Abstract
We describe a new autosomal recessive white matter disorder ('hypomyelination and congenital cataract') characterized by hypomyelination of the central and peripheral nervous system, progressive neurological impairment and congenital cataract. We identified mutations in five affected families, resulting in a deficiency of hyccin, a newly identified 521–amino acid membrane protein. Our study highlights the essential role of hyccin in central and peripheral myelination.
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Acknowledgements
We thank R. Gatti, P. Palazzolo, V. Costa and the families of the affected individuals for their collaborative efforts and P. Broda for technical assistance. This work has been supported by the Pierfranco and Luisa Mariani Foundation ONLUS (grant R-04-37), the Telethon Italy Foundation (grant GGP05156), the Istituto Superiore della Sanità (grant 526/A32) and a donation from R. Bulgarelli. F.S. and M.P.L. were supported by grants from the US National Institutes of Health and the American Heart Association. The samples were obtained from the 'Cell Line and DNA Bank from Patients Affected by Genetic Diseases' collection (http://www.gaslini.org/labdppm.htm) supported by Italian Telethon grants (project number GTF04002).
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Contributions
F.Z.: study design, supervision of the molecular study, writing of the manuscript; L.B. and S.G.: linkage analysis, mutational screening, RNA analysis; R.B., C.B., G.U., M.S.v.K: phenotype assessment; S.A., E.G., S.S.: immunoblot and cell fractionation; F.S., X.B.W., M.P.L.: subcellular localization and immuofluorescence; A.S.: nerve biopsy pathology; A.R. and P.T.-D.: neuroradiological evaluation; C.M.: study design, supervision of the clinical study, writing of the manuscript.
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Supplementary information
Supplementary Fig. 1
Pedigrees and chromosome 7p21.1-p15.3 haplotypes in five HCC families. (PDF 153 kb)
Supplementary Fig. 2
Multiple sequence alignment of hyccin. (PDF 386 kb)
Supplementary Fig. 3
Expression analysis of DRCTNNB1A. (PDF 286 kb)
Supplementary Fig. 4
Prediction of membrane-spanning regions of hyccin by TMpred. (PDF 61 kb)
Supplementary Fig. 5
Immunoblot analysis of transfected COS-7 cells. (PDF 114 kb)
Supplementary Table 1
Clinical and neurological findings. (PDF 68 kb)
Supplementary Table 2
Family-specific and cumulative lod scores for chromosome 7 markers. (PDF 60 kb)
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Zara, F., Biancheri, R., Bruno, C. et al. Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract. Nat Genet 38, 1111–1113 (2006). https://doi.org/10.1038/ng1870
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DOI: https://doi.org/10.1038/ng1870
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