Download genetic basis of congenital heart disease and molecular

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 2
This 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, elastin
This 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 family
The 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 progenitors
The 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 Tdomain 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 chromatinremodelling 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 musclerestricted histone methyltransferase (also known as BOP) is a
crucial regulator of cardiac chamber growth and differentiation
The End