title: Cryptic out-of-frame translational initiation of TBCE rescues tubulin formation in compound heterozygous HRD.
abstract: Microtubules are indispensable dynamic structures that contribute to many essential biological functions. Assembly of the native alpha/beta 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 alpha- and beta-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.
authors.affiliation: Department of Biochemistry, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Guoling
authors.initials: G
authors.lastname: Tian
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Huang
authors.forename: Ruti
authors.initials: R
authors.lastname: Parvari
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cowan
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000483:Alleles; D001483:Base Sequence; D019281:Dimerization; D005145:Face / Q000002:abnormalities; D017353:Gene Deletion; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007011:Hypoparathyroidism / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics*; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D014176:Protein Biosynthesis; D013577:Syndrome; D014404:Tubulin / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; C469270:TBCE protein, human; D014404:Tubulin