HGNC Approved Gene Symbol: BBS1
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38): 11:66,510,635-66,533,598 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | Bardet-Biedl syndrome 1 | 209900 | Autosomal recessive; Digenic recessive | 3 |
BBS1 is 1 of 7 BBS proteins that form the stable core of a protein complex required for ciliogenesis (Nachury et al., 2007).
By positional cloning, Mykytyn et al. (2002) identified the gene that is mutant in Bardet-Biedl syndrome-1 (BBS1; 209900). It was selected for further examination because it encodes a protein with modest similarity to the BBS2 protein (606151). The gene consists of 3,370 bp with an open reading frame of 593 codons. By Northern blot analysis, Mykytyn et al. (2002) demonstrated that BBS1 was ubiquitously expressed, including expression in fetal tissues, testis, retina, and adipose tissue. The pattern of expression was similar to those seen for BBS2, BBS4 (600374), and BBS6 (MKKS; 604896).
Mykytyn et al. (2002) found that the BBS1 gene contains 17 exons and spans approximately 23 kb. Mykytyn et al. (2003) showed that the BBS1 gene is highly conserved between mouse and human.
Mykytyn et al. (2002) identified the BBS1 gene within the critical region defined for Bardet-Biedl syndrome-1 on chromosome 11q34.
Based on genomic sequence analysis, Sheffield (2003) assigned the mouse Bbs1 gene to chromosome 19.
Nachury et al. (2007) found that BBS1, BBS2 (606151), BBS4 (600374), BBS5 (603650), 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.
Ishizuka et al. (2011) reported that phosphorylation of DISC1 (605210) acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons in mice. Unphosphorylated DISC1 regulates canonical Wnt signaling via an interaction with GSK3-beta (605004), whereas specific phosphorylation at serine-710 triggers the recruitment of Bardet-Biedl syndrome (see 209900) proteins to the centrosome. In support of this model, loss of BBS1 (209901) leads to defects in migration, but not proliferation, whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, whereas a phospho-mimic mutant rescues exclusively migration defects. Ishizuka et al. (2011) concluded that their data highlight a dual role for DISC1 in corticogenesis and indicate that phosphorylation of this protein at serine-710 activates a key developmental switch.
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.
Mykytyn et al. (2002) sequenced the BBS1 gene in the probands from 6 families (5 of Puerto Rican and 1 of Turkish ancestry) showing linkage to the BBS1 region on chromosome 11. In a consanguineous Puerto Rican family, they found a homozygous G-to-T transversion in exon 16 that results in a nonsense mutation, glu549 to ter (E549X; 209901.0002). In a second consanguineous Puerto Rican family, they found a homozygous T-to-G transversion in exon 12, predicted to result in a nonconservative substitution from methionine to arginine at codon 390 (M390R; 209901.0001). Two additional Puerto Rican families were compound heterozygotes with respect to the E549X and M390R mutations. Analysis of a fifth Puerto Rican revealed the presence of a heterozygous E549X mutation and a heterozygous G-to-A transition at the +1 position of the splice donor site in exon 4 (432+1G-A; 209901.0003). Affected individuals in the consanguineous Turkish family showed a homozygous deletion of 1 bp in exon 10, resulting in a premature termination at codon 288 (Tyr284fsTer288; 209901.0004). In an evaluation of 60 unrelated North American probands with BBS of mostly northern European ancestry for the presence of the 4 mutations identified in the extended families, using single-strand conformation polymorphism (SSCP) analysis, Mykytyn et al. (2002) identified 22 individuals who had at least 1 copy of the M390R mutation. Of these 22 individuals, 16 were homozygous with respect to this variant (allele frequency = 0.32). A sequence variant was not detected in 192 control chromosomes from individuals of mostly northern European ancestry.
