User:Tereza Čalounová/Sandbox 1

Function

Gene ontology

Molecular function

• 1-acylglycerol-3-phosphate O-acyltransferase activity
• 1-acylglycerophosphocholine O-acyltransferase activity
• O-acyltransferase activity ^[2]

Biological process

• cardiac muscle contraction
• cardiac muscle tissue development
• cardiolipin acyl-chain remodeling
• cardiolipin biosynthetic process
• cristae formation
• heart development
• hemopoiesis
• inner mitochondrial membrane organization
• mitochondrial ATP synthesis coupled electron transport
• mitochondrial respiratory chain complex I assembly
• muscle contraction
• positive regulation of ATP biosynthetic
• positive regulation of cardiolipin metabolic process
• regulation of gene expression
• skeletal muscle tissue development ^[2]

Cardiolipin

TAZ gene

Tafazzin is encoded by a TAZ gene (G4.5). This gene is located on the long arm of the X chromosome at position 28 (Xq28). ^[3] Several isoforms are known. Isoforms that lack the N-terminus are found in leukocytes and fibroblasts, but not in heart and skeletal muscle. ^[4] Human TAZ consists of 11 exons and produces four alternatively spliced mRNA transcripts: a full-length transcript containing all exons (FL), a transcript lacking exon 5 (Δ5), a transcript lacking exon 7 (Δ7) and a transcript lacking both exons 5 and 7 (Δ5Δ7). Of these four alternatively spliced variants of human TAZ, FL and Δ5 encode proteins with transacylase activity, while Δ7 and Δ5Δ7 do not. ^[5]

Disease - Barth syndrome

Barth syndrome (BTHS), also known as 3-Methylglutaconic aciduria type II, is an X-linked genetic disorder. The disease is caused by mutation in TAZ gene which encodes for protein tafazzin. ^[6] Tafazzin works as an acyltransferasein complex lipid metabolism, it is responsible for altering immature cardiolipin- intermediate monolysocardiolipin(with three linoleic acid side chains) (MLCL). ^{[7] [8]} Cardiolipin makes up 20% of mitochondrial lipids and is closely connected with the electron transport chain proteins and the inner membrane structure of the mitochondria. ^[9] Mutations in TAZ gene lead to tafazzin not working properly, immature cardiolipin accumulates whereas the level of cardiolipin is low (mature cardiolopin has four linoleic acid side chains).^[7][8] Mitochondria in affected patients are not having a normal shape and functions. Reduced energy production of mitochondria results in apoptosis of cells in tissues with high energy demands, especially cardiac and skeletal muscles. Moreover abnormally shaped mitochondria in white blood cells may affect their ability to proliferate. This causes neutropenia- decreased amount of white blood cells leading to higher risk of infections. ^[6]

UPRAVIT:

This results in deficiency of cardiolipin (CL) with four linoleic acid side chains and relative excess of monolysocardiolipin (MLCL, with just three side chains), and hence to a highly abnormal MLCL/CL ratio (Valianpour et al., 2005; Schlame, 2007). This feature has recently allowed the development of a highly sensitive and specific assay applicable to lymphocytes, platelets, muscle biopsies, fibroblasts or even single stored neonatal bloodspots (Kulik et al., 2008). ^[8]

Symptoms

• dilated cardiomyopathy (CMD)
• endocardial fibroelastosis (EFE)
• a predominantly proximal skeletal myopathy
• growth retardation
• neutropenia
• organic aciduria
• excess of 3-methylglutaconic acid
• characteristic facial features (tall and broad forehead, round face, full cheeks, prominent pointed chin, large ears, and deep-set eyes)

Risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. Cardiomyopathy almost always presents before age five. ^[10]

Diagnosis

Urinary 3-methylglutaconic acid (3-MGC) can be increased 5- to 20-fold, urinary 3-methylglutaric acid and 2-ethylhydracrylic acid may be moderately increased. The diagnosis is established in patient with increased MLCL:CL ratio or detected TAZ pathogenic variant on molecular genetic testing. ^[10]

3D Structure: Homology Model