Abstract
Dupuytren’s disease (palmar fibromatosis) involves nodules in fascia of the hand that leads to flexion contractures. Ledderhose disease (plantar fibromatosis) is similar with nodules of the foot. While clinical aspects are well-described, genetic mechanisms are unknown. We report a family with cardiac disease due to a heterozygous LMNA mutation (c.736C>T, p.Gln246Stop) with palmar/plantar fibromatosis and investigate the hypothesis that a second rare DNA variant increases the risk for fibrotic disease in LMNA mutation carriers. The proband and six family members were evaluated for the cardiac and hand/feet phenotypes and tested for the LMNA mutation. Fibroblast RNA studies revealed monoallelic expression of the normal LMNA allele and reduced lamin A/C mRNAs consistent with LMNA haploinsufficiency. A novel, heterozygous missense variant (c.230T>C, p.Val77Ala) in the Asteroid Homolog 1 (ASTE1) gene was identified as a potential risk factor in fibrotic disease using exome sequencing and family studies of five family members: four LMNA mutation carriers with fibromatosis and one individual without the LMNA mutation and no fibromatosis. With a possible role in epidermal growth factor receptor signaling, ASTE1 may contribute to the increased risk for palmar/plantar fibromatosis in patients with Lamin A/C haploinsufficiency.
Highlights
Dupuytren’s disease (DD) or palmar fibromatosis is characterized by abnormal proliferation of fibroblasts in the palmar fascia and leads to progressive and disabling contractures of the fingers [1].Initially, a palmar nodule is observed which is followed by cord formation as the disease progresses.Disease pathogenesis is complex and involves activation of fibroblasts to myofibroblasts, production of several profibrotic cytokines including transforming growth factor beta 1 (TGF-beta1), transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF), dysregulation of signaling pathways including mitogen-activated protein kinase (MAPK), Akt, and Wnt/beta-catenin signaling pathways, and increased extracellular matrix proteins including collagen I and III [2]
LMNA mutation in a mouse model was associated with increased MAPK activity in response to stress that resulted in aberrant expression of target genes and with decreased Wnt/beta-catenin activity that supports the involvement of both signaling in the pathogenesis for lamin-cardiomyopathy [15,17]
These findings suggest that both palmar and plantar fibromatosis could be a part of the primary laminopathy phenotype, extra-cardiac features with clinical variability
Summary
Dupuytren’s disease (DD) or palmar fibromatosis is characterized by abnormal proliferation of fibroblasts in the palmar fascia and leads to progressive and disabling contractures of the fingers [1].Initially, a palmar nodule is observed which is followed by cord formation as the disease progresses.Disease pathogenesis is complex and involves activation of fibroblasts to myofibroblasts, production of several profibrotic cytokines including transforming growth factor beta 1 (TGF-beta1), transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF), dysregulation of signaling pathways including mitogen-activated protein kinase (MAPK), Akt, and Wnt/beta-catenin signaling pathways, and increased extracellular matrix proteins including collagen I and III [2]. Dupuytren’s disease (DD) or palmar fibromatosis is characterized by abnormal proliferation of fibroblasts in the palmar fascia and leads to progressive and disabling contractures of the fingers [1]. A palmar nodule is observed which is followed by cord formation as the disease progresses. Disease pathogenesis is complex and involves activation of fibroblasts to myofibroblasts, production of several profibrotic cytokines including transforming growth factor beta 1 (TGF-beta1), transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF), dysregulation of signaling pathways including mitogen-activated protein kinase (MAPK), Akt, and Wnt/beta-catenin signaling pathways, and increased extracellular matrix proteins including collagen I and III [2]. Cells 2017, 6, 40 fibromatosis is a rarer disease that affects the plantar fascia as nodules and cords formed along the tendons of the foot, which can lead to painful walking or standing with disease progression [4,5,6].
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