Mutations in the ARAP3 Gene in Three Families with Primary Lymphedema Negative for Mutations in Known Lymphedema-Associated Genes

Maurizio Ricci; Rita Compagna; Bruno Amato; Sercan Kenanoglu; Dominika Veselenyiova; Danjela Kurti; Mirko Baglivo; Syed Hussain Basha; Roberta Serrani; Giacinto Abele Donato Miggiano; Barbara Aquilanti; Giuseppina Matera; Giuseppe Marceddu; Valeria Velluti; Lucilla Gagliardi; Munis Dundar; Juraj Krajcovic; Matteo Bertelli

doi:10.1155/2020/3781791

Mutations in the ARAP3 Gene in Three Families with Primary Lymphedema Negative for Mutations in Known Lymphedema-Associated Genes

Int J Genomics. 2020 Aug 25:2020:3781791. doi: 10.1155/2020/3781791. eCollection 2020.

Authors

Maurizio Ricci¹, Rita Compagna², Bruno Amato³, Sercan Kenanoglu^{4

5}, Dominika Veselenyiova^{5

6}, Danjela Kurti^{5

7}, Mirko Baglivo⁵, Syed Hussain Basha⁸, Roberta Serrani¹, Giacinto Abele Donato Miggiano^{9

10}, Barbara Aquilanti⁹, Giuseppina Matera⁹, Giuseppe Marceddu⁵, Valeria Velluti⁹, Lucilla Gagliardi⁹, Munis Dundar⁴, Juraj Krajcovic⁶, Matteo Bertelli^{5

11

12}

Affiliations

¹ Division of Rehabilitation Medicine, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Italy.
² Department of Public Health, University of Naples Federico II, Naples, Italy.
³ Department of General and Geriatric Surgery, University of Naples "Federico II", Naples, Italy.
⁴ Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
⁵ MAGI Euregio, Bolzano, Italy.
⁶ Department of Biology, Faculty of Natural Sciences, University of Ss. Cyril and Methodius in Trnava, Trnava, Slovakia.
⁷ MAGI-Balkan, Tirana, Albania.
⁸ Innovative Informatica Technologies, Hyderabad, India.
⁹ UOC Nutrizione Clinica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
¹⁰ Centro di Ricerche in Nutrizione Umana, Università Cattolica Sacro Cuore, Rome, Italy.
¹¹ EBTNA-Lab, Rovereto, Italy.
¹² MAGI's Lab, Rovereto, Italy.

Abstract

Background: ARAP3 is a small GTPase-activating protein regulator, which has important functions in lymphatic vessel organogenesis and modulation of cell adhesion and migration. Mutations in the ARAP3 gene are associated with impaired lymphatic vessel formation.

Objective: The aim of our study was to determine the genotypes of lymphedema patients in relation to variants in the ARAP3 gene in order to explore its role in the development of lymphedema.

Methods and results: We applied next-generation sequencing to DNA samples of a cohort of 246 Italian patients with lymphatic malformations. When we tested probands for known lymphedema genes, 235 out of 246 were negative. Retrospectively, we tested the DNA of these 235 patients for new candidate lymphedema-associated genes, including ARAP3. Three out of 235 probands proved to carry rare missense heterozygous variants in ARAP3. In the case of two families, other family members were also tested and proved negative for the ARAP3 variant, besides being unaffected by lymphedema. According to in silico analysis, alterations due to these variants have a significant impact on the overall structure and stability of the resulting proteins.

Conclusions: Based on our results, we propose that variants in ARAP3 could be included in genetic testing for lymphedema.