Aortic types 1 and 2, valvular disease ... (Aortic Valve Disease types 1 and 2 -AOVD1 and AOVD2-) - Genes NOTCH1 and SMAD6

Aortic valve disease is a disorder characterized by the presence of a bicuspid aortic valve, or bicommissural, in which the aortic valve instead of three valves (tricuspid) has only two, and consequently triggers an aortic valve stenosis or aortic valve insufficiency. In extreme cases blood flow is restricted while the left ventricle does not develop, resulting in a hypoplastic left heart syndrome. The valve calcification seen in bicuspid aortic valve is due to inadequate activation of gene expression specific osteoclasts.

They described two types of aortic valve disease which differ depending on their genetic cause. Valvular disease aortic type 1 (AOVD1: Aortic Valve Disease 1) is due to mutations in the NOTCH1 gene while valvular disease type aortic 2 (AOVD2: Aortic Valve Disease 2), is due to mutations in the SMAD6 gene.

NOTCH1 gene, located on the long arm of chromosome 9 (9q34.3), encoding a protein of the NOTCH family, including transmembrane proteins that share many structural features, including the extracellular domain of multiple epidermal growth factors ( EGF) and an intracellular domain of multiple types. This family of proteins involved in the regulation of various processes of development. Notch1 protein, is cleaved in the Golgi network and is presented on the cell surface as a heterodimer, which acts as a receptor for ligands bound to the membrane (Jagged1, Jagged2, delta1), and participates in many stages of development. After being activated by the ligand releases the intracellular domain NICD transcriptional activator forming a complex with rbpj / RBPSUH, which in turn activates genes affecting differentiation, proliferation and apoptosis. It may also be important for the normal function of lymphocytes, so when altered, can contribute to the transformation or progression of some neoplasias T. participates cells in the maturation of CD4 + and CD8 + cells in the thymus. It is also considered to be involved in follicular differentiation during cerebellar development and can act as a neuronal receptor DNER and development of Bergmann glia. Mutations in the transcription regulator NOTCH1 signals and cause a set of aortic valve abnormalities and intense development calcifications.

Meanwhile, the SMAD6 gene, located on the long arm of chromosome 15 (15q22), encoding a protein belonging to the family of SMAD proteins, which are modulators of transduction and transcription mediating many signaling pathways, negatively regulating signals BMP and TGF-beta. Variants of transcripts of this gene, encoding different isoforms. Mediate the antiinflammatory TGF-beta and BMP activity. Also suppress IL1R-TLR signaling through their direct interaction with PEL-1, preventing activation of NF-kappa-B, nuclear transport and expression mediated NF-kappa-B of proinflammatory genes. It can block the pathways of BMP-SMAD1 signals competing with receptor SMAD4 by fixing SMAD1.

Tests in IVAMI: in IVAMI perform detection aortic associated mutations conenfermedad valve, by complete PCR amplification of the exons of NOTCH1 genes (aortic valve disease type 1) and SMAD6 (aortic valve disease type 2), respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).