HGNC Approved Gene Symbol: BBS2
Cytogenetic location: 16q13 Genomic coordinates (GRCh38) : 16:56,470,403-56,520,024 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q13 | Bardet-Biedl syndrome 2 | 615981 | Autosomal recessive | 3 |
| Retinitis pigmentosa 74 | 616562 | Autosomal recessive | 3 |
BBS2 is 1 of 7 BBS proteins that form the stable core of a protein complex required for ciliogenesis (Nachury et al., 2007).
Nishimura et al. (2001) used physical mapping and sequence analysis to identify a novel BBS gene (designated BBS2) on chromosome 16q21. The BBS2 locus had been initially mapped to an 18-cM interval in a large inbred Bedouin kindred (Kwitek-Black et al., 1993); further analysis refined this locus to a 2-cM region distal to marker D16S408. The BBS2 open reading frame of 2163 bp encodes 721 amino acids. The gene is evolutionarily conserved and displays a wide pattern of tissue expression, including brain, kidney, adrenal gland, and thyroid gland. Mutations in the gene were identified in 3 of 18 unrelated BBS families.
Using microarray analysis, Shah et al. (2008) showed that human airway epithelia expressed all 12 BBS genes. Immunohistochemical analysis localized BBS2 and BBS4 (600374) to cellular structures associated with motile cilia.
Nishimura et al. (2001) found that the BBS2 gene contains 17 exons.
By physical mapping and sequence analysis, Nishimura et al. (2001) mapped the BBS2 gene to chromosome 16q21.
Gross (2015) mapped the BBS2 gene to chromosome 16q13 based on an alignment of the BBS2 sequence (GenBank AF342736) with the genomic sequence (GRCh38).
Nachury et al. (2007) found that BBS1 (209901), BBS2, 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.
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.
Bardet-Biedl Syndrome 2
By mutation screening of the BBS2 gene, Nishimura et al. (2001) revealed a homozygous 1-bp deletion in exon 8 (606151.0001) in a family with BBS (BBS2; 615981), predicting a protein product that is truncated 10 amino acids downstream of the deletion at codon 324. Two sequence variants were found on the affected chromosome in the other family. A T-to-G transversion at nucleotide 224, predicting a val75-to-gly substitution (606151.0002) in exon 2, was postulated to be the disease-causing mutation in this family.
In several families with Bardet-Biedl syndrome, Katsanis et al. (2001) identified numerous novel nonsense, frameshift, and missense mutations in the BBS2 gene in homozygosity and compound heterozygosity. Interestingly, 40% of these patients also had a third mutation in another BBS gene.
Retinitis Pigmentosa 74
In a Moroccan Jewish family in which 3 sibs with nonsyndromic retinitis pigmentosa (RP74; 616562) were found to be negative for mutations in previously reported RP-associated genes, Shevach et al. (2015) performed exome sequencing of the BBS2 gene and identified compound heterozygous missense mutations (A33D, 606151.0019 and P134R, 606151.0020) that segregated with the disorder. In further studies of 4 Ashkenazi Jewish families, Shevach et al. (2015) identified additional homozygous and compound heterozygous mutations in the BBS2 gene (see, e.g., 606151.0009-606151.0010).
Nishimura et al. (2004) found that Bbs2 -/- mice were born at less than the expected mendelian ratios. Mutant mice showed major components of the human phenotype, including obesity and retinopathy, and they also showed defective social function. The retinopathy in mutant mice was associated with cilia dysfunction. Other phenotypes in mutant mice associated with cilia dysfunction included renal cysts, male infertility, and a deficit in olfaction. Except for male infertility, these phenotypes were not caused by a complete absence of cilia. Bbs2 retinopathy involved normal retina development, followed by apoptotic death of photoreceptors. Photoreceptor death was preceded by mislocalization of rhodopsin, indicating a defect in protein transport.
Using mice lacking Bbs2, Bbs4, or Bbs6 (MKKS; 604896) and mice with the met390-to-arg (M390R; 209901.0001) mutation in Bbs1 (209901), 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.
Berbari et al. (2008) reported that BBS proteins are required for the localization of G protein-coupled receptors to primary cilia on central mouse neurons. Neurons deficient in Bbs2 or Bbs4 lacked ciliary localization of Sstr3 (182453) and Mchr1 (GPR24; 601751). Because MCHR1 is involved in the regulation of feeding behavior, Berbari et al. (2008) concluded that the BBS phenotype is due to altered signaling caused by mislocalization of ciliary signaling proteins.
Rahmouni et al. (2008) studied Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice and found that obesity was associated with hyperleptinemia (164160) and resistance to the anorectic and weight-reducing effects of leptin. Although all 3 of the BBS mouse models were similarly resistant to the metabolic actions of leptin, only Bbs4 -/- and Bbs6 -/- mice remained responsive to the effects of leptin on renal sympathetic nerve activity and arterial pressure and developed hypertension. The authors also found that BBS mice had decreased hypothalamic expression of proopiomelanocortin (POMC; 176830), and suggested that BBS genes play an important role in maintaining leptin sensitivity in POMC neurons.
