Alternative titles; symbols
HGNC Approved Gene Symbol: BBS7
Cytogenetic location: 4q27 Genomic coordinates (GRCh38) : 4:121,824,329-121,870,474 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q27 | Bardet-Biedl syndrome 7 | 615984 | Autosomal recessive | 3 |
BBS7 is 1 of 7 BBS proteins that form the stable core of a protein complex required for ciliogenesis (Nachury et al., 2007).
To facilitate the recognition of critical domains in members of the BBS2 (606151) gene family, Badano et al. (2003) searched for genes with moderate similarity to BBS2 by performing phylogenetic and genomic studies using the human and zebrafish BBS2 peptide sequences to search the expressed sequence tag database (dbEST) and the translation of the draft human genome provided by the Human Genome Project. They identified 2 novel genes, initially named BBS2L1 and BBS2L2, that exhibited modest similarity with 2 discrete, overlapping regions of BBS2. They showed that BBS2L1 mutations caused Bardet-Biedl syndrome (BBS7; 615984), thereby defining a novel locus for this syndrome, BBS7, whereas BBS2L2 was shown independently to be BBS1 (209901) (Mykytyn et al., 2002). The BBS7 gene contains a single 672-amino acid open reading frame (ORF). The orthologous mouse protein exhibits 91.5% identity to the human BBS7 protein. Northern blot analysis of human adult and fetal tissues detected a 2.7-kb BBS7 transcript expressed at low to moderate levels in most human tissues. Northern blot analysis and RT-PCR confirmed the presence of 2 alternatively spliced isoforms.
Badano et al. (2003) established the presence of 19 exons in the BBS7 gene.
The BBS7 gene maps to chromosome 4q27 (Badano et al., 2003).
Nachury et al. (2007) found that BBS1 (209901), BBS2, BBS4 (600374), BBS5 (603650), BBS7, 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).
BBS7 exhibits similarity with a 252-amino acid region of BBS2, between residues 147 and 398. Badano et al. (2003) identified a domain that lies in the conserved area between residues 171 to 315 that is predicted to encode a 6-bladed beta-propeller structure. Local alignment of BBS1, BBS2, and BBS7 indicated that both BBS1 and BBS7 contain partially overlapping portions of this domain. Badano et al. (2003) concluded that this potential structural link between BBS1, BBS2, and BBS7 may indicate that these genes belong to a distinct subfamily of proteins, mutations in any of which lead to the same clinical entity.
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.
Badano et al. (2003) searched for mutations in the BBS7 gene by screening all exons and splice junctions of both splice variants of the gene in patients from 84 independent families of primarily European ancestry who had BBS. Potentially pathogenic mutations were identified in 3 pedigrees. To test whether the 'BBS2L1' locus (subsequently designated the BBS7 locus) was indeed pathogenic, Badano et al. (2003) examined genomewide genotypes from 9 consanguineous pedigrees of Saudi Arabian origin, each of which had been excluded from harboring recessive mutations in all previously known loci by haplotype and sequence analysis. In 1 pedigree, they identified a more than 5-cM region of homozygosity, on 4q26-q27, that encompassed the BBS7 genomic locus. Performing additional linkage studies, they established that only the affected individual was homozygous across the region extending at least 2.6 cM proximally and more than 3 cM distal to BBS7, and they derived a multipoint lod score of 1.8 at theta = 0.001 for D4S408, which lies 2.6 cM proximal to BBS7. A homozygous frameshift mutation (607590.0003) was found in the affected individual.
By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a 6-bp deletion in the BBS7 gene (607590.0004) in affected members of a family (M324) segregating Bardet-Biedl syndrome.
Using homozygosity mapping in a worldwide cohort of 45 BBS families, Harville et al. (2010) identified 17 causative homozygous mutations, 4 of which occurred in the BBS7 gene, in 20 families.
For a discussion of triallelic inheritance in Bardet-Biedl syndrome, see 209900.
