HGNC Approved Gene Symbol: BBS5
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38) : 2:169,479,494-169,506,655 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Bardet-Biedl syndrome 5 | 615983 | Autosomal recessive | 3 |
BBS5 is 1 of 7 BBS proteins that form the stable core of a protein complex required for ciliogenesis (Nachury et al., 2007).
To identify proteins involved in ciliary and basal body biogenesis and function, Li et al. (2004) undertook a comparative genomics approach that subtracted the nonflagellated proteome of Arabidopsis from the shared proteome of the ciliated/flagellated organisms Chlamydomonas and human. They identified 688 genes present exclusively in organisms with flagella and basal bodies and validated these data through a series of in silico, in vitro, and in vivo studies. Li et al. (2004) referred to this collection of genes as the flagellar apparatus-basal body (FABB) proteome. Two genes of the FABB proteome were present in the BBS5 interval on chromosome 2q31, and Li et al. (2004) identified one of these as the BBS5 gene. Amplification of exons 4 to 9 of BBS5 in a lymphoblastoid cell line and subsequent cloning and sequencing of the PCR products revealed 2 splice variants, one with exons 4 through 9 and the other lacking exon 8.
Li et al. (2004) stated that the BBS5 gene contains 12 coding exons.
By genomic sequence analysis, Li et al. (2004) mapped the BBS5 gene to chromosome 2q31.
Li et al. (2004) showed that the Bbs5 protein localizes to basal bodies in mouse and C. elegans, is under the regulatory control of Daf19 gene (600595) in C. elegans, and is necessary for the generation of both cilia and flagella.
Nachury et al. (2007) found that BBS1 (209901), BBS2 (606151), BBS4 (600374), BBS5, BBS7 (607590), BBS8 (TTC8; 608132), and BBS9 (607968) 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.
Li et al. (2004) identified pathogenic mutations in the BBS5 gene in several patients with BBS (615983). The data suggested that BBS5 contributes approximately 2% to the BBS mutation pool, an estimate consistent with the contributions of most other BBS loci. Li et al. (2004) also presented evidence that BBS5 may interact genetically with BBS1 (209901).
Hjortshoj et al. (2008) identified mutations in the BBS5 gene (603650.0005 and 603650.0006) in 5 patients from 2 unrelated non-Caucasian families with BBS.
Meehan et al. (2017) reported that knockout of Bbs5 in mice caused obesity with impaired glucose homeostasis and abnormal retinal morphology.
Li et al. (2004) found that patients with Bardet-Biedl syndrome (BBS5; 615983) from a Newfoundland family (NFB9) that defined the BBS5 locus were homozygous for an A-to-G transition at the +3 position of the exon 6 splice donor site in the BBS5 gene. The 2 available affected individuals were homozygous G/G, both parents were heterozygous A/G, and 4 unaffected sibs were either homozygous A/A or heterozygous A/G. Because this allele segregated with the disease and was absent from 100 Newfoundland control chromosomes, its effect in a lymphoblastoid cell line from one of the NFB9 patients was investigated. In contrast to the 2 BBS5 splice variants produced in a control cell line, patient NFB9 produced 3 variants, all of which resulted in a frameshift and premature termination in exon 7.
In both affected sibs of a consanguineous Saudi Arabian family (KK63) with Bardet-Biedl syndrome (BBS5; 615983), Li et al. (2004) identified a mutation in exon 6 of the BBS5 gene that resulted in a leu142-to-ter (L142X) substitution. The mutation was not present in 166 ethnically matched control chromosomes. Li et al. (2004) suggested that this mutation may lead to nonsense-mediated decay of the message.
In a consanguineous Turkish family (PB108) with Bardet-Biedl syndrome (BBS5; 615983), Li et al. (2004) identified an insertion-deletion mutation at nucleotide 263 of the BBS5 gene that had the net effect of removing a single base, resulting in a premature termination codon.
In a Kurdish family (PB127) with Bardet-Biedl syndrome (BBS5; 615983), Li et al. (2004) identified a homozygous nonsense mutation in the BBS5 gene, trp59 to ter (W59X), that was predicted to lead to premature termination.
In 4 affected sibs of a Somali family with Bardet-Biedl syndrome (BBS5; 615983), Hjortshoj et al. (2008) identified a homozygous 214G-A transition in exon 4 of the BBS5 gene, resulting in a gly72-to-ser (G72S) substitution. Each unaffected parent was heterozygous for the mutation, which was not identified in 202 ethnically matched controls.
In a patient with Bardet-Biedl syndrome (BBS5; 615983) from Sri Lanka, Hjortshoj et al. (2008) identified a homozygous 547A-G transition in exon 7 of the BBS5 gene, resulting in a thr173-to-ala (T183A) substitution. The patient was adopted, and no biologic family members were available for testing.
Hjortshoj, T. D., Gronskov, K., Philp, A. R., Nishimura, D. Y., Adeyemo, A., Rotimi, C. N., Sheffield, V. C., Rosenberg, T., Brondum-Nielsen, K. Novel mutations in BBS5 highlight the importance of this gene in non-Caucasian Bardet-Biedl syndrome patients. (Letter) Am. J. Med. Genet. 146A: 517-520, 2008. [PubMed: 18203199] [Full Text: https://doi.org/10.1002/ajmg.a.32136]
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]
Li, J. B., Gerdes, J. M., Haycraft, C. J., Fan, Y., Teslovich, T. M., May-Simera, H., Li, H., Blacque, O. E., Li, L., Leitch, C. C., Lewis, R. A., Green, J. S., and 9 others. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117: 541-552, 2004. [PubMed: 15137946] [Full Text: https://doi.org/10.1016/s0092-8674(04)00450-7]
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]
Meehan, T. F., Conte, N., West, D. B., Jacobsen, J. O., Mason, J., Warren, J., Chen, C.-K., Tudose, I., Relac, M., Matthews, P., Karp, N., Santos, L., and 52 others. Disease model discovery from 3,328 gene knockouts by the International Mouse Phenotyping Consortium. Nature Genet. 49: 1231-1238, 2017. [PubMed: 28650483] [Full Text: https://doi.org/10.1038/ng.3901]
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]
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]