Evaluation of a mitochondrial DNA mutation in maternally inherited and sporadic cases of Dupuytren disease.

Dupuytren disease (DD) is a progressive and irreversible fibrosis of the palmar fascia of the hand. The fibrotic process begins with palmar nodules followed by rope-like cord formation that over time produces progressive contraction of the digits at the metacarpalphalangeal and proximal interphalangeal joints. The ring finger is most frequently affected, followed by the small, thumb, long, and index fingers. The symptoms are usually unilateral but may progress to bilateral disease.1,2 In some patients, the subsequent flexion deformities of the hand severely limit the ability to perform normal activities and negatively impact quality of life. In Caucasians, DD is considered one of the most common hereditary connective tissue disorders, predominantly affecting individuals of Northern European descent. Approximately 40% of DD patients have an affected relative based on several familial aggregation studies.2 Prevalence of DD in the United States ranges from 0.5% to 11%, with the annual number of new cases of physician-diagnosed DD in the year 2007 estimated at 3 per 10,000.1 Most patients diagnosed with DD are over age 60, and men are affected 3 to 5 times more often than women.1–3 Currently, there is no cure for DD, and treatment options include open excision of the diseased fascia, percutaneous needle fasciotomy, and injections with steroids or collagenase.1,3 However, these treatment options are associated with risk of neurovascular injury and have recurrence rates between 8%–66%, depending on the treatment and severity of disease.3 The potential for recurrence underscores the inability of current treatments to target the underlying pathology as the etiology of disease is not completely understood. We do know that environmental factors such as alcohol consumption, tobacco use, repeated hand injuries, diabetes, and epilepsy have been associated with DD.1–3 These factors are thought to play a role in the cellular trauma and ischemia that result in tissue inflammation and fibrosis seen in DD. The process by which cellular transformation occurs, and to what degree, remains unknown. The primary cell type involved in DD is the myofibroblast, and its direct interaction with the extracellular matrix of collagen is linked to the development of DD.2,4 Studies have shown that growth factors such as transforming growth factor beta (TGF-β) and epidermal growth factor (EGF) can stimulate excess myofibroblast activity and fascial contraction in DD.4,5 Cell adhesion glycoproteins like fibronectins and catenins (ie, β-catenin) are modified and/or over-expressed.4 Additionally, extracellular proteins of the metalloproteinase family exhibit many dysfunctions responsible for collagenic proliferation.4 The genetic mode of DD inheritance appears to be heterogeneous, and mostly autosomal dominant with variable penetrance.2,3,6 Numerous genetic studies have been performed in order to more clearly understand the genetic basis of disease. These studies have shown an association of DD with regions of chromosomes 6, 11, and 16, alterations in copy number and structure of chromosomes, and a possible linkage with the DUPC1 locus at 16q.2 Other studies have identified several candidate genes associated with DD, including MafB, MMPs, TGF-β, ADAM 12, POSTN, TNC, ADAMTS3, BMP5, ALDH1A1, IRX6, PRG4, PDGF-B, and C-MYC.4,7–13 It has also been suggested that given the role of mitochondria in cellular metabolism and apoptosis, a mutation in mitochondrial DNA may have a role in the development of DD.6 Normally, mitochondria produce the majority of cellular ATP and generate physiologically appropriate levels of reactive oxygen species (ROS), which are further moderated by antioxidant enzymes. As tissues age and/or become diseased, mitochondrial function becomes impaired and increased levels of ROS are generated while antioxidant enzyme activities and ATP production decrease.6,14 Mitochondrial DNA is more susceptible to damage than nuclear DNA due to a lack of protective histones, limited DNA repair capacity, lack of introns, and its exposure to ROS.14 Additionally, mutations in mitochondrial DNA have been shown to accumulate with age. These mutations can induce nuclear stress signaling pathways leading to decreased energy production, increased ROS, deleterious protein modifications, abnormal phenotypic changes, apoptosis, and even more mutations.6,15,16 A combination of mitochondrial DNA mutations and increased levels of ROS could lead to the over expression of TGF-β leading to excess myofibroblast activity, fascial contraction, and DD.6 Mitochondrial DNA and ROS also play roles in the regulation of apoptosis. Increased levels of ROS trigger mitochondrial-mediated apoptosis, and mutated mitochondrial DNA can alter the regulation of apoptosis.6,17 Compared to normal tissue, DD tissue contains larger numbers of myofibroblasts, which in turn contain abnormally high numbers of mitochondria as confirmed by electron microscopy.2,6 This situation allows more opportunity for increased levels of ROS and potential for mitochondrial DNA mutations. Pursuing the role(s) that mitochondrial DNA may play in the development of DD, a group of researchers was able to identify a previously unknown heteroplasmic mutation within the 16s rRNA region of the mitochondrial genome. Using a multiplex denaturing high-performance liquid chromatography technique, the mutation at position C2839A was present in 90% of their subjects with maternally inherited DD and 0% of controls.6 In the present study, we tested the hypothesis that DD is associated with the reported mitochondrial mutation by analyzing the DNA of those with and without a familial pattern of DD. Validating the results of the prior study and finding the mutation in sporadic cases of DD could further our understanding of the disease.