RESUMEN
SVEP1, also known as Polydom, is a large extracellular mosaic protein with functions in protein interactions and adhesion. Since Svep1 knockout animals show severe edema and lymphatic system malformations, the aim of this study is to evaluate the presence of SVEP1 variants in patients with lymphedema. We analyzed DNA from 246 lymphedema patients for variants in known lymphedema genes, 235 of whom tested negative and underwent a second testing for new candidate genes, including SVEP1, as reported here. We found three samples with rare heterozygous missense single-nucleotide variants in the SVEP1 gene. In one family, healthy members were found to carry the same variants and reported some subclinical edema. Based on our findings and a review of the literature, we propose SVEP1 as a candidate gene that should be sequenced in patients with lymphatic malformations, with or without lymphedema, in order to investigate and add evidence on its possible involvement in the development of lymphedema.
Asunto(s)
Anomalías Linfáticas , Linfedema , Moléculas de Adhesión Celular , Humanos , Linfangiogénesis/genética , Anomalías Linfáticas/diagnóstico , Anomalías Linfáticas/genética , Sistema Linfático/metabolismo , Linfedema/diagnóstico , Linfedema/genética , Linfedema/metabolismo , MorfogénesisRESUMEN
PECAM1 is a member of the immunoglobulin superfamily and is expressed in monocytes, neutrophils, macrophages and other types of immune cells as well as in endothelial cells. PECAM1 function is crucial for the development and maturation of B lymphocytes. The aim of this study was to link rare PECAM1 variants found in lymphedema patients with the development of lymphatic system malformations. Using NGS, we previously tested 246 Italian lymphedema patients for variants in 29 lymphedema-associated genes and obtained 235 negative results. We then tested these patients for variants in the PECAM1 gene. We found three probands with rare variants in PECAM1. All variants were heterozygous missense variants. In Family 1, the unaffected mother and brother of the proband were found to carry the same variant as the proband. Lymphoscintigraphy was performed to determine possible lymphatic malformations and showed that in both cases a bilateral slight reduction in the speed and lymphatic clearance of the lower limbs. PECAM1 function is important for lymphatic vasculature formation. We found variants in PECAM1 that may be associated with susceptibility to lymphedema.
Asunto(s)
Variación Genética , Linfedema/diagnóstico , Linfedema/etiología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Familia , Pruebas Genéticas , Heterocigoto , Humanos , Anomalías Linfáticas/diagnóstico , Anomalías Linfáticas/genética , Linfocintigrafia , Mutación MissenseRESUMEN
SEMA3A is a semaphorin involved in cell signaling with PlexinA1 and Neuropilin-1 (NRP1) receptors and it is responsible for recruiting dendritic cells into lymphatics. Mutations in the SEMA3A gene result in abnormalities in lymphatic vessel development and maturation. We investigated the association of SEMA3A variants detected in lymphedema patients with lymphatic maturation and lymphatic system malfunction. First, we used NGS technology to sequence the SEMA3A gene in 235 lymphedema patients who carry wild type alleles for known lymphedema genes. We detected three different missense variants in three families. Bioinformatic results showed that some protein interactions could be altered by these variants. Other unaffected family members of the probands also reported different episodes of subclinical edema. We then evaluated the importance of the SEMA3A gene in the formation and maturation of lymphatic vessels. Our results determined that SEMA3A variants segregate in families with lymphatic system malformations and recommend the inclusion of SEMA3A in the gene panel for testing of patients with lymphedema.
Asunto(s)
Linfangiogénesis/genética , Vasos Linfáticos/metabolismo , Linfedema/etiología , Linfedema/metabolismo , Semaforina-3A/genética , Animales , Biología Computacional/métodos , Susceptibilidad a Enfermedades , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Linfedema/diagnóstico , Semaforina-3A/metabolismoRESUMEN
CYP26B1 is a member of the cytochrome P450 family and is responsible for the break-down of retinoic acid for which appropriate levels are important for normal development of the cardiovascular and lymphatic systems. In a cohort of 235 patients with lymphatic malformations, we performed genetic testing for the CYP26B1 gene. These probands had previously tested negative for known lymphedema genes. We identified two heterozygous missense CY-P26B1 variants in two patients. Our bioinformatic study suggested that alterations caused by these variants have no major effect on the overall stability of CYP26B1 protein structure. Balanced levels of retinoic acid maintained by CYP26B1 are crucial for the lymphatic system. We identified that CYP26B1 could be involved in predisposition for lymphedema. We propose that CYP26B1 be further explored as a new candidate gene for genetic testing of lymphedema patients.
Asunto(s)
Linfangiogénesis , Linfedema/patología , Mutación Missense , Ácido Retinoico 4-Hidroxilasa/genética , Femenino , Humanos , Linfedema/genética , Linfedema/metabolismo , Persona de Mediana Edad , Pronóstico , Conformación Proteica , Ácido Retinoico 4-Hidroxilasa/química , Ácido Retinoico 4-Hidroxilasa/metabolismoRESUMEN
OBJECTIVE: To summarize the latest information on the relationship between genes and common forms of obesity, and to review genetic markers (SNPs and miRNA) that play a role in predisposing to common forms of obesity and related disorders. MATERIALS AND METHODS: We searched PubMed with the following keywords: (obesity[Title/Abstract]) AND predisposition[Title/Abstract]) AND miRNA[Title/Abstract]) OR polymorphism[Title/Abstract]. RESULTS: From the search we obtained a total of 44 gene loci and 48 miRNAs associated with common obesity. CONCLUSIONS: It is now widely accepted that obesity involves interactions between environmental risk factors (physical inactivity, excessive calorie intake, chronic stress, taste perception) and a genetic background of risk. Analysis of the genetic background of obese subjects is therefore an important way to determine the molecular mechanisms controlling the link between food intake and obesity, enabling a better understanding of how these interactions may differ from person to person.