Seo et al. (2009) showed that BBS proteins were required for leptin receptor (LEPR; 601007) signaling in the hypothalamus in mice. Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice were resistant to the action of leptin to reduce body weight and food intake regardless of serum leptin (LEP; 164160) levels and obesity. Activation of hypothalamic Stat3 (102582) by leptin was significantly decreased in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice. In contrast, downstream melanocortin receptor (see 155555) signaling was unaffected, indicating that Lepr signaling was specifically impaired in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice. Impaired Lepr signaling in BBS mice was associated with decreased Pomc (176830) gene expression. The human BBS1 protein physically interacted with LEPR, and loss of BBS proteins perturbed LEPR trafficking in human cells. Seo et al. (2009) concluded that BBS proteins mediate LEPR trafficking and that impaired LEPR signaling may underlie energy imbalance in BBS.
In affected members of a family with Bardet-Biedl syndrome (BBS2; 615981), Nishimura et al. (2001) identified a homozygous 1-bp deletion in exon 8 (940delA) of the BBS2 gene, predicting a truncated protein 10 amino acids downstream from codon 324.
In the large inbred Bedouin BBS (BBS2; 615981) family described by Kwitek-Black et al. (1993) (family 1), Nishimura et al. (2001) revealed a T-to-G transversion at position 224 of the BBS2 gene, resulting in a val75-to-gly substitution in exon 2. Two sequence variants were found on the affected chromosome in this family; this sequence variant was postulated to be the disease-causing mutation.
Katsanis et al. (2001) identified homozygosity for a tyrosine-to-termination substitution at codon 24 (Y24X) of the BBS2 gene in 2 unrelated patients with Bardet-Biedl syndrome (BBS2; 615981). One of those patients carried an additional mutation in the BBS6 gene (ala242-to-ser; see 604896.0001). The Y24X mutation was also found in compound heterozygosity with the gln59-to-ter mutation (606151.0004) in a patient who carried a third mutation in the MKKS gene (Q147X; 604896.0012).
In a BBS2 (615981) patient, Katsanis et al. (2001) identified compound heterozygosity for a glutamine-to-termination substitution at codon 59 in the BBS2 gene. This mutation was found with the Y24X mutation (606151.0003) and also the gln147-to-ter mutation in MKKS (604896.0012).
In a BBS2 (615981) patient, Katsanis et al. (2001) identified an arg-to-ter substitution at codon 275 of the BBS2 gene in homozygosity.
In a patient with Bardet-Biedl syndrome (BBS2; 615981), Katsanis et al. (2001) found homozygosity for an arg-to-trp mutation at codon 315 of the BBS2 gene. This patient was also homozygous by descent for the BBS4 locus (600374).
In a patient with Bardet-Biedl syndrome (BBS2; 615981), Katsanis et al. (2001) identified homozygosity for a frameshift mutation at codon 170 of the BBS2 gene, resulting in a termination codon at codon 171. In addition to these 2 mutations, the patient was also homozygous by descent for the BBS1 locus (209901).
In a patient with Bardet-Biedl syndrome (BBS2; 615981), Katsanis et al. (2001) identified homozygosity for a frameshift at codon 210 of the BBS2 gene, resulting in a termination codon at residue 246.
Bardet-Biedl Syndrome 2
In a patient with Bardet-Biedl syndrome (BBS2; 615981), Katsanis et al. (2001) identified compound heterozygosity for an aspartic acid-to-alanine substitution at codon 104 (D104A) of the BBS2 gene. The other allele contained an arg-to-pro substitution at codon 634 (later corrected to arg632-to-pro (R632P; 606151.0010) by Shevach et al., 2015). Katsanis et al. (2001) also identified a patient who was linked to the BBS1 locus who carried the D104A mutation in BBS2.
Retinitis Pigmentosa 74
In 2 brothers in a nonconsanguineous Ashkenazi Jewish family (MOL0970) with nonsyndromic retinitis pigmentosa-74 (RP74; 616562) who were found to be negative for previously reported RP-associated genes and for other genes associated with BBS, Shevach et al. (2015) identified homozygosity for a c.311A-C transversion in the BBS2 gene, resulting in a D104A substitution. In 2 patients with nonsyndromic RP from unrelated nonconsanguineous Ashkenazi Jewish families (MOL0714 and RD158), Shevach et al. (2015) identified compound heterozygosity for D104A and R632P (606151.0010).
Bardet-Biedl Syndrome 2
In a patient with Bardet-Biedl syndrome (BBS2; 615981) but with normal development and no evidence of renal dysplasia, Katsanis et al. (2001) identified compound heterozygosity for mutations in the BBS2 gene: an arg-to-pro substitution at codon 634 (later corrected to codon 632 (R632P) by Shevach et al., 2015) and an asp-to-ala substitution at codon 104 (D104A; 606151.0009).
