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.
- Calcium and bone
- clinical genetics
- molecular genetics
- cell biology
- renal medicine
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HHA, EMHFB, NVAMK and RR contributed equally to this work.
Funding This research was supported by grants from the Dutch Kidney Foundation (KJPB 0.009; to HHA), the European Community's Seventh Framework Programme FP7/2009 under grant agreement No 241955, SYSCILIA (to RR) and a grant from the Netherlands Organization for Scientific Research (NWO Vidi-91786396; to RR).
Competing interests None.
Patient consent Obtained. This includes written informed consent from the parents of the patients (II:1 and II:2) for publication of the images.
Ethics approval This study was conducted with the approval of the medical ethics committee of Radboud University Nijmegen Medical Centre.
Provenance and peer review Not commissioned; externally peer reviewed.