GENETIC BASIS OF CONGENITAL HEART DISEASE AND MOLECULAR

PATHOPHYSIOLOGY

Negin parsamanesh

Functions of the causative genes of CHD

CFC1, cripto, FRL-1, cryptic family 1 This gene encodes a member of the EGF-Cripto, Frl-1, and

Cryptic (CFC) family. These proteins play key roles in intercellular signaling pathways during vertebrate embryogenesis. Mutations in this gene can cause autosomal visceral heterotaxy. This protein is involved in left-right asymmetric morphogenesis during organ development

PROSIT240, MED13L, mediator complex subunit 13-like Also known as THRAP2, The evolutionarily conserved THRAP

genes encode a family of proteins that regulate embryonic development. THRAP2 is involved in early development of the heart and brain

ZFPM2, zinc finger protein, multitype 2 The zinc finger protein encoded by this gene is a widely

expressed member of the FOG family of transcription factors. The family members modulate the activity of GATA family proteins, which are important regulators of hematopoiesis and cardiogenesis in mammals

Jagged 1, jagged 1 (Alagille syndrome) The jagged 1 protein encoded by JAG1 is the human

homolog of the Drosophila jagged protein. Human jagged 1 is the ligand for the receptor notch 1. Mutations that alter the jagged 1 protein cause Alagille syndrome

LEFTYA, left-right determination factor 2This gene encodes a member of the TGF-β family of proteins. The

encoded protein is secreted and plays a role in left-right asymmetry determination of organ systems during development. Mutations in this gene have been associated with left-right axis malformations, particularly in the heart and lungs

ELN, elastinThis gene encodes a protein that is one of the two components of

elastic fibers. Deletions and mutations in this gene are associated with supravalvular aortic stenosis and autosomal dominant cutis laxa

MEK2, MAP2K2, mitogen-activated protein kinase 2

The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome

TGFBR2, transforming growth factor receptor 2

This gene encodes a member of the Ser/Thr protein kinase family and the TGFB receptor subfamily. Mutations in this gene have been associated with Marfan syndrome, Loeys– Deitz Aortic Aneurysm syndrome, and the development of various types of tumors

Cardiac transcription: a multipartner affair

• The complex morphologic events and tissue remodeling that take place during heart formation are accompanied by equally complex changes of gene expression that produce dynamically regulated chamber as well as left–right specific patterns

The GATA familyThe GATA family belongs to the zinc finger superfamily of TFs that

bind the DNA sequence A/G GATA A/T. Six members are present in mammals GATA-6 is also found in myocardial as well as vascular smooth muscle cells.

GATA-5 transcripts are largely restricted to endocardial cells, while GATA-4 is detected in all cardiac progenitorsThe number of cardiac promoters regulated directly by GATA-4 is more than 30

The MEF2 family

MEF2 proteins were originally isolated by virtue of their binding to A/T-rich regulatory sequences present on several skeletal muscle promoters. MEF2 proteins can also be recruited to target genes via interaction with GATA proteins

Gene targeting in drosophila and mice suggests a role for MEF2 in later stages of cardiomyocyte and vascular cell differentiation

The NK family

Nkx2.5 binds DNA through its homeodomain. At the molecular level, Nkx2.5 is a GATA-4 collaborator and an important interacting partner of Tbx5

In human, mutations of Nkx2.5—most of which occur within the homeodomain—are associated with septal defects and conduction abnormalities

Since Nkx2.5 is expressed throughout the myocardium, its role in heart regionalization likely reflects combinatorial interaction with other cardiac regulators.

The T-box family

Tbx proteins form a newly identified family of important developmental regulators that share a conserved 180 AA region (the T-domain or T-box) responsible for DNA binding.

The first evidence for a role of Tbx proteins in the heart came from the finding that Tbx5 is the gene mutated in HOS

Epignetics

epigenetic regulators play crucial roles in the global shaping and maintenance of developmental patterning. This involves dynamic tissue and cell type-specific changes during patterning, as well as the maintenance of the cellular memory that is required for developmental stability. BAF60C (a subunit of chromatin-remodelling complex BAF) (also known as SMARCD3), a subunit of the Swi/ Snf-like chromatin-remodelling complex BAF, physically links cardiac transcription factors to the BAF complex

Loss of BAF60C results in severe defects in cardiac morphogenesis and impaired activation of a subset of cardiac genes. The muscle-restricted histone methyltransferase (also known as BOP) is a crucial regulator of cardiac chamber growth and differentiation

The End