Cargando…

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

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 cardi...

Descripción completa

Detalles Bibliográficos
Autores principales: Zaragoza, Michael V., Nguyen, Cecilia H. H., Widyastuti, Halida P., McCarthy, Linda A., Grosberg, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753070/
https://www.ncbi.nlm.nih.gov/pubmed/29104234
http://dx.doi.org/10.3390/cells6040040
_version_ 1783290199701192704
author Zaragoza, Michael V.
Nguyen, Cecilia H. H.
Widyastuti, Halida P.
McCarthy, Linda A.
Grosberg, Anna
author_facet Zaragoza, Michael V.
Nguyen, Cecilia H. H.
Widyastuti, Halida P.
McCarthy, Linda A.
Grosberg, Anna
author_sort Zaragoza, Michael V.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5753070
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-57530702018-01-07 Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene Zaragoza, Michael V. Nguyen, Cecilia H. H. Widyastuti, Halida P. McCarthy, Linda A. Grosberg, Anna Cells Article 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. MDPI 2017-11-01 /pmc/articles/PMC5753070/ /pubmed/29104234 http://dx.doi.org/10.3390/cells6040040 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zaragoza, Michael V.
Nguyen, Cecilia H. H.
Widyastuti, Halida P.
McCarthy, Linda A.
Grosberg, Anna
Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene
title Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene
title_full Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene
title_fullStr Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene
title_full_unstemmed Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene
title_short Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene
title_sort dupuytren’s and ledderhose diseases in a family with lmna-related cardiomyopathy and a novel variant in the aste1 gene
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753070/
https://www.ncbi.nlm.nih.gov/pubmed/29104234
http://dx.doi.org/10.3390/cells6040040
work_keys_str_mv AT zaragozamichaelv dupuytrensandledderhosediseasesinafamilywithlmnarelatedcardiomyopathyandanovelvariantintheaste1gene
AT nguyenceciliahh dupuytrensandledderhosediseasesinafamilywithlmnarelatedcardiomyopathyandanovelvariantintheaste1gene
AT widyastutihalidap dupuytrensandledderhosediseasesinafamilywithlmnarelatedcardiomyopathyandanovelvariantintheaste1gene
AT mccarthylindaa dupuytrensandledderhosediseasesinafamilywithlmnarelatedcardiomyopathyandanovelvariantintheaste1gene
AT grosberganna dupuytrensandledderhosediseasesinafamilywithlmnarelatedcardiomyopathyandanovelvariantintheaste1gene