Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.
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.
Parvari
Ruti
R
Department of Developmental Molecular Genetics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
Hershkovitz
Eli
E
Grossman
Nili
N
Gorodischer
Rafael
R
Loeys
Bart
B
Zecic
Alexandra
A
Mortier
Geert
G
Gregory
Simon
S
Sharony
Reuven
R
Kambouris
Marios
M
Sakati
Nadia
N
Meyer
Brian F
BF
Al Aqeel
Aida I
AI
Al Humaidan
Abdul Karim
AK
Al Zanhrani
Fatma
F
Al Swaid
Abdulrahman
A
Al Othman
Johara
J
Diaz
George A
GA
Weiner
Rory
R
Khan
K Tahseen S
KT
Gordon
Ronald
R
Gelb
Bruce D
BD
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
D018832:Molecular Chaperones; C469270:TBCE protein, human