mapped to chromosome 1q21 [6].…”

Síndrome de Urbach-Wiethe: relato de caso

“…Este material é composto por ácido hialurônico e colesterol. Estudo realizado com vários pacientes na África do Sul identificou como responsável pela doença a mutação homozigótica Q276X no exon 7 do gene ECM1 (extracellular matrix protein 1 (10,12) ). O papel do gene ECM1 na pele de humanos não está esclarecido (13) , entretanto, na epiderme, pode ter reduplicação da lâmina basal perivascular sugere aumento da produção de colágenos tipos IV e V pelas células endoteliais vasculares e tipos I e II pelos fibroblastos.…”