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DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology.
D'Apolito, Maria; Santacroce, Rosa; Vazquez, Daniel Osvaldo; Cordisco, Giorgia; Fantini, Claudio Agustin; D'Andrea, Giovanna; Leccese, Angelica; Colia, Anna Laura; Martinez, Pablo; Zanichelli, Andrea; Josviack, Darío; Margaglione, Maurizio.
Afiliação
  • D'Apolito M; Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
  • Santacroce R; Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
  • Vazquez DO; Clinica Privada Monte Grande, Servicio de Alergia, Buenos Aires, Argentina.
  • Cordisco G; Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
  • Fantini CA; HIGA Oscar Alende, Unidad de Alergia e Immunologia, Mar del Plata, Buenos Aires, Argentina.
  • D'Andrea G; Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
  • Leccese A; Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
  • Colia AL; Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
  • Martinez P; Universidad Nacional del Sur, Argentina Hospital Penna de Bahia Blanca, Bahia Blanca, Argentina.
  • Zanichelli A; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy; Operative Unit of Medicine, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, San Donato Milanese, Milan, Italy.
  • Josviack D; Instituto de Medicina Respiratoria, Rafaela, Santa Fe, Argentina.
  • Margaglione M; Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy. Electronic address: maurizio.margaglione@unifg.it.
Article em En | MEDLINE | ID: mdl-38823490
ABSTRACT

BACKGROUND:

In the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified.

OBJECTIVES:

To identify new genetic targets associated with HAE, a large Argentine family with HAE-UNK spanning 3 generations was studied.

METHODS:

Whole exome sequencing was performed on affected family members to identify potential genetic variants associated with HAE-UNK. In silico analyses and experimental studies were applied to assess the role of the identified gene variant.

RESULTS:

A missense variant (p.D239N) in DAB2IP was identified. The variant occurred in the C2-domain, the region interacting with vascular endothelial growth factor receptor 2 (VEGFR2). It was found to be rare, and predicted to have a detrimental effect on the functionality of DAB2IP. Protein structure modeling predicted changes in the mutant p.D239N protein structure, impacting protein stability. The p.D239N variant affected the subcellular localization of VEGFR2. Cells transfected with the DAB2IP-239N transcript exhibited an intracellular distribution, and VEGFR2 remained associated with the cell membrane. The altered localization pattern indicated reduced colocalization of the mutant protein with VEGFR2, suggesting a diminished ability of VEGFR2 binding.

CONCLUSIONS:

The study identified a novel missense variant (p.D239N) in DAB2IP in a family with HAE-UNK and highlighted the role of dysregulated VEGF-mediated signaling in altered endothelial permeability. DAB2IP loss-of-function pathogenic variants lead to the impairment of the endothelial VEGF/VEGFR2 ligand system and represent a new pathophysiologic cause of HAE-UNK.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article