Mykytyn et al. (2002) found that in their families with BBS1 the disorder segregated as an autosomal recessive disease, with no evidence of involvement of the common M390R mutation in triallelic inheritance. See the INHERITANCE section of 209900 for a full discussion. Badano et al. (2003) found heterozygous mutation in BBS1 (209901.0006) and homozygous mutation in BBS7 (607590.0002) in affected individuals, raising the possibility that BBS7 may interact genetically with other loci to produce the BBS phenotype.
Beales et al. (2003) presented a comprehensive analysis of the spectrum, distribution, and involvement in nonmendelian trait transmission of mutant alleles in BBS1, the most common BBS locus. Analyses of 259 independent families segregating a BBS phenotype indicated that BBS1 participates in complex inheritance and that, in different families, mutations in BBS1 can interact genetically with mutations at each of the other known BBS genes, as well as genes at unknown loci, to cause the phenotype. Consistent with this model, they identified homozygous M390R alleles (209901.0001), the most frequent BBS1 mutation, in asymptomatic individuals in 2 families. Moreover, their statistical analyses indicated that the prevalence of the M390R allele in the general population is consistent with an oligogenic rather than a recessive model of disease transmission. Although all BBS alleles appeared to be capable of interacting genetically with each other, some genes, especially BBS2 and BBS6, are more likely to participate in triallelic inheritance, suggesting a variable ability of the BBS proteins to interact genetically with each other.
Mykytyn et al. (2003) evaluated the involvement of the BBS1 gene in a cohort of 129 probands with BBS and reported 10 novel BBS1 mutations, including a leu518-to-pro (L518P; 209901.0005) mutation.
Davis et al. (2007) generated a knockin mouse model of the BBS1 M390R mutation. Mice homozygous for M390R recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. Morphologic evaluation of Bbs1 mutant brain revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Ultrastructural examination of the ependymal cell cilia that lined the enlarged third ventricle of Bbs1 mutant brains showed that, whereas the 9+2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Davis et al. (2007) concluded that the M390R mutation does not affect axonemal structure, but it may play a role in regulation of cilia assembly and/or function.
Using mice lacking Bbs2, Bbs4, or Bbs6 and mice with the M390R mutation in Bbs1, Shah et al. (2008) showed that expression of BBS proteins was not required for ciliogenesis, but their loss caused structural defects in a fraction of cilia covering airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia, and this same misshapen appearance was present in airway cilia from all mutant mouse strains. Cilia of Bbs4-null and Bbs1 mutant mice beat at a lower frequency than wildtype cilia. Neither airway hyperresponsiveness nor inflammation increased in Bbs2- or Bbs4-null mice immunized with ovalbumin compared with wildtype mice. Instead, mutant animals were partially protected from airway hyperresponsiveness.
By immunostaining for axonemal proteins, Tan et al. (2007) demonstrated that mouse dorsal root ganglion neurons contain cilia. Bbs1-null and Bbs4-null mice demonstrated behavioral deficits in thermosensation and mechanosensation associated with alterations in the trafficking of the thermosensory channel Trpv1 (602076) and the mechanosensory channel Stoml3 (608327) within sensory neurons. The findings were replicated in C. elegans lacking Bbs7 or Bbs8 (TTC8; 608132). Detailed examination of 9 patients with BBS showed a noticeable decrease in peripheral sensation in most of them.
Mykytyn et al. (2002) identified a met390-to-arg (M390R) mutation in the BBS1 gene in affected members of a consanguineous Puerto Rican family with Bardet-Biedl syndrome (BBS1; 209900). The substitution results from a T-to-G transversion at nucleotide 1169 (1169T-G) in exon 12 (Mykytyn, 2002). Two other Puerto Rican families carried this mutation and the glu549-to-ter mutation (209901.0002) in compound heterozygosity. Mykytyn et al. (2002) found the M390R mutation in 22 of 60 unrelated North American probands with Bardet-Biedl syndrome of mostly northern European ancestry. Sixteen of the 22 individuals were homozygous for the variant (allele frequency = 0.32).
