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

Nature Genetics volume 32, pages 448–452 (2002)Cite this article

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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Figure 1: Haplotype data for markers tightly linked to the critical region.
Figure 2: TBCE mutation analysis and expression studies.
Figure 3: Tubulin expression in cells homozygous with respect to the del42–55 mutation and in control lymphoblastoid cells.
Figure 4: Immunostaining for α-tubulin in lymphoblastoid, dermal fibroblast and epidermal keratinocyte cells from affected del52–55 homozygotes.
Figure 5: Subcellular localization of Golgi and late endosomal compartments.
Figure 6: Ultrastructural studies of diseased dermal fibroblasts.

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GenBank/EMBL/DDBJ

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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.

Author information

Authors and Affiliations

  1. Department of Developmental Molecular Genetics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, 84105, Israel

    Ruti Parvari

  2. Department of Pediatrics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, 84105, Israel

    Eli Hershkovitz & Rafael Gorodischer

  3. Department of Skin Bank and Investigative Dermatology Laboratory and Department of Microbiology and Immunology, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, 84105, Israel

    Nili Grossman

  4. Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium

    Bart Loeys & Geert Mortier

  5. Department of Neonatology, Ghent University Hospital, Ghent, Belgium

    Alexandra Zecic

  6. The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Simon Gregory

  7. The Genetic Institute, Sapir Medical Center, Meir Hospital, Sackler School of Medicine, Tel Aviv University, Israel

    Reuven Sharony

  8. King Faisal Specialist Hospital & Research Center, Riyadh, 11211, Kingdom of Saudi Arabia

    Marios Kambouris, Nadia Sakati, Brian F. Meyer, Aida I. Al Aqeel, Abdul Karim Al Humaidan & Fatma Al Zanhrani

  9. Department of Pediatrics, Riyadh Armed Forces Hospital, Kingdom of Saudi Arabia

    Aida I. Al Aqeel, Abdulrahman Al Swaid & Johara Al Othman

  10. Department of Human Genetics, Mount Sinai School of Medicine, One Gustave Levy Place, New York, 10029, New York, USA

    George A. Diaz, Rory Weiner & Bruce D. Gelb

  11. Department of Pediatrics, Mount Sinai School of Medicine, One Gustave Levy Place, New York, 10029, New York, USA

    George A. Diaz & Bruce D. Gelb

  12. Department of Pediatrics, Al-Jahra Hospital, Safat, Kuwait

    K. Tahseen S. Khan

  13. Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA

    Ronald Gordon

Consortia

The HRD/Autosomal Recessive Kenny–Caffey Syndrome Consortium

  • Group 1

    • Ruti Parvari
    • , Eli Hershkovitz
    • , Nili Grossman
    • , Rafael Gorodischer
    • , Bart Loeys
    • , Alexandra Zecic
    • , Geert Mortier
    • , Simon Gregory
    •  & Reuven Sharony

  • Group 2

    • Marios Kambouris
    • , Nadia Sakati
    •  & Brian F. Meyer

  • Group 3

    • Aida I. Al Aqeel
    • , Abdul Karim Al Humaidan
    • , Fatma Al Zanhrani
    • , Abdulrahman Al Swaid
    •  & Johara Al Othman

  • Group 4

    • George A. Diaz
    • , Rory Weiner
    • , K. Tahseen S. Khan
    • , Ronald Gordon
    •  & Bruce D. Gelb

Corresponding author

Correspondence to George A. Diaz.

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The author declare no competing financial interests.

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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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