Alternative titles; symbols
HGNC Approved Gene Symbol: BBS10
Cytogenetic location: 12q21.2 Genomic coordinates (GRCh38): 12:76,344,474-76,348,415 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q21.2 | Bardet-Biedl syndrome 10 | 615987 | Autosomal recessive | 3 |
Stoetzel et al. (2006) identified the C12ORF58 gene in a genomewide scan for novel Bardet-Biedl syndrome (BBS; 209900) genes. The C12ORF58 gene encodes a 723-amino acid protein that defines a novel chaperonin subfamily.
The C12ORF58 gene is composed of 2 exons (Stoetzel et al., 2006).
The C12ORF58 gene maps to chromosome 12q (Stoetzel et al., 2006).
Marion et al. (2009) found that human preadipocytes transiently formed a primary cilium that carried Wnt (see WNT1; 164820) and hedgehog (see SHH; 600725) receptors during preadipocyte differentiation. Immunohistochemical showed that both BBS10 and BBS12 (610683) localized to the basal body of this primary cilium, and both proteins maintained this localization in unciliated fat cells. Knockdown of BBS10 and BBS12 expression by RNA interference reduced the number of ciliated cells and increased the amount of unphosphorylated active GSK3 (see GSK3A; 606784), a key regulator of adipogenesis that is repressed by Wnt signaling. Furthermore, differentiation of BBS10 and BBS12 patient fibroblasts into fat-accumulating cells was associated with increased triglyceride content compared with control cells. Marion et al. (2009) concluded that a primary dysfunction of adipogenesis results in the development of obesity in BBS.
In a population-based study including 93 BBS patients from 74 families of various ethnicities, Billingsley et al. (2010) determined that the chaperonin-like BBS6 (604896), BBS10, and BBS12 genes are a major contributor to the disorder. Biallelic mutations in these 3 genes were found in 36.5% of the families: 4 patients had mutations in BBS6, 19 had mutations in BBS10, and 10 had mutations in BBS12. Overall, 26 (68%) of 38 mutations were novel. Six patients had mutations present in more than 1 chaperonin-like BBS gene, and 1 patient with a very severe phenotype had 4 mutations in BBS10. The phenotypes observed were beyond the classic BBS phenotype and overlapped with characteristics of MKKS (236700), including congenital heart defect, vaginal atresia, hydrometrocolpos, and cryptorchidism, and with Alstrom syndrome (203800), including diabetes, hearing loss, liver abnormalities, endocrine anomalies, and cardiomyopathy.
In affected members of a large, consanguineous kindred of Lebanese origin with Bardet-Biedl syndrome-10 (BBS10; 615987), Stoetzel et al. (2006) identified a homozygous missense mutation in the C12ORF58 gene (S311A; 610148.0004). The mutation, which was found by linkage analysis followed by candidate gene sequencing, was not present in 107 Lebanese or 50 European control individuals. Analysis of this gene in a few multiplex or consanguineous families in which linkage analysis was compatible with a chromosome 12 locus uncovered several truncating mutations (see, e.g., 610148.0001), indicating that C12ORF58 indeed represented a new BBS locus, BBS10. Stoetzel et al. (2006) found C12ORF58 to be mutated in about 20% of an unselected cohort of families of various ethnic origins, including some families with mutations in other BBS genes, consistent with oligogenic inheritance. In zebrafish, mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants.
Putoux et al. (2010) identified homozygous or compound heterozygous C12ORF58 mutations in 5 of 21 patients with antenatal onset of severe renal cystic anomalies and polydactyly, without the biliary or hepatic abnormalities characteristic of Meckel syndrome (MKS; 249000); the phenotype was thus consistent with BBS. Four of the patients were fetuses between ages 21 and 26 weeks' gestation, and the fifth was a 20-year-old woman with BBS who was found to have hyperechogenic kidneys and polydactyly on antenatal ultrasound. The most common mutation was a 1-bp duplication (271dupT; 610148.0001), found on 6 of 10 mutant C12ORF58 alleles. Putoux et al. (2010) noted that the diagnosis of severe lethal BBS is suggested in utero by the findings of severe cystic kidneys and polydactyly without biliary dysgenesis or brain anomalies, and concluded that mutations in the C12ORF58 gene may account for a high percentage of such cases.
Stoetzel et al. (2006) modeled loss of function of the BBS10 gene in zebrafish. Suppression of the maternal bbs10 message caused shortening of the rostrocaudal body axis; dorsal thinning, broadening, and kinking of the notochord; elongation of the somites; and decreased somitic definition and symmetry. Mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants.
The most common mutation in the BBS10 gene found by Stoetzel et al. (2006) among families with Bardet-Biedl syndrome (BBS10; 615987) was a 1-bp insertion (271dupT) in residue 91 leading to premature termination 4 codons later (Cys91fsTer95). The 271dupT mutation accounted for 46% of BBS10 mutant alleles. Although this allele was most frequent in Europeans, reminiscent of the prevalence of the M390R mutation (209901.0001) in Europeans in BBS1, Stoetzel et al. (2006) also found it in families of Turkish and Afghan origin, suggesting that it may represent either an ancient allele or a site of recurrent mutations. A SNP-based haplotype analysis showed the former to be the likely case, since a common haplotype on the 271dupT-bearing chromosome extending at least 175 kb distally in all ethnic groups in the cohort was found.