Mykytyn et al. (2003) found that the M390R mutation accounts for approximately 80% of all BBS1 mutations and is found on a similar genetic background across populations.
Beales et al. (2003) identified homozygous M390R alleles in asymptomatic individuals in 2 separate families. They interpreted this as consistent with an oligogenic rather than a recessive model of disease transmission, as seen in triallelic inheritance.
Fan et al. (2004) reported the cases of 2 sisters homozygous for the M390R mutation. One sister, who was also heterozygous for a G169A mutation in the BBS3 gene (600151.0002), was more severely affected than the sister without the additional mutation, suggesting a modifying effect of the mutation in BBS3.
In a 53-year-old woman with 'juvenile retinitis pigmentosa-like' retinal features consistent with those seen in other BBS1 patients, but who had no syndromic features, Wang et al. (2013) identified homozygosity for the M390R mutation in the BBS1 gene. The authors stated that the mutation segregated with disease in the family, and noted that such patients should be followed for the potential development of syndromic phenotypes.
In a consanguineous Puerto Rican family with Bardet-Biedl syndrome (BBS1; 209900), Mykytyn et al. (2002) found a homozygous G-to-T transversion at nucleotide 1655 (1655G-T) in exon 16 of the BBS1 gene that resulted in a glu549-to-ter (E549X) nonsense mutation.
In a Puerto Rican family with Bardet-Biedl syndrome (BBS1; 209900), Mykytyn et al. (2002) found a heterozygous G-to-A transition at the +1 position of the splice donor site in exon 4 of the BBS1 gene (432+1G-A). Affected individuals were compound heterozygous for the E549X mutation (209901.0002).
In a consanguineous Turkish family with Bardet-Biedl syndrome (BBS1; 209900), Mykytyn et al. (2002) found a homozygous deletion of 1 bp in exon 10 of the BBS1 gene (851delA), resulting in premature termination at codon 288 (Tyr284fsTer288).
One of 10 novel mutations in the BBS1 gene reported by Mykytyn et al. (2003) was a 1553T-C transition in exon 15 of the cDNA, resulting in a leu518-to-pro (L518P) change. It was detected in 3 patients with Bardet-Biedl syndrome (BBS1; 209900), all in combination with the M390R mutation (209901.0001), and in none of 96 control subjects.
In a family with Bardet-Biedl syndrome (BBS1; 209900), Badano et al. (2003) found a heterozygous glu234-to-lys (E234K) mutation in the BBS1 gene in all 3 affected members. These individuals were also homozygous for a thr211-to-ile (T211I) amino acid substitution in the BBS7 gene (607590.0002), raising the possibility that the BBS1 and BBS7 loci interact. Since none of the unaffected sibs was homozygous for the defect in BBS7, it was considered equally likely that the third mutant allele (in BBS1) is either required for pathogenesis of the BBS7 phenotype or modifies the phenotype.
In 2 sisters with BBS1 (209900), Badano et al. (2003) identified compound heterozygosity for mutations in the BBS1 gene: a 1-bp deletion in exon 16, 1650delC, resulting in a frameshift at codon 548 and a premature stop at codon 579, and met390-to-arg (M390R; 209901.0001). The more severely affected sister was heterozygous for a thr325-to-pro substitution in the MKKS gene (T325P; 604896.0014).
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Badano, J. L., Kim, J. C., Hoskins, B. E., Lewis, R. A., Ansley, S. J., Cutler, D. J., Castellan, C., Beales, P. L., Leroux, M. R., Katsanis, N. Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. Hum. Molec. Genet. 12: 1651-1659, 2003. [PubMed: 12837689] [Full Text: https://doi.org/10.1093/hmg/ddg188]
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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]
Mykytyn, K. Personal Communication. Iowa City, Iowa 11/18/2002.
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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]
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Sheffield, V. C. Personal Communication. Iowa City, Iowa 3/6/2003.
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