Alternative titles; symbols
HGNC Approved Gene Symbol: BBS9
Cytogenetic location: 7p14.3 Genomic coordinates (GRCh38): 7:33,129,285-33,635,767 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p14.3 | Bardet-Biedl syndrome 9 | 615986 | Autosomal recessive | 3 |
PTHB1 is 1 of 7 BBS proteins that form the stable core of a protein complex required for ciliogenesis (Nachury et al., 2007).
Adams et al. (1999) used mRNA differential display of osteoblastic cell line (SaoS-2/B10) total RNA and identified B1 as a gene downregulated by parathyroid hormone (PTH; 168450). By 5-prime RACE of SaoS-2/B10 RNA, they obtained a full-length B1 cDNA and several B1 splice variants. The deduced 802-amino acid protein is encoded by a 3.5-kb clone and shows characteristics of a globular intracellular protein. Northern blot analysis using sequence-specific probes detected multiple transcripts of 1.2 to 4.4 kb expressed in the SaoS-2/B10 cell line and several normal tissues. Expression was detected in adult heart, skeletal muscle, lung, liver, kidney, placenta, and brain, and in fetal kidney, lung, liver, and brain.
Vernon et al. (2003) identified several isoforms of B1, including isoforms containing unspliced introns 12 and 21. RT-PCR detected expression of tissue-specific B1 isoforms in all adult and fetal tissues examined. Vernon et al. (2003) also identified several unique isoforms specific to Wilms tumor-5 (WT5; 601583) tumors.
Vernon et al. (2003) determined that the B1 gene contains 24 exons and spans more than 700 kb. Exon 23 is part of a mammalian apparent long-terminal repeat retrotransposon.
By genomic sequence analysis, Adams et al. (1999) mapped the B1 gene to chromosome 7 in a region containing a locus for retinitis pigmentosa (RP9; 607331). By genomic sequence analysis of a breakpoint associated with a WT5 tumor, Vernon et al. (2003) mapped the B1 gene to chromosome 7p14.
Nachury et al. (2007) found that BBS1 (209901), BBS2 (606151), BBS4 (600374), BBS5 (603650), BBS7 (607590), BBS8 (TTC8; 608132), and BBS9 copurified in stoichiometric amounts from human retinal pigment epithelium (RPE) cells and from mouse testis. PCM1 (600299) and alpha-tubulin (see 602529)/beta-tubulin (191130) copurified in substoichiometric amounts. The apparent molecular mass of the complex, which Nachury et al. (2007) called the BBSome, was 438 kD, and it had a sedimentation coefficient of 14S. The complex localized with PCM1 to nonmembranous centriolar satellites in the cytoplasm and, in the absence of PCM1, to the ciliary membrane. Cotransfection and immunoprecipitation experiments suggested that BBS9 was the complex-organizing subunit and that BBS5 mediated binding to phospholipids, predominantly phosphatidylinositol 3-phosphate. BBS1 mediated interaction with RABIN8 (RAB3IP; 608686), the guanine nucleotide exchange factor for the small G protein RAB8 (RAB8A; 165040). Nachury et al. (2007) found that RAB8 promoted ciliary membrane growth through fusion of exocytic vesicles to the base of the ciliary membrane. They concluded that BBS proteins likely function in membrane trafficking to the primary cilium.
Loktev et al. (2008) found that BBIP10 (613605) copurified and cosedimented with the BBS protein complex from RPE cells. Knockdown of BBIP10 in RPE cells via small interfering RNA compromised assembly of the BBS protein complex and caused failure of ciliogenesis. Knockdown of BBS1, BBS5, or PCM1 resulted in a similar failure of ciliogenesis in RPE cells. Depletion of BBIP10 or BBS8 increased the frequency of centrosome splitting in interphase cells. BBIP10 also had roles in cytoplasmic microtubule stabilization and acetylation that appeared to be independent of its role in assembly of the BBS protein complex.
Using a protein pull-down assay with homogenized bovine retina, Jin et al. (2010) showed that ARL6 (608845) bound the BBS protein complex. Depletion of ARL6 in human RPE cells did not affect assembly of the complex, but it blocked its localization to cilia. Targeting of ARL6 and the protein complex to cilia required GTP binding by ARL6, but not ARL6 GTPase activity. When in the GTP-bound form, the N-terminal amphipathic helix of ARL6 bound brain lipid liposomes and recruited the BBS protein complex. Upon recruitment, the complex appeared to polymerize into an electron-dense planar coat, and it functioned in lateral transport of test cargo proteins to ciliary membranes.