Putoux et al. (2010) identified the 271dupT mutation in exon 2 of the BBS10 gene in 4 unrelated fetuses and a patient who presented antenatally with cystic renal anomalies and polydactyly. One fetus was homozygous, and 3 were compound heterozygous with another pathogenic BBS10 mutation (see, e.g., 610148.0006 and 610148.0007); the fifth patient, a 20-year-old woman with BBS, was homozygous for 271dupT and also carried a truncating mutation in the BBS6 gene (604896).
Of 16 different missense mutations of the BBS10 gene detected by Stoetzel et al. (2006) in families with Bardet-Biedl syndrome (BBS10; 615987), arg34-to-pro (R24P) was the one closest to the N terminus.
In a family with Bardet-Biedl syndrome (BBS10; 615987), Stoetzel et al. (2006) detected a single BBS10 mutation, Ser303fsTer305, in association with 2 bona fide BBS1 mutations, M390R (209901.0001) and E549X (209901.0002).
In the large consanguineous Lebanese family in which Bardet-Biedl syndrome (BBS10; 615987) showing linkage to chromosome 12q was identified, Stoetzel et al. (2006) detected a homozygous ser311-to-ala (S311A) amino acid change in the BBS10 gene as the cause of the disorder.
In the only affected individual from a sibship within a large consanguineous Lebanese kindred with Bardet-Biedl syndrome reported by Stoetzel et al. (2006), Laurier et al. (2006) found compound heterozygosity for the S311A mutation and a val11-to-gly (V11G) mutation (610148.0005) in the BBS10 gene. Affected individuals from 3 other sibships in this kindred were homozygous for the S311A mutation. Laurier et al. (2006) commented on the unusual finding of homozygosity and compound heterozygosity for mutations in the same gene within a single large consanguineous kindred.
For discussion of the val11-to-gly (V11G) mutation in the BBS10 gene that was found in compound heterozygous state in a patient with Bardet-Biedl syndrome (BBS10; 615987) by Laurier et al. (2006), see 610148.0004.
In 2 fetuses diagnosed with Bardet-Biedl syndrome (BBS10; 615987), Putoux et al. (2010) identified compound heterozygosity for a 2-bp deletion (1044delTT) in exon 2 of the BBS10 gene, resulting in a frameshift and premature termination, and another pathogenic mutation in the BBS10 gene: 271dupT (610148.0001) and a 273C-G transversion in exon 2, resulting in a cys91-to-trp (C91W; 610148.0007) substitution, respectively. The fetuses were identified at 26 and 21 weeks' gestation, respectively, on the basis of ultrasonographic findings of severe cystic kidney disease and polydactyly. One of the fetuses was found to have situs ambiguus, a less common clinical finding in BBS.
For discussion of the cys91-to-trp (C91W) mutation in the BBS10 gene that was found in compound heterozygous state in a fetus diagnosed with Bardet-Biedl syndrome (BBS10; 615987) by Putoux et al. (2010), see 610148.0006.
Billingsley, G., Bin, J., Fieggen, K. J., Duncan, J. L., Gerth, C., Ogata, K., Wodak, S. S., Traboulsi, E. I., Fishman, G. A., Paterson, A., Chitayat, D., Knueppel, T., Millan, J. M., Mitchell, G. A., Deveault, C., Heon, E. Mutations in chaperonin-like BBS genes are a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population. J. Med. Genet. 47: 453-463, 2010. [PubMed: 20472660] [Full Text: https://doi.org/10.1136/jmg.2009.073205]
Laurier, V., Stoetzel, C., Muller, J., Thibault, C., Corbani, S., Jalkh, N., Salem, N., Chouery, E., Poch, O., Licaire, S., Danse, J.-M., Amati-Bonneau, P., Bonneau, D., Megarbane, A., Mandel, J.-L., Dollfus, H. Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism. Europ. J. Hum. Genet. 14: 1195-1203, 2006. [PubMed: 16823392] [Full Text: https://doi.org/10.1038/sj.ejhg.5201688]
Marion, V., Stoetzel, C., Schlicht, D., Messaddeq, N., Koch, M., Flori, E., Danse, J. M., Mandel, J.-L., Dollfus, H. Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc. Nat. Acad. Sci. 106: 1820-1825, 2009. [PubMed: 19190184] [Full Text: https://doi.org/10.1073/pnas.0812518106]
Putoux, A., Mougou-Zerelli, S., Thomas, S., Elkhartoufi, N., Audollent, S., Le Merrer, M., Lachmeijer, A., Sigaudy, S., Buenerd, A., Fernandez, C, Delezoide, A.-L., Gubler, M.-C., Salomon, R., Saad, A., Cordier, M.-P., Vekemans, M., Bouvier, R., Attie-Bitach, T. BBS10 mutations are common in 'Meckel'-type cystic kidneys. J. Med. Genet. 47: 848-852, 2010. [PubMed: 20805367] [Full Text: https://doi.org/10.1136/jmg.2010.079392]
Stoetzel, C., Laurier, V., Davis, E. E., Muller, J., Rix, S., Badano, J. L., Leitch, C. C., Salem, N., Chouery, E., Corbani, S., Jalk, N., Vicaire, S., and 23 others. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nature Genet. 38: 521-524, 2006. Note; Erratum: Nature Genet. 38: 727 only, 2006. [PubMed: 16582908] [Full Text: https://doi.org/10.1038/ng1771]