Mei et al. (2014) found that pk2 (PRICKLE2; 608501) knockdown disrupted morphogenesis of Kupffer vesicles (KVs) in zebrafish, similar to findings in bbs7 knockdown zebrafish, suggesting that pk2 and bbs7 might functionally interact. However, KV morphology defects in pk2 and bbs7 double-knockdown zebrafish appeared to be additive rather than synergistic. Further analysis of cilia length, neural tube polarity, protein localization, protein interaction, and intracellular transport confirmed that pk2 and bbs7 did not act synergistically. The authors proposed that pk2 and bbs7 act independently in distinct pathways that, in specific tissue contexts, converge on the same processes.
In 2 pedigrees, Badano et al. (2003) found that individuals with Bardet-Biedl syndrome (BBS7; 615984) were homozygous for a his323-to-arg (H323R) alteration in exon 10 of the BBS7 gene.
In both arms of a family, Badano et al. (2003) found that individuals with Bardet-Biedl syndrome (BBS7; 615984) were homozygous for a thr211-to-ile (T211I) alteration in the BBS7 gene. In one arm of the family an affected individual was the offspring of a consanguineous mating. Affected individuals also carried a glu234-to-lys (E234K) alteration in exon 8 of BBS1 (209901.0006), raising the possibility that BBS7 may interact genetically with other loci to produce the BBS phenotype.
In a consanguineous Saudi pedigree with Bardet-Biedl syndrome (BBS7; 615984), Badano et al. (2003) identified a homozygous 4-bp deletion in the BBS7 gene that abolished the lysine at position 237 in exon 7 and which, by conceptual translation, resulted in premature termination in exon 9, at residue 296 (K237fsX296). That this alteration eliminated nearly 65% of the predicted protein, its absence from 288 control chromosomes, including 96 chromosomes of normal, unrelated Saudi individuals, and previously obtained mutational data supported the view that BBS2L1 represents a novel BBS locus, which was termed BBS7.
In a family (M324) in which 4 of 6 children of first-cousin parents had Bardet-Biedl syndrome (BBS7; 615984) characterized by severe intellectual disability, polydactyly, and obesity, Najmabadi et al. (2011) identified a 6-bp deletion at codon 533 (chr4:122973915-122973920, NCBI36) in the BBS7 gene. This mutation was found in homozygosity in affected individuals and segregated with the disease in the family.
Badano, J. L., Ansley, S. J., Leitch, C. C., Lewis, R. A., Lupski, J. R., Katsanis, N. Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am. J. Hum. Genet. 72: 650-658, 2003. [PubMed: 12567324] [Full Text: https://doi.org/10.1086/368204]
Harville, H. M., Held, S., Diaz-Font, A., Davis, E. E., Diplas, B. H., Lewis, R. A., Borochowitz, Z. U., Zhou, W., Chaki, M., MacDonald, J., Kayserili, H., Beales, P. L., Katsanis, N., Otto, E., Hildebrandt, F. Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping. J. Med. Genet. 47: 262-267, 2010. [PubMed: 19797195] [Full Text: https://doi.org/10.1136/jmg.2009.071365]
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]
Mei, X., Westfall, T. A., Zhang, Q., Sheffield, V. C., Bassuk, A. G., Slusarski, D. C. Functional characterization of Prickle2 and BBS7 identify overlapping phenotypes yet distinct mechanisms. Dev. Biol. 392: 245-255, 2014. [PubMed: 24938409] [Full Text: https://doi.org/10.1016/j.ydbio.2014.05.020]
Mykytyn, K., Nishimura, D. Y., Searby, C. C., Shastri, M., Yen, H., Beck, J. S., Braun, T., Streb, L. M., Cornier, A. S., Cox, G. F., Fulton, A. B., Carmi, R., Luleci, G., Chandrasekharappa, S. C., Collins, F. S., Jacobson, S. G., Heckenlively, J. R., Weleber, R. G., Stone, E. M., Sheffield, V. C. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nature Genet. 31: 435-438, 2002. [PubMed: 12118255] [Full Text: https://doi.org/10.1038/ng935]
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]
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]
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]