Dupuytren's and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene - PubMed (original) (raw)

Michael V Zaragoza et al. Cells. 2017.

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.

Keywords: ASTE1 gene; Dupuytren’s disease; LMNA gene; Ledderhose disease; arrhythmias; cardiomyopathy; fibromatosis; genetic susceptibility; lamin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Pedigree: _LMNA_-related cardiac disease, Dupuytren’s disease (DD), and Ledderhose disease (LD). Squares denote males and circles females with current age below. Short horizontal lines mark individuals consented in the study. Diagonal lines indicate deceased individuals with age of death (d). The proband (IV-2) is designated with an arrow. Complete-filled symbols indicate cardiac disease (cardiomyopathy, arrhythmia or sudden death), Dupuytren’s disease, and Ledderhose disease. Left half-filled indicate only cardiac disease and right half-filled symbols indicate only Dupuytren’s disease (upper right) or only Ledderhose disease (lower right). Individuals with unknown or unconfirmed clinical status are noted with a question mark. The presence (+) or absence (−) of the LMNA c.736C>T (p.Gln246Stop) is provided. One additional family member (Patient 3) was removed after consent to publish was declined.

Figure 2

Figure 2

Dupuytren’s and Ledderhose disease. Photographs: (top panel) right hand, left hand, and left foot of the aunt (III-4), (bottom panel, left-middle) right hand and feet of the proband (IV-2) and (bottom panel, right) left foot of the sister (IV-3) with skin tethering/puckering or dimpling (white arrows), cord formation (yellow arrows), and central medial plantar nodules (black arrows). An image from one additional family member (Patient 3) was removed after consent to publish was declined.

Figure 3

Figure 3

LMNA c.736C>T (p.Gln246Stop). Top panel shows the Sanger sequencing chromatograms: normal allele for unaffected individuals and heterozygous mutation for affected individuals. Bottom panel depicts the location of the nonsense mutation and two expressed polymorphisms rs538089 (c.861T>C, Ala287Ala) and rs505058 (c.1338T>C, Asp446Asp) in the mRNA and Lamin A/C protein.

Figure 4

Figure 4

Expression analysis of LMNA in patient and control fibroblasts. (a) Electrophoresis: cDNA fragment analysis of LMNA mRNA (Exon 1–4, Exon 1–10, and Exon 10–11) for fibroblasts from two unaffected family members: C1 (IV-5) and C2 (IV-1) (HOM Normal: lanes 1–2), four patients: P1 (IV-4), P2 (IV-3), P3 and P4 (III-4) (HET Mutation: lanes 3–6), and an unrelated control (lane 7). Genomic DNA served as a negative control (lane 8). Only the expected products were observed with cDNA amplification (lanes 1–7): 898 bp for Exon 1–4, 1886 bp for Exon 1–10, and 297 bp for Exon 10–11. No products were observed with gDNA amplification (lane 8) for Exon 1–4 and Exon 1–10. For Exon 10–11, the expected 1041 bp product was observed with gDNA (lane 8) and was absent with cDNA amplification (lanes 1–7); (b) Allelic Expression: Sanger sequencing chromatograms from genomic DNA and cDNA for control C1 (IV-5) and patient P4 (III-4). For control fibroblasts, biallelic expression (C/T) in the cDNA and heterozygosity for C/T in the genomic DNA is shown at variants rs538089 in exon 5 and rs505058 in exon 7. In contrast, detection of only the normal C allele at the mutation site in exon 4 and single C alleles at rs538089 and rs505058 demonstrates monoallelic expression for patient fibroblasts; (c) Lamin A/C transcript quantification: RT-qPCR results from patient and control cDNA measuring the relative transcript level of Lamin A and Lamin C. Results shown are the mean transcript levels ± error (SEM) of patient: P1 (IV-4), P2 (IV-3) and control: C1 (IV-5) and C2 (IV-1). For both Lamin A and C, there is a significant reduction of transcribed mRNA in patient fibroblasts compared to control fibroblasts (n = 6, ** p < 0.05).

Figure 5

Figure 5

Whole Exome Sequencing (WES) Studies and Variant Sharing of Four Family Members to Identify Candidate Variants in DD and LD. Diagram provided to represent the total number of potentially deleterious variants found in the three affected individuals: 1677 variants for III-4, 1681 variants for IV-3, and 1815 variants for Patient 3 (red circles) and the one unaffected individual: 1,761 variants for IV-1 (green circle). For the affected individuals, the central overlapping region represents the shared variants (n = 275). When compared to the variants of the unaffected individual, 177 shared variants (overlapping region) were excluded and 98 unshared variants (non-overlapping region) were identified as candidates in DD and LD.

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