Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy

Abstract

Hereditary sensory and autonomic neuropathy type II (HSAN II) leads to severe mutilations because of impaired nociception and autonomic dysfunction. Here we show that loss-of-function mutations in FAM134B, encoding a newly identified cis-Golgi protein, cause HSAN II. Fam134b knockdown results in structural alterations of the cis-Golgi compartment and induces apoptosis in some primary dorsal root ganglion neurons. This implicates FAM134B as critical in long-term survival of nociceptive and autonomic ganglion neurons.

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Figure 1: Clinical presentation, disease mutations and expression of FAM134B.
Figure 2: Impact of Fam134b knockdown.

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Acknowledgements

We are grateful to all affected individuals and their relatives who participated in the study. This work was supported by grants of the Werner-Otto-Stiftung to I.K., a Methusalem grant of the University of Antwerp and grants of the DFG and IZKF Jena to C.A.H. We thank T. Deufel for continuous support and J. Müller for help with the implementation of the lentiviral-mediated knockdown. We acknowledge the excellent technical assistance of W. Bigott, K. Küchler and S. Vanek. This work was also supported by the University of Antwerp, the Fund for Scientific Research (FWO-Flanders), an FFM grant of the Universitätsklinikum Hamburg Eppendorf, the Medical Foundation Queen Elisabeth (GSKE) and the Interuniversity Attraction Poles P6/43 program of the Belgian Federal Science Policy Office (BELSPO). A.R. and J.B. are supported by PhD fellowships of the Institute for Science and Technology (IWT) and FWO-Flanders, respectively. J.S. is a Heisenberg fellow of the Deutsche Forschungsgemeinschaft.

Author information

I.K. performed genetic and functional assays, coordinated the study and wrote the manuscript. T.P., J.C.H., A.K.H. and C.K. developed and performed functional assays. D.S. and A.R. performed molecular genetic analyses. J.B., J.S., H.T., S.A.F., P.D.J. and V.T. provided DNA samples and collected clinical data. G.N. and P.N. performed genetic mapping. A.G. edited the manuscript. C.A.H. initiated, planned and coordinated the study and wrote the manuscript.

Correspondence to Ingo Kurth or Christian A Hübner.

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Supplementary Methods, Supplementary Tables 1 and 2 and Supplementary Figures 1–8 (PDF 1001 kb)

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