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Current Research into the Pathogenesis and Treatment Prospects for Primary...
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Current Research into the Pathogenesis and Treatment Prospects for Primary Lymphedema

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (25 June 2021) | Viewed by 9137

Special Issue Editor

Dr. Paolo Enrico Maltese

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Guest Editor
MAGI's Lab, 38068 Rovereto, Italy

Special Issue Information

Dear Colleagues,

Primary lymphedema (PL) is a chronic disabling condition that results in the swelling of the extremities due to altered lymphatic flow. It is more frequent in the lower limbs but can also affect the arms, face and genitalia. Patients are susceptible to recurrent local infections and physical impairment. The disorder can appear at birth or later in life, may be familial or sporadic, and may manifest as an isolated trait or as part of a syndrome. There is always a genetic cause, which may have Mendelian inheritance. Today, we know that mutations in most of the genes involved in the regulation of lymphangiogenesis can lead to lymphedema. Since a genetic diagnosis can only be reached in 15–20% of patients, we clearly do not know all the genes that govern the disorder and our understanding of its molecular pathogenesis is still far from complete. This phenotypic and genetic heterogeneity has made treatment difficult, especially gene therapy. Indeed, the few research studies in the literature are nearly all pre-clinical.

Basic research, aimed at understanding the genetic-molecular mechanisms of the disease, is essential for timely diagnosis and the development of targeted therapies that could offer hope to patients with this incapacitating disease.

For this Special Issue, we are calling for reviews, mini-reviews and research articles focusing on the wider aspects of lymphedema genetics, from pathogenic mechanisms to new therapeutic approaches, including genetic epidemiology, genetic screening, case reports and case series that make a substantial contribution to the literature, as well as experimental studies on new treatments.

Dr. Paolo Enrico Maltese
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Lymphedema
  • Molecular testing
  • Genetic screening
  • Next-generation sequencing
  • Genotype–phenotype correlations
  • Gene therapy
  • Targeted therapies

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Published Papers (3 papers)

