Cryptic out-of-frame translational initiation of TBCE rescues tubulin formation in compound heterozygous HRD

Guoling Tian, Melissa C. Huang, Ruti Parvari, George A. Diaz, Nicholas J. Cowan

    Research output: Contribution to journalArticlepeer-review

    21 Scopus citations

    Abstract

    Microtubules are indispensable dynamic structures that contribute to many essential biological functions. Assembly of the native α/β tubulin heterodimer, the subunit that polymerizes to form microtubules, requires the participation of several molecular chaperones, namely prefoldin, the cytosolic chaperonin CCT, and a series of five tubulin-specific chaperones termed cofactors A-E (TBCA-E). Among these, TBCC, TBCD, and TBCE are essential in higher eukaryotes; they function together as a multimolecular machine that assembles quasinative CCT-generated α- and β-tubulin polypeptides into new heterodimers. Deletion and truncation mutations in the gene encoding TBCE have been shown to cause the rare autosomal recessive syndrome known as HRD, a devastating disorder characterized by congenital hypoparathyroidism, mental retardation, facial dysmorphism, and extreme growth failure. Here we identify cryptic translational initiation at each of three out-of-frame AUG codons upstream of the genetic lesion as a unique mechanism that rescues a mutant HRD allele by producing a functional TBCE protein. Our data explain how afflicted individuals, who would otherwise lack the capacity to make functional TBCE, can survive and point to a limiting capacity to fold tubulin heterodimers de novo as a contributing factor to disease pathogenesis.

    Original languageEnglish
    Pages (from-to)13491-13496
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume103
    Issue number36
    DOIs
    StatePublished - 5 Sep 2006

    ASJC Scopus subject areas

    • General

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