The Application of Clinical Genetics (Dec 2020)
A Novel Splice-Site Mutation in the ELN Gene Suggests an Alternative Mechanism for Vascular Elastinopathies
Abstract
Camilo Andres Velandia-Piedrahita,1 Adrien Morel,2,* Dora Janeth Fonseca-Mendoza,2,* Victor Manuel Huertas-Quiñones,3– 5 David Castillo,6 Juan Diego Bonilla,7 Camilo José Hernandez-Toro,1 Marta Catalina Miranda-Fernández,1 Carlos Martin Restrepo,2 Rodrigo Cabrera1,2 1Laboratorio de Biología Molecular y Pruebas Diagnósticas de Alta Complejidad, Fundación Cardioinfantil‐Instituto de Cardiología, Bogotá, Colombia; 2Center for Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia; 3Instituto de Cardiopatías Congénitas, Fundación Cardioinfantil‐Instituto de Cardiología, Bogotá, Colombia; 4Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia; 5Facultad de Medicina, Universidad del Rosario, Bogotá, Colombia; 6Servicio de Dermatología, Fundación Para la Investigación en Dermatología FUNINDERMA, Bogotá, Colombia; 7Servicio de Dermatología, Universidad El Bosque, Bogotá, Colombia*These authors contributed equally to this workCorrespondence: Rodrigo CabreraLaboratorio de Biología Molecular y Pruebas Diagnósticas de Alta Complejidad, Fundación Cardioinfantil‐Instituto de Cardiología, Calle 163A # 13B-60, Bogotá CP 110131, ColombiaTel +57 1 6672727 ext 11611Fax +57 1 6672727 Ext 73206Email [email protected]: The ELN gene encodes elastin, a fundamental protein of the extracellular matrix that confers elasticity to different tissues including blood vessels. The formation of elastin fibers is a complex process involving monomer coacervation and subsequent crosslinking. Mutations in exons 1– 29 of the ELN gene have been linked to supravalvular aortic stenosis (SVAS) whereas mutations in exons 30– 33 are associated with autosomal dominant cutis laxa (ADCL). This striking segregation has led to the hypothesis that distinct molecular mechanisms underlie both diseases. SVAS is believed to arise through haploinsufficiency while ADCL is hypothesized to be caused by a dominant negative effect. Here, we describe a patient with SVAS harboring a novel splice-site mutation in the last exon of ELN. The location of this mutation is not consistent with current knowledge of SVAS, since all mutations reported in the C-terminus have been found in ADCL patients, and a thorough evaluation did not reveal significant skin involvement in this case. RT-PCR analysis of skin tissue showed that C-terminal mutations in the region can lead to the production of aberrant transcripts through intron retention and activation of cryptic splice sites and suggest that disruption of the very last exon can lead to functional haploinsufficiency potentially related to SVAS.Keywords: SVAS, ELN, ADCL, coacervation, splicing