By mass spectrometric analysis of transgenic mouse testis, Seo et al. (2011) found that Lxtfl1 (606568) copurified with human BBS4 and with the core mouse BBS complex subunits Bbs1, Bbs2, Bbs5, Bbs7, Bbs8, and Bbs9. Immunohistochemical analysis of human RPE cells showed colocalization of LXTFL1 and BBS9 in cytoplasmic punctae. Use of small interfering RNA revealed distinct functions for each BBS subunit in BBS complex assembly and trafficking. LZTFL1 depletion and overexpression studies showed a negative role for LZTFL1 in BBS complex trafficking, but no effect of LZTFL1 on BBS complex assembly. Mutation analysis revealed that the C-terminal half of Lztfl1 interacted with the C-terminal domain of Bbs9 and that the N-terminal half of Lztfl1 negatively regulated BBS complex trafficking. Depletion of several BBS subunits and LZTFL1 also altered Hedgehog (SHH; 600725) signaling, as measured by GLI1 (165220) expression and ciliary trafficking of SMO (SMOH; 601500).
Using computational analysis, Jin et al. (2010) found that the BBS protein complex shares structural features with the canonical coat complexes COPI (601924), COPII (see 610511), and clathrin AP1 (see 603531). BBS4 and BBS8 consist almost entirely of tetratricopeptide repeats (TPRs) (13 and 12.5 TPRs, respectively), which are predicted to fold into extended rod-shaped alpha solenoids. BBS1, BBS2, BBS7, and BBS9 each have an N-terminal beta-propeller fold followed by an amphipathic helical linker and a gamma-adaptin (AP1G1; 603533) ear motif. In BBS2, BBS7, and BBS9, the ear motif is followed by an alpha/beta platform domain and an alpha helix. In BBS1, a 4-helix bundle is inserted between the second and third blades of the beta propeller. BBS5 contains 2 pleckstrin (PLEK; 173570) homology domains and a 3-helix bundle, while BBIP10 consists of 2 alpha helices. Jin et al. (2010) concluded that the abundance of beta propellers, alpha solenoids, and appendage domains inside the BBS protein complex suggests that it shares an evolutionary relationship with canonical coat complexes.
Using homozygosity mapping of small consanguineous families with Bardet-Biedl syndrome (see BBS9; 615986) followed by comparative genomic analysis, expression studies, and sequencing, Nishimura et al. (2005) identified the parathyroid hormone-responsive gene B1 as a novel BBS gene, BBS9. The tissue expression pattern of B1 was similar to that of other BBS genes; as is the case with other BBS genes, the B1 gene is expressed in ciliated cells in C. elegans. Nishimura et al. (2005) stated that the B1 protein has no similarity to other known BBS proteins.
Vernon et al. (2003) found that the B1 gene was interrupted by a translocation t(1;7)(q42;p15) associated with WT5 in a child with Wilms tumor and skeletal abnormalities. The breakpoint bisected intron 1 of the obscurin gene (608616) on chromosome 1 and intron 22 of the B1 gene on chromosome 7. The translocation altered expression of 2 B1 isoforms. Vernon et al. (2003) also identified additional B1 splice isoforms and aberrant isoform expression in 2 of 8 additional WT5 tumors that showed 7p loss of heterozygosity. These splice variants were tumor-specific and were not associated with tumor differentiation.
In a patient with Bardet-Biedl syndrome-9 (BBS9; 615986) with consanguineous parents, Nishimura et al. (2005) demonstrated homozygosity for a splice site mutation, IVS17+1G-A (IVS17+1G-A, NM_198428), in the PTHB1 gene.
In a patient with Bardet-Biedl syndrome-9 (BBS9; 615986), Nishimura et al. (2005) identified homozygosity for an arg598-to-stop (R598X) mutation that arose from a 1792C-T transition (c.1792C-T, NM_198428) in exon 18 of the PTHB1 gene.
In a patient with Bardet-Biedl syndrome-9 (BBS9; 615986), Nishimura et al. (2005) identified homozygosity for a 1-bp insertion in exon 19 of the PTHB1 gene (c.2046insC, NM_198428) predicting a frameshift mutation, Lys683fsTer687 (K683fsX687).
In a brother and sister with Bardet-Biedl syndrome-9 (BBS9; 615986), Nishimura et al. (2005) identified a homozygous G-to-A transition in exon 5 of the PTHB1 gene (c.421G-A, NM_198428) predicting a missense mutation, gly141-to-arg (G141R).
