Human IFT57 blocking peptide

The intraflagellar transport IFT57 protein is essential for ciliary growth and maintenance. Also known as HIPPI, human IFT57 can be translocated to the nucleus via a molecular partner of the Huntingtin, Hip1, inducing gene expression changes. In Paramecium tetraurelia, we identified four IFT57 genes forming two subfamilies IFT57A/B and IFT57C/D arising from whole genome duplications. The depletion of proteins of the two subfamilies induced ciliary defects and IFT57A and IFT57C localized in basal bodies and cilia. We observed that IFT57A, but not IFT57C, is also present in the macronucleus and able to traffic toward the developing anlage during autogamy. Analysis of chimeric IFT57A-IFT57C-GFP-tagged proteins allowed us to identify a region of IFT57A necessary for nuclear localization. We studied the localization of the unique IFT57 protein of Paramecium caudatum, a species, which diverged from P.tetraurelia before the whole genome duplications. The P.caudatumIFT57C protein was excluded from the nucleus. We also analyzed whether the overexpression of IFT57A in Paramecium could affect gene transcription as the human protein does in HeLa cells. The expression of some genes was indeed affected by overexpression of IFT57A, but the set of affected genes poorly overlaps the set of genes affected in human cells.

Background: Transposition of the great arteries (TGA) is an uncommon but severe congenital heart malformation of unknown etiology. Rare copy number variations (CNVs) have been implicated in other, more common conotruncal heart defects like tetralogy of Fallot (TOF), but there are as yet no CNV studies dedicated to TGA. Methods: Using high-resolution genome-wide microarrays and rigorous methods, we investigated CNVs in a group of prospectively recruited adults with TGA (n = 101) from a single center. We compared rare CNV burden to well-matched cohorts of controls and TOF cases, adjudicating rarity using 10,113 independent population-based controls and excluding all subjects with 22q11.2 deletions. We identified candidate genes for TGA based on rare CNVs that overlapped the same gene in unrelated individuals, and pre-existing evidence suggesting a role in cardiac development. Results: The TGA group was significantly enriched for large rare CNVs (2.3-fold increase, p = 0.04) relative to controls, to a degree comparable with the TOF group. Extra-cardiac features were not reliable predictors of rare CNV burden. Smaller rare CNVs helped to narrow critical regions for conotruncal defects at chromosomes 10q26 and 13q13. Established and novel candidate susceptibility genes identified included ACKR3, IFT57, ITGB8, KL, NF1, NKX1-2, RERE, SLC8A1, SOX18, and ULK1. Conclusions: These data demonstrate a genome-wide role for rare CNVs in genetic risk for TGA. The findings provide further support for a genetically-related spectrum of congenital heart disease that includes TGA and TOF. (C) 2015 Elsevier Ireland Ltd. All rights reserved.