Genetics of Dupuytren's disease
ABSTRACT Dupuytren's disease (DD) is a progressive fibrosis of the palmar fascia characterized by the formation of a nodule, which evolves into a cord. DD is the most common hereditary disease of the connective tissue preferentially affecting Caucasoids originating from Northern Europe. Some environmental factors are associated with DD, namely alcohol consumption, tobacco exposure and, possibly, manual activities. Diabetes and epilepsy are the most frequently reported DD-associated diseases. The genetic mode of inheritance is not well understood, but seems to be heterogeneous: most frequently, autosomal dominant with variable penetrance, and rarely recessive autosomal or maternal (matrilinear), suggesting a mitochondrial heredity. Initially, a suggestion of linkage with the DUPC1 locus at 16q was proposed. Then, among the genomic variations observed in DD, alterations in the copy number of genes in chromosomal regions 10q22, 16p12.1 and 17p12, associations with the HLA-DRB1*15 allele and a mutation in the rRNA 16s identified in forms with a matrilinear heredity, were reported. Finally, a genome-wide study has shown a genetic association of DD with 6, 11 and 16 chromosomes. Pathophysiology of DD involves mainly myofibroblasts and the extracellular matrix of collagen. Gene and protein expression studies have confirmed the central role of the β catenin of the TGFβ pathways in the pathogenesis of DD.
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- "Risk factors include age, sex, alcohol and tobacco intake, trauma, diabetes, epilepsy and hyperlipidaemia . The disease is often familial but the mode of inheritance is currently unknown . A recent genome wide association study highlighted loci relevant to the Wnt signaling pathway as involved in the genetic susceptibility to Dupuytren's disease . "
ABSTRACT: Dupuytren's disease (DD) is a common fibrotic condition of the palmar fascia, leading to deposition of collagen-rich cords and progressive flexion of the fingers. The molecular mechanisms underlying the disease are poorly understood. We have previously shown altered expression of extracellular matrix-degrading proteases (matrix metalloproteases, MMPs, and 'a disintegrin and metalloprotease domain with thrombospondin motifs', ADAMTS, proteases) in palmar fascia from DD patients compared to control and shown that the expression of a sub-set of these genes correlates with post-operative outcome. In the current study we used an in vitro model of collagen contraction to identify the specific proteases which mediate this effect. We measured the expression of all MMPs, ADAMTSs and their inhibitors in fibroblasts derived from the palmar fascia of DD patients, both in monolayer culture and in the fibroblast-populated collagen lattice (FPCL) model of cell-mediated contraction. Key proteases, previously identified in our tissue studies, were expressed in vitro and regulated by tension in the FPCL, including MMP1, 2, 3, 13 and 14. Knockdown of MMP2 and MMP14 (but not MMP1, 3 and 13) inhibited cell-mediated contraction, and knockdown of MMP14 inhibited proMMP-2 activation. Interestingly, whilst collagen is degraded during the FPCL assay, this is not altered upon knockdown of any of the proteases examined. We conclude that MMP-14 (via its ability to activate proMMP-2) and MMP-2 are key proteases in collagen contraction mediated by fibroblasts in DD patients. These proteases may be drug targets or act as biomarkers for disease progression.Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 02/2012; 1822(6):897-905. DOI:10.1016/j.bbadis.2012.02.001 · 5.09 Impact Factor
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ABSTRACT: The natural history of Dupuytren's disease in the severe initial affections leads to less satisfactory results after surgery, than they should be and to high rate of recurrences in the long-term follow-up. Our purpose,in reviewing 97 patients treated by a Bruner and Skoog approches with a 6 years of mean follow- up,was to evaluate rate and factors of recurrences. We had 32% true recurrences, 36% extensions and 13% scar retractions. Some factors had a negative effect on final results,favouring the recurrences:early age of onset,family history of Du- puytren'disease,epilepsy, smoke and alcohol and the PIP contracture of the small finger. The authors stress the value of the prevention of the recurrences trough earlier surgery on potentially severe and ag- gressive cases .The non-operative treatment using percutaneous Callagenase can represent the future but at present it needed of long-term follow-up.. Riv Chir Mano 2001; 38: 209-218
Article: Dupuytren's diseaseThe Bone & Joint Journal 06/2003; 85(4):469-77. DOI:10.1302/0301-620X.85B4.14215 · 2.80 Impact Factor