Alternative titles; symbols
HGNC Approved Gene Symbol: BBS12
Cytogenetic location: 4q27 Genomic coordinates (GRCh38) : 4:122,700,442-122,744,939 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q27 | Bardet-Biedl syndrome 12 | 615989 | Autosomal recessive | 3 |
Stoetzel et al. (2007) used combined SNP array homozygosity mapping with in silico analysis to identify the BBS12 gene. Among 40 genes within a 6-Mb candidate region on chromosome 4q26-q27 that showed linkage to Bardet-Biedl syndrome (BBS; see 209900), the authors noted 1 transcript, FLJ35630, that showed distant homology to group II chaperonins and to the BBS6 (604896) and BBS10 (610148) genes. The FLJ35630 gene, renamed BBS12 and also known as C4ORF24, encodes a predicted protein of 710 amino acids. BBS12 is vertebrate-specific and, together with BBS6 and BBS10, defines a novel branch of the type II chaperonin superfamily.
Stoetzel et al. (2007) determined that the BBS12 gene maps to chromosome 4q27, and that the BBS7 gene is also located in this region, approximately 1 Mb centromeric to BBS12.
Stoetzel et al. (2007) noted that the BBS6, BBS10, and BBS12 genes are characterized by unusually rapid evolution and are likely to perform ciliary functions specific to vertebrates that are important in the pathophysiology of the syndrome and together they account for about one-third of the total BBS mutational load. Consistent with this notion, suppression of each family member in zebrafish yielded gastrulation with movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all 3 members resulted in severely affected embryos, possibly hinting at partial functional redundancy in this protein family.
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 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.
Stoetzel et al. (2007) found that patients from 2 Gypsy BBS families (BBS12; 615989) were homozygous and haploidentical in a 6-Mb region of 4q27 containing the BBS12 gene. Stoetzel et al. (2007) found pathogenic BBS12 mutations in both Gypsy families, as well as in 14 other families of various ethnic backgrounds, indicating that BBS12 accounts for approximately 5% of all BBS cases.
Dulfer et al. (2010) reported 2 female sibs with BBS resulting from compound heterozygous truncating mutations in the BBS12 gene. Each also carried a third heterozygous mutation in the BBS10 gene (610148). Dulfer et al. (2010) noted the phenotypic variability between these sibs, and suggested that hydrometrocolpos should be considered a feature in females with BBS. The authors also questioned whether the BBS10 mutation had any influence on the phenotype, since the BBS12 mutations were sufficient to cause the disorder.
In 2 consanguineous Gypsy families, not known to be related and partially settled in 2 different regions of France, with Bardet-Biedl syndrome (BBS12; 615989), Stoetzel et al. (2007) identified homozygosity for the same homozygous nonsense mutation in the BBS12 gene, 1062C-T, that resulted in an arg355-to-stop (R355X) substitution in the gene product.
In a Chinese family with Bardet-Biedl syndrome (BBS12; 615989), Stoetzel et al. (2007) reported a homozygous 3-bp deletion in the BBS12 gene (335delTAG, val113del).
In a Kurdish family, Stoetzel et al. (2007) found that the Bardet-Biedl syndrome (BBS12; 615989) was related to a homozygous frameshift mutation in the BBS12 gene, 1483delGA (Glu495fsTer498).
In a Caucasian family, Stoetzel et al. (2007) found that Bardet-Biedl syndrome (BBS12; 615989) was caused by homozygosity for a missense mutation in the BBS12 gene: 865G-C, ala289 to pro (A289P).
In 4 families with Bardet-Biedl syndrome (BBS12; 615989), Stoetzel et al. (2007) found the same 2-bp deletion in the BBS12 gene that resulted in frameshift and premature termination of the protein (Phe372fsTer373). The mutation was found in homozygosity or compound heterozygosity and occurred on 6 alleles.
Dulfer, E., Hoefsloot, L. H., Timmer, A., Mom, C., van Essen, A. J. Two sibs with Bardet-Biedl syndrome due to mutations in BBS12: no clues for modulation by a third mutation in BBS10. (Letter) Am. J. Med. Genet. 152A: 2666-2669, 2010. [PubMed: 20827784] [Full Text: https://doi.org/10.1002/ajmg.a.33650]
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]
Stoetzel, C., Muller, J., Laurier, V., Davis, E. E., Zaghloul, N. A., Vicaire, S., Jacquelin, C., Plewniak, F., Leitch, C. C., Sarda, P., Hamel, C., de Ravel, T. J. L., and 10 others. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am. J. Hum. Genet. 80: 1-11, 2007. [PubMed: 17160889] [Full Text: https://doi.org/10.1086/510256]