In a brother and sister with Bardet-Biedl syndrome-9 (BBS9; 615986), Nishimura et al. (2005) identified homozygosity for a C-to-T transition (c.1063C-T, NM_198428) in exon 10 of the PTHB1 gene that resulted in a gln355-to-ter (Q355X) substitution.
In a patient with Bardet-Biedl syndrome-9 (BBS9; 615986), Nishimura et al. (2005) found compound heterozygosity for 2 mutations in the PTHB1 gene. One of the mutations involved a splice donor site (IVS5+1G-C, NM_198428); the other was a deletion of 4 nucleotides, 1877_1880delAACA (607968.0007), which was found in homozygous state in another family. The 4-bp deletion predicted a frameshift, Lys626fsTer647 (K626fsX647).
For discussion of the 4-bp deletion (c.1877_1880delAACA, NM_198428) in the BBS9 gene that was found in compound heterozygous state in a patient with Bardet-Biedl syndrome-9 (BBS9; 615986) by Nishimura et al. (2005), see 607968.0006.
In 3 Arab sibs with Bardet-Biedl syndrome-9 (BBS9; 615986), Abu-Safieh et al. (2012) identified a homozygous mutation in the PTHB1 gene (c.442+3_704del, NM_014451.3), resulting in the deletion of exon 6 (G148_V234del). One sib had most of the major features of the disorder, including obesity, mental retardation, renal disease, polydactyly, and retinitis pigmentosa, but the other 2 sibs had retinitis pigmentosa with no additional features. The findings indicated an unusually high degree of intrafamilial variability in BBS.
Abu-Safieh, L., Al-Anazi, S., Al-Abdi, L., Hashem, M., Alkuraya, H., Alamr, M., Sirelkhatim, M. O., Al-Hassnan, Z., Alkuraya, B., Mohamed, J. Y., Al-Salem, A., Alrashed, M., and 11 others. In search of triallelism in Bardet-Biedl syndrome. Europ. J. Hum. Genet. 20: 420-427, 2012. [PubMed: 22353939] [Full Text: https://doi.org/10.1038/ejhg.2011.205]
Adams, A. E., Rosenblatt, M., Suva, L. J. Identification of a novel parathyroid hormone-responsive gene in human osteoblastic cells. Bone 24: 305-313, 1999. [PubMed: 10221542] [Full Text: https://doi.org/10.1016/s8756-3282(98)00188-4]
Jin, H., White, S. R., Shida, T., Schulz, S., Aguiar, M., Gygi, S. P., Bazan, J. F., Nachury, M. V. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141: 1208-1219, 2010. [PubMed: 20603001] [Full Text: https://doi.org/10.1016/j.cell.2010.05.015]
Loktev, A. V., Zhang, Q., Beck, J. S., Searby, C. C., Scheetz, T. E., Bazan, J. F., Slusarski, D. C., Sheffield, V. C., Jackson, P. K., Nachury, M. V. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev. Cell 15: 854-865, 2008. [PubMed: 19081074] [Full Text: https://doi.org/10.1016/j.devcel.2008.11.001]
Nachury, M. V., Loktev, A. V., Zhang, Q., Westlake, C. J., Peranen, J., Merdes, A., Slusarski, D. C., Scheller, R. H., Bazan, J. F., Sheffield, V. C., Jackson, P. K. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129: 1201-1213, 2007. [PubMed: 17574030] [Full Text: https://doi.org/10.1016/j.cell.2007.03.053]
Nishimura, D. Y., Swiderski, R. E., Searby, C. C., Berg, E. M., Ferguson, A. L., Hennekam, R., Merin, S., Weleber, R. G., Biesecker, L. G., Stone, E. M., Sheffield, V. C. Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am. J. Hum. Genet. 77: 1021-1033, 2005. [PubMed: 16380913] [Full Text: https://doi.org/10.1086/498323]
Seo, S., Zhang, Q., Bugge, K., Breslow, D. K., Searby, C. C., Nachury, M. V., Sheffield, V. C. A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened. PLoS Genet. 7: e1002358, 2011. Note: Electronic Article. [PubMed: 22072986] [Full Text: https://doi.org/10.1371/journal.pgen.1002358]
Vernon, E. G., Malik, K., Reynolds, P., Powlesland, R., Dallosso, A. R., Jackson, S., Henthorn, K., Green, E. D., Brown, K. W. The parathyroid hormone-responsive B1 gene is interrupted by a t(1;7)(q42;p15) breakpoint associated with Wilms' tumour. Oncogene 22: 1371-1380, 2003. [PubMed: 12618763] [Full Text: https://doi.org/10.1038/sj.onc.1206332]