Human CFC1 blocking peptide

Ail vertebrates display a characteristic asymmetry of internal organs with the cardiac apex, stomach and spleen towards the left, and the liver and gall bladder on the right(1-3). Left-right (L-R) axis abnormalities or laterality defects are common in humans (1 in 8,500 live births). Several genes (such as Nodal, Ebaf and Pitx2) have been implicated in L-R organ positioning in model organisms(2-4), In humans, relatively few genes have been associated with a small percentage of human situs defects. These include ZIC3 (ref. 5), LEFTB (formerly LEFTY2; ref. 6) and ACVR2B (encoding activin receptor IIB; ref, 7). The EGF-CFC genes(8), mouse Cfc1 (encoding the Cryptic protein; ref. 9) and zebrafish one-eyed pinhead (oep; refs 10,11) are essential for the establishment of the L-R axis(12,13). EGF-CFC proteins act as co-factors for Nodal-related signals(11), which have also been implicated in L-R axis development(4). Here we identify loss-of-function mutations in human CFC1 (encoding the CRYPTIC protein) in patients with heterotaxic phenotypes (randomized organ positioning). The mutant proteins have aberrant cellular localization in transfected cells and are functionally defective in a zebrafish oepmutant rescue assay. Our findings indicate that the essential role of EGF-CFC genes and Nodal signalling in left-right axis formation is conserved from fish to humans. Moreover, our results support a role for environmental and/or genetic modifiers in determining the ultimate phenotype in humans.

Background: Transposition of great arteries (TGA) represents the most frequent cyanotic heart defect diagnosed in the neonatal period. Several genes had been identified to be associated with the pathogenesis of dextro-transposition of the great arteries (d-TGA). These genes are located in different chromosomes and their mutations can only explain few clinical cases. Besides, no genetic scan for TGA has been implemented in China. Methods: To evaluate whether aberrations in any of the 13 reported mutations in seven genes (MED13L, ZIC3, CFC1, NODAL, FOXH1, GDF1 and NKX2-5) could completely or in part be the genetic component involved in TGA in Chinese population, we screened 102 Chinese patients with d-TGA by direct sequencing for mutations within the seven genes. Results: We found none of the reported 13 mutations in those 102 Chinese d-TGA patients. Conclusions: These reported 13 mutations may not be a common cause of d-TGA in Chinese population due to racial variation and genetic heterogeneity of TGA. New approaches including the whole exome sequencing technology are required to effectively identify genetic variants in TGA patients in China.