title: Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.
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.
authors.affiliation: Department of Developmental Molecular Genetics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: Ruti
authors.initials: R
authors.lastname: Parvari
authors.forename: Eli
authors.initials: E
authors.lastname: Hershkovitz
authors.forename: Nili
authors.initials: N
authors.lastname: Grossman
authors.forename: Rafael
authors.initials: R
authors.lastname: Gorodischer
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zecic
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Simon
authors.initials: S
authors.lastname: Gregory
authors.forename: Reuven
authors.initials: R
authors.lastname: Sharony
authors.forename: Marios
authors.initials: M
authors.lastname: Kambouris
authors.forename: Nadia
authors.initials: N
authors.lastname: Sakati
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.forename: Aida I
authors.initials: AI
authors.lastname: Al Aqeel
authors.forename: Abdul Karim
authors.initials: AK
authors.lastname: Al Humaidan
authors.forename: Fatma
authors.initials: F
authors.lastname: Al Zanhrani
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Al Swaid
authors.forename: Johara
authors.initials: J
authors.lastname: Al Othman
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
authors.forename: Rory
authors.initials: R
authors.lastname: Weiner
authors.forename: K Tahseen S
authors.initials: KT
authors.lastname: Khan
authors.forename: Ronald
authors.initials: R
authors.lastname: Gordon
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D002878:Chromosomes, Human, Pair 1; D004252:DNA Mutational Analysis; D005145:Face / Q000002:abnormalities*; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005808:Genes, Recessive; D006056:Golgi Apparatus / Q000378:metabolism; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007011:Hypoparathyroidism / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics*; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000235:genetics* / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010026:Osteosclerosis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D018832:Molecular Chaperones; C469270:TBCE protein, human