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Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia

Abstract

Inherited peripheral neuropathies are frequent neuromuscular disorders known for their clinical and genetic heterogeneity. In 33 families, we identified 8 mutations in HINT1 (encoding histidine triad nucleotide–binding protein 1) by combining linkage analyses with next-generation sequencing and subsequent cohort screening of affected individuals. Our study provides evidence that loss of functional HINT1 protein results in a distinct phenotype of autosomal recessive axonal neuropathy with neuromyotonia.

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Figure 1: Functional characterization of HINT1 mutations.

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Acknowledgements

We are grateful to the study participants and their families for their cooperation. We thank A. Suls, N. Avonce, G. Milternberger-Milteny, B. Ramirez Escorcia, W. Glassee, E. Ydens and C. Claes for their expert help with some of the experiments; the VIB Genetic Service Facility for sequencing and cell maintenance support; and C. Brenner (University of Iowa) for providing the BY8-5c yeast strain. This work was supported by the University of Antwerp (in part by IWS BOF 2008 23064 to A.J. and P.D.J.); the Fund for Scientific Research–Flanders (to A.J., P.D.J. and V.T.); the Medical Foundation Queen Elisabeth (GSKE; to P.D.J. and V.T.); the Interuniversity Attraction Poles P6/43 program of the Belgian Federal Science Policy Office (BELSPO; to A.J., P.D.J. and V.T.); the Methusalem Excellence Grant of the Flemish Government; the Association Belge Contre les Maladies Neuromusculaires (ABMM; to A.J., J.B., P.D.J. and V.T.); the VIB TechWatch Fund (to A.J. and P.D.J.), the Medizinische Forschungsfonds Tirol (MFF Tirol) (to S.L. and A.R.J.), the US National Institue of Neurological Disorders and Stroke (NINDS; R01NS075764, U54NS065712-03 and R01NS052767 to S.Z.), the Austrian Science Fond (FWF; P23223-B19 to M.A.-G.) and the Ministry of Science and Technology of the Republic of Serbia (17 3016 and 17 508 to V.M.R. and D.S.-P.). J.B., M.Z. and K.P. are supported by a PhD fellowship, and P. Van Damme is supported by a clinical investigatorship of the Fund for Scientific Research Flanders (FWO-Vlaanderen). All patients or their legal representatives signed an informed consent form prior to enrollment. This study was approved by local institutional review boards.

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Authors

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M.Z., J.B., V.M.R., A.R.J., P.D.J. and A.J. designed the study strategy. M.Z., E.F., S.L. and A.R.J. performed and analyzed genetic mapping. P.D.R. and B.-S.P. generated and performed primary analysis of next-generation sequencing data. M.Z., P.D.R. and A.R.J. analyzed next-generation sequencing data. M.Z., E.D.V. and S.L., performed mutational analysis in the cohorts of affected individuals. J.B., P.D.J. and V.M.R. supervised the clinical aspects of the study. J.B., J.N., Y.P., E.B., Z. Matur, V.G., I.T., M.A.-G., T.M., P. Van Damme, W.N.L., N.B., Z. Mitrovic, S.C.P., H.T., G.B., A.B.-M., S.T., D.S.-P., B.I., A.F.H., S.Z., V.M.R., A.R.J. and P.D.J. recruited subjects, gathered clinical data and contributed DNA samples. M.Z., L.A.-S., K.P., T.O., V.T., P. Van Dijck and A.J. designed and performed functional analyses. M.Z., J.B., L.A.-S., A.R.J., P.D.J. and A.J. wrote the manuscript.

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Correspondence to Peter De Jonghe or Albena Jordanova.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Methods, Supplementary Figures 1–4 and Supplementary Tables 1–4 (PDF 4448 kb)

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Zimoń, M., Baets, J., Almeida-Souza, L. et al. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet 44, 1080–1083 (2012). https://doi.org/10.1038/ng.2406

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