Retinitis Pigmentosa 74
In 2 Ashkenazi Jewish patients with nonsyndromic retinitis pigmentosa-74 (RP74; 616562) from unrelated nonconsanguineous families (MOL0714 and RD158), Shevach et al. (2015) identified the same compound heterozygous mutations in the BBS2 gene that had been identified in a patient with Bardet-Biedl syndrome-2 reported by Katsanis et al. (2001): a c.1895G-C transversion (rs138043021), resulting in an R632P substitution, and D104A (606151.0009).
In a patient (PB045) with Bardet-Biedl syndrome (see BBS2, 615981) genetically excluded from the BBS2 locus, Katsanis et al. (2001) nevertheless identified one BBS2 mutation, a G-to-C substitution at the splice acceptor site of intron 1.
In a patient with Bardet-Biedl syndrome (BBS2; 615981) linked to the BBS1 locus (209901), Katsanis et al. (2001) found a third mutation in BBS2: a frameshift mutation at codon 158, resulting in a premature termination codon at residue 200.
In a BBS (615981) patient homozygous for a missense mutation in the MKKS gene (Y37C; 604896.0003), Katsanis et al. (2001) identified a third mutation in the BBS2 gene: an asparagine-to-serine substitution at codon 70.
In a patient with Bardet-Biedl syndrome (BBS2; 615981), Katsanis et al. (2001) identified compound heterozygosity for 2 termination codons in the BBS2 gene: the first was a frameshift mutation at codon 168, resulting in a termination codon at residue 170. This was in compound heterozygosity with an arg216-to-ter mutation (606151.0016). This patient was also found to have a third mutation in the MKKS gene, cys499-to-ser (604896.0013).
In a patient with Bardet-Biedl syndrome (BBS2; 615981), Katsanis et al. (2001) found homozygosity for a threonine-to-isoleucine substitution at codon 560 of the BBS2 gene. This patient also was homozygous by descent for the BBS4 locus (600374).
In a patient with Bardet-Biedl syndrome (BBS2; 615981), Katsanis et al. (2001) identified compound heterozygosity for mutations in the BBS2 gene, a frameshift mutation at codon 168 (606151.0014) and an arg-to-ter substitution at codon 216. This patient also carried a third mutation at the MKKS locus (cys499 to ser; 604896.0013).
In 2 affected individuals from a sibship within the large consanguineous Lebanese kindred with Bardet-Biedl syndrome (BBS2; 615981) reported by Stoetzel et al. (2006), Laurier et al. (2006) identified a homozygous gly139-to-val (G139V) substitution in the BBS2 gene. Other affected individuals in different sibships of the same kindred were found to have mutations in the BBS10 gene (610148.0004 and 610148.0005). There was no evidence for triallelism. The authors commented on the unusual finding of mutations in 2 different genes within a single large consanguineous kindred.
In a 19-year-old Hutterite man with Bardet-Biedl syndrome (BBS2; 615981), Innes et al. (2010) identified a homozygous G-to-A transition in intron 3 of the BBS2 gene (472-2A-G), resulting in a splice site mutation. The mutation was identified by genomewide SNP microarray analysis, as microsatellite analysis failed to confirm a candidate region of homozygosity by descent. Two abnormal transcripts were identified from the patient's cDNA: 1 lacking exon 4 and the other lacking exons 3 and 4. Three additional Hutterite patients with BBS were found to share the same haplotype surrounding the mutation, consistent with a founder effect in this population. Innes et al. (2010) estimated the age of the mutation to be more than 135 years.
Among 1,518 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 42 heterozygotes and no homozygotes for the BBS2 IVS3-2A-G mutation, for a frequency of 0.028, or 1 in 36. This is a private mutation in the Hutterite population.
In a nonconsanguineous Moroccan Jewish family (MOL0369) in which 3 sibs with nonsyndromic retinitis pigmentosa (RP74; 616562) were found to be negative for mutations in previously reported RP-associated genes, Shevach et al. (2015) performed exome sequencing of the BBS2 gene and identified compound heterozygous missense mutations: a c.98C-A transversion, resulting in an ala-to-asp (A33D) substitution, and a c.401C-G transversion, resulting in a pro134-to-arg (P134R; 606151.0020) substitution. The affected amino acids are highly conserved in evolution. The mutations segregated with the disorder in the family. The c.98C-A mutation was absent in 160 control chromosomes, and the c.401C-G mutation was found in 1 of 160 control chromosomes. Neither mutation was found in the Exome Variant Server database.
For discussion of the c.401C-G transversion in the BBS2 gene, resulting in a pro134-to-arg (P134R) substitution, that was found in compound heterozygous state in patients with nonsyndromic retinitis pigmentosa (RP74; 616562) by Shevach et al. (2015), see 606151.0019.
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Gross, M. B. Personal Communication. Baltimore, Md. 9/21/2015.
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