Microtubules constitute one of the major building blocks of cells, and play vital roles in such diverse cellular processes as division, growth, motility, transport, and maintenance of cell shape. The microtubules are made up of alpha and beta-tubulin heterodimers. The formation of these heterodimers is facilitated by a group of five chaperone proteins, called the Tubulin Specific Chaperones (TBC). These chaperone proteins prevent these tubulin proteins from intercting with other proteins and forming non-functional dimers. TBCE is one of these chaperones. Specifically, TBCE facilitates the folding of the alpha-tubulin protein.
Keeping in mind the important function played by microtubules in cells, it is easy to see how defects in the TBCE protein can lead to pathological situations. Sanjad Sakati (HRD) syndrome, an autosomal recessive disorder characterized by short stature, mental retardation and seizures, and, the similarly featured, Kenny-Caffey syndrome type I are caused by defects in the TBCE gene.
The TBCE gene is located on the long arm of chromosome 1. With its 17 exons, the gene spans a total length of around 84 Kb. The gene produces two transcript variants that code for the same protein product. The TBCE protein itself contains 527 amino acids and has a size of close to 60 kDa. The protein contains three functional domains: a glycine-rich cytoskeleton associated protein domain called the CAP-Gly, a string of leucine-rich repeats (LRR), and a ubiquitin-like domain (UBL). The CAP-Gly domain is involved with binding to alpha-tubulin, whereas the LRR and UBL mediate protein-protein interactions.
The most common mutation in the TBCE gene leading to Sanjad Sakati syndrome is a 12 bp deletion (c.155-166del12), which results in a version of the protein lacking four amino acids in the Cap-Gly domain. Although cells with this mutation do not show any difference in the total microtubule levels, microtubule density and polarity are changed.
Diaz et al. (1998) conducted a genome-wide search using polymorphic short tandem repeat markers on eight consanguineous unrelated Kuwaiti kindreds to determine the gene causing the autosomal recessive form of Kenny-Caffey syndrome (KCS). Six of the eight pedigrees studied by Diaz et al. (1998) had previously been described by Khan et al. (1997). The employment of D1S2649 marker resulted in a significant linkage to a locus located at chromosome 1q42-q43 showing a maximal two-point lod score of 13.30. Haplotype analysis of flanking markers was used and showed recombination events describing the KCS locus to a zone among markers D1S2800 on the centromeric boundary and D1S2850 on the telomeric boundary with an estimate of 4-cM interval. It was found that all affected subjects were homozygous for identical alleles at markers D1S2649 and D1S235, proposing that there is a single ancestral mutation underlying KCS in these families.
[See: Saudi Arabia > Parvari et al., 2002; Padidela et al., 2009].
Parvari et al. (2002) demonstrated homozygosity for a 12-bp deletion in the second coding exon of the TBCE gene in more than 50 Middle Eastern individuals with hypoparathyroidism-retardation-dysmorphism syndrome. The deletion was not present in more than 350 control chromosomes from Arab individuals. However, the phenotype in 8 pedigrees with 13 affected individuals was that of autosomal recessive Kenny-Caffey syndrome, differing from the phenotype in HRD families (17 Saudi pedigrees, 27 affected individuals; 9 Palestinian pedigrees, 25 affected individuals) owing to the additional presence of medullary stenosis of the long bones, calvarial osteosclerosis, and susceptibility to bacterial infection. The presence of patchy osteosclerosis in the long bones of some Saudi subjects with HRD and deaths secondary to sepsis in some Palestinian Bedouin individuals with HRD suggested variable expression of these phenotypic features in a pedigree-specific fashion. Furthermore, 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 demonstrated that HRD and KCS are chaperone diseases caused by genetic defect in the tubulin assembly pathway and established a potential connection between tubulin physiology and the development of the parathyroid.
Padidela et al. (2009) described two sisters with HRD syndrome born to unrelated parents of Saudi and Palestinian origin. Both patients were found to be homozygous for the c.155-166del12 mutation in the TBCE gene.