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The Genetic Basis of Dupuytren’s Disease
Gloria R. Sue, Yong Kong, J. Grant Thomson, Carrie R. Swigart, Deepak Narayan.
Yale University, New Haven, CT, USA.

Dupuytren’s contracture (DC) is a common heritable connective tissue disorder characterized by permanent shortening of palmar fascia secondary to fibrosis. The etiology of DC remains largely unknown, though it appears to have a genetic predisposition and is associated with Caucasian populations, older age, the male gender, diabetes, and antiepileptic usage. Given that oxidative stress pathways are associated with DC, we postulated that the mitochondria might be a potential etiologic agent in the development of DC. We sought to evaluate the mitochondrial and nuclear genomes among patients with DC. Additionally, we sought to compare the genomes between diseased tissue and blood to look for potential somatic mutations in the diseased tissue.
Twenty-three patients with DC undergoing open fasciectomy for standard clinical indications were enrolled in this study. Diseased fascia and venous blood samples were collected from enrolled patients. The entire mitochondrial genome and whole nuclear exomes were sequenced for all collected samples and aligned to the reference human genome hg19.
Upon sequencing and subsequent bioinformatics analysis, no differences were observed in the mitochondrial or nuclear genomes when aligning the diseased fascia to the corresponding blood sample. Additionally, when we compared the nuclear genome of our patient cohort to controls, we observed some potentially significant genetic differences. We identified a number of single nucleotide polymorphisms or mutations that are possibly associated with DC. Two novel mutations leading to amino acid changes were present in all patients in the disease cohort but not in controls: these were a T3670P mutation in mucin 4 (MUC4) and a T34S mutation in protein phosphatase 1 regulatory subunit 32 (PPP1R32).
We did not observe any differences in the mitochondrial or nuclear genomes between diseased fascia and venous blood samples that originated from the same patient, suggesting that the acquisition of local somatic mutations in the hand is unlikely to account for the development of DC. We identified genes that warrant further investigation as potential mediators in the pathophysiology of DC.

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