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9 pages, 1268 KiB  
Article
FLT4 Mutations Are Associated with Segmental Lymphatic Dysfunction and Initial Lymphatic Aplasia in Patients with Milroy Disease
by Ningfei Liu and Minzhe Gao
Genes 2021, 12(10), 1611; https://doi.org/10.3390/genes12101611 - 13 Oct 2021
Cited by 9 | Viewed by 2706
Abstract
This study explored mutations in the Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of [...] Read more.
This study explored mutations in the Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of MD, while 13 patients exhibited sporadic MD. Clinical signs, FLT4 mutations, indocyanine green (ICG) lymphography findings, and skin tissue immunohistochemical staining results were evaluated. Twenty-eight variants in FLT4 were identified. Twelve of these have previously been reported, while 16 are novel. Of the 28 variants, 26 are missense mutations, and the remaining two comprise a splicing mutation and a non-frame shift mutation. Twenty-five variants are located in the intracellular protein tyrosine kinase domain; three are located in the extracellular immunoglobulin domain. Substantially delayed contrast-enhanced tortuous lymphatic vessels were visualized to the ankle or knee level in 15 of 23 patients who underwent ICG lymphography. No initial lymphatic vessels were visualized in skin specimens from four patients who did not exhibit lymphatic vessels during imaging analyses. No specific variant was identified in relation to the unique clinical phenotype. Segmental dysfunction of lymphatic vessels and initial lymphatic aplasia are present in MD patients with FLT4 mutations. Full article
(This article belongs to the Special Issue Current Research into the Pathogenesis and Treatment Prospects for Primary Lymphedema)
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13 pages, 16761 KiB  
Article
Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift Mutations
by Sara Missaglia, Daniela Tavian, Sandro Michelini, Paolo Enrico Maltese, Andrea Bonanomi and Matteo Bertelli
Genes 2021, 12(5), 650; https://doi.org/10.3390/genes12050650 - 27 Apr 2021
Cited by 6 | Viewed by 2674
Abstract
Forkhead-box C2 (FOXC2) is a transcription factor involved in lymphatic system development. FOXC2 mutations cause Lymphedema-distichiasis syndrome (LD). Recently, a natural antisense was identified, called lncRNA FOXC2-AS1, which increases FOXC2 mRNA stability. No studies have evaluated FOXC2 and FOXC2-AS1 blood expression in LD [...] Read more.
Forkhead-box C2 (FOXC2) is a transcription factor involved in lymphatic system development. FOXC2 mutations cause Lymphedema-distichiasis syndrome (LD). Recently, a natural antisense was identified, called lncRNA FOXC2-AS1, which increases FOXC2 mRNA stability. No studies have evaluated FOXC2 and FOXC2-AS1 blood expression in LD and healthy subjects. Here, we show that FOXC2 and FOXC-AS1 expression levels were similar in both controls and patients, and a significantly higher amount of both RNAs was observed in females. A positive correlation between FOXC2 and FOXC2-AS1 expression was found in both controls and patients, excluding those with frameshift mutations. In these patients, the FOXC2-AS1/FOXC2 ratio was about 1:1, while it was higher in controls and patients carrying other types of mutations. The overexpression or silencing of FOXC2-AS1 determined a significant increase or reduction in FOXC2 wild-type and frameshift mutant proteins, respectively. Moreover, confocal and bioinformatic analysis revealed that these variations caused the formation of nuclear proteins aggregates also involving DNA. In conclusion, patients with frameshift mutations presented lower values of the FOXC2-AS1/FOXC2 ratio, due to a decrease in FOXC2-AS1 expression. The imbalance between FOXC2 mRNA and its lncRNA could represent a molecular mechanism to reduce the amount of FOXC2 misfolded proteins, protecting cells from damage. Full article
(This article belongs to the Special Issue Current Research into the Pathogenesis and Treatment Prospects for Primary Lymphedema)
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17 pages, 3896 KiB  
Article
Segregation Analysis of Rare NRP1 and NRP2 Variants in Families with Lymphedema
by Sandro Michelini, Bruno Amato, Maurizio Ricci, Sercan Kenanoglu, Dominika Veselenyiova, Danjela Kurti, Mirko Baglivo, Elena Manara, Munis Dundar, Juraj Krajcovic, Syed Hussain Basha, Sasi Priya, Roberta Serrani, Giacinto A. D. Miggiano, Barbara Aquilanti, Giuseppina Matera, Valeria Velluti, Lucilla Gagliardi, Astrit Dautaj and Matteo Bertelli
Genes 2020, 11(11), 1361; https://doi.org/10.3390/genes11111361 - 17 Nov 2020
Cited by 4 | Viewed by 3176
Abstract
Neuropilins are transmembrane coreceptors expressed by endothelial cells and neurons. NRP1 and NRP2 bind a variety of ligands, by which they trigger cell signaling, and are important in the development of lymphatic valves and lymphatic capillaries, respectively. This study focuses on identifying rare [...] Read more.
Neuropilins are transmembrane coreceptors expressed by endothelial cells and neurons. NRP1 and NRP2 bind a variety of ligands, by which they trigger cell signaling, and are important in the development of lymphatic valves and lymphatic capillaries, respectively. This study focuses on identifying rare variants in the NRP1 and NRP2 genes that could be linked to the development of lymphatic malformations in patients diagnosed with lymphedema. Two hundred and thirty-five Italian lymphedema patients, who tested negative for variants in known lymphedema genes, were screened for variants in NRP1 and NRP2. Two probands carried variants in NRP1 and four in NRP2. The variants of both genes segregated with lymphedema in familial cases. Although further functional and biochemical studies are needed to clarify their involvement with lymphedema and to associate NRP1 and NRP2 with lymphedema, we suggest that it is worthwhile also screening lymphedema patients for these two new candidate genes. Full article
(This article belongs to the Special Issue Current Research into the Pathogenesis and Treatment Prospects for Primary Lymphedema)
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