RT Journal Article
SR Electronic
T1 <em>C14ORF179</em> encoding IFT43 is mutated in Sensenbrenner syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 390
OP 395
DO 10.1136/jmg.2011.088864
VO 48
IS 6
A1 Heleen H Arts
A1 Ernie M H F Bongers
A1 Dorus A Mans
A1 Sylvia E C van Beersum
A1 Machteld M Oud
A1 Emine Bolat
A1 Liesbeth Spruijt
A1 Elisabeth A M Cornelissen
A1 Janneke H M Schuurs-Hoeijmakers
A1 Nicole de Leeuw
A1 Valérie Cormier-Daire
A1 Han G Brunner
A1 Nine V A M Knoers
A1 Ronald Roepman
YR 2011
UL http://jmg.bmj.com/content/48/6/390.abstract
AB Background Sensenbrenner syndrome is a heterogeneous ciliopathy that is characterised by skeletal and ectodermal anomalies, accompanied by chronic renal failure, heart defects, liver fibrosis and other features.Objective To identify an additional causative gene in Sensenbrenner syndrome.Methods Single nucleotide polymorphism array analysis and standard sequencing techniques were applied to identify the causative gene. The effect of the identified mutation on protein translation was determined by western blot analysis. Antibodies against intraflagellar transport (IFT) proteins were used in ciliated fibroblast cell lines to investigate the molecular consequences of the mutation on ciliary transport.Results Homozygosity mapping and positional candidate gene sequence analysis were performed in two siblings with Sensenbrenner syndrome of a consanguineous Moroccan family. In both siblings, a homozygous mutation in the initiation codon of C14ORF179 was identified. C14ORF179 encodes IFT43, a subunit of the IFT complex A (IFT-A) machinery of primary cilia. Western blots showed that the mutation disturbs translation of IFT43, inducing the initiation of translation of a shorter protein product from a downstream ATG. The IFT-A protein complex is implicated in retrograde ciliary transport along axonemal microtubules. It was shown that in fibroblasts of one of the siblings affected by Sensenbrenner syndrome, disruption of IFT43 disturbs this transport from the ciliary tip to its base. As anterograde transport in the opposite direction apparently remains functional, the IFT complex B proteins accumulate in the ciliary tip. Interestingly, similar results were obtained using fibroblasts from a patient with Sensenbrenner syndrome with mutations in WDR35/IFT121, encoding another IFT-A subunit.Conclusions The results indicate that Sensenbrenner syndrome is caused by disrupted IFT-A-mediated retrograde ciliary transport.