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. 2002 Nov;32(3):448-52.
doi: 10.1038/ng1012. Epub 2002 Oct 21.

Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome

Ruti Parvari  1 , Eli Hershkovitz, Nili Grossman, Rafael Gorodischer, Bart Loeys, Alexandra Zecic, Geert Mortier, Simon Gregory, Reuven Sharony, Marios Kambouris, Nadia Sakati, Brian F Meyer, Aida I Al Aqeel, Abdul Karim Al Humaidan, Fatma Al Zanhrani, Abdulrahman Al Swaid, Johara Al Othman, George A Diaz, Rory Weiner, K Tahseen S Khan, Ronald Gordon, Bruce D Gelb; HRD/Autosomal Recessive Kenny-Caffey Syndrome Consortium
Affiliations

Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome

Ruti Parvari et al. Nat Genet. 2002 Nov.

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 populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (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 mutation. 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 alpha-tubulin subunits and the formation of alpha-beta-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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