Abstract
The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad–Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations1,2,3. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny–Caffey syndrome4 (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43–44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation7. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of α-tubulin subunits and the formation of α–β-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.
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Acknowledgements
This research was supported in part by the Israel Science foundation (to R.P. and R.G.), the US National Institutes of Health (the Mount Sinai Child Health Research Center, Mount Sinai Microscopy Shared Instrument Facility; to B.D.G. and G.A.D.) and the March of Dimes (to G.A.D.). The authors would like to thank the families that participated in the study, S. Zhang and P. Hernandez for excellent technical assistance, T. Volberg for help with the tubulin immunofluoresence staining studies and Y. Ioannou for helpful discussions and critical reading of the manuscript. We gratefully acknowledge the contributions of the Sanger Institute mapping and sequencing groups.
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The HRD/Autosomal Recessive Kenny–Caffey Syndrome Consortium. Mutation of TBCE causes hypoparathyroidism– retardation–dysmorphism and autosomal recessive Kenny–Caffey syndrome. Nat Genet 32, 448–452 (2002). https://doi.org/10.1038/ng1012
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DOI: https://doi.org/10.1038/ng1012
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