Molecular characterisation of the extracellular matrix protein 1 gene in lipoid proteinosis in South Africa

[摘要] Lipoid proteinosis (LP) (OMIM 247100) is a rare autosomal recessive disorder that iscaused by mutations within the extracellular matrix protein 1 gene (ECM1). The ECM1gene has been shown to play a role in angiogenesis and connective tissue matrixgeneration, especially in skin and bone. The role of ECM1 in normal skin developmentand maintenance is further highlighted by its role in LP and in lichen sclerosis whereautoantibodies are raised against ECM1.LP usually presents in the first year of life with a faint or hoarse cry and is due to ahyaline-like material deposited in the mucous membranes of the vocal cords. Gradually(over years) there is diffuse skin infiltration and general skin thickening with a yellow,waxy appearance. There is excessive scarring with scars often appearing at sites of minorinjury or stress. In many cases, the eyelids show typical beaded papules. In some cases,calcification of certain aspects of the temporal lobes have been observed, and may or maynot be associated with variable neurological, psychiatric and neuropsychologicalsequelae. Although the prevalence of LP in South Africa is unknown, thedisproportionately high number of case reports originating from South Africa indicatesthat LP is unusually common in certain South African populations, most notably theColoured population of Namaqualand and the Afrikaans-speaking White population. Thismay be due to a possible LP founder effect that occurred early during the Europeancolonisation of South Africa.The founder effect was investigated in the South African LP patients by conductingECM1 mutation and linked marker analysis. The data supported a LP founder effect asthe Q276X mutation in exon seven of ECM1 was present in the homozygous state in allLP patients investigated. In addition, the Q276X mutation was associated with a singlefounder haplotype of 19-12-23-22 (ND1-D1S2343-D1S305-D1S2624). These markerswere in significant linkage disequilibrium with each other and with the Q276X mutation.VIAs variation within ECM1 may alter properties of skin such as healing and scarformation, ECM1 exons two through five and the first part of exon six were investigatedfor nucleotide variation using denaturing high performance liquid chromatography(dHPLC) and direct DNA sequencing in three different South African populations. Eightnucleotide variants were identified, of which six were cytosine to thymine transitions.Seven of the eight variants identified were either intronic or synonymous, with onevariant being a missense variant, changing a methionine residue to a threonine residue(T130M).

[发布机构] University of the Witwatersrand