Dupuytren's and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene

• Published in: Cells (Basel, Switzerland) Vol. 6; no. 4; p. 40
• Main Authors: Zaragoza, Michael V, Nguyen, Cecilia H H, Widyastuti, Halida P, McCarthy, Linda A, Grosberg, Anna
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-11-2017; MDPI
• Subjects: arrhythmias; ASTE1 gene; Cardiomyopathy; Clinical aspects; Coronary artery disease; Deoxyribonucleic acid; Disease; DNA; Dupuytren’s disease; Epidermal growth factor; Family studies; Fascia; fibromatosis; genetic susceptibility; Haploinsufficiency; Heart diseases; lamin; Ledderhose disease; LMNA gene; Mutation; Nodules; Plantar flexion; Ribonucleic acid; RNA; ASTE1 gene; fibromatosis; lamin; arrhythmias; Dupuytren’s disease; cardiomyopathy; genetic susceptibility; LMNA gene; Ledderhose disease
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells6040040

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
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
mutation carriers. The proband and six family members were evaluated for the cardiac and hand/feet phenotypes and tested for the
mutation. Fibroblast RNA studies revealed monoallelic expression of the normal
allele and reduced lamin A/C mRNAs consistent with
haploinsufficiency. A novel, heterozygous missense variant (c.230T>C, p.Val77Ala) in the Asteroid Homolog 1 (
) gene was identified as a potential risk factor in fibrotic disease using exome sequencing and family studies of five family members: four
mutation carriers with fibromatosis and one individual without the
mutation and no fibromatosis. With a possible role in epidermal growth factor receptor signaling,
may contribute to the increased risk for palmar/plantar fibromatosis in patients with Lamin A/C haploinsufficiency.