Identification of a Novel BBS Gene (BBS12) Highlights the Major Role of a Vertebrate-Specific Branch of Chaperonin-Related Proteins in Bardet-Biedl Syndrome

Abstract

Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive ciliopathy characterized by progressive retinal degeneration, obesity, cognitive impairment, polydactyly, and kidney anomalies. The disorder is genetically heterogeneous, with 11 BBS genes identified to date, which account for ~70% of affected families. We have combined single-nucleotide-polymorphism array homozygosity mapping with in silico analysis to identify a new BBS gene, BBS12. Patients from two Gypsy families were homozygous and haploidentical in a 6-Mb region of chromosome 4q27. FLJ35630 was selected as a candidate gene, because it was predicted to encode a protein with similarity to members of the type II chaperonin superfamily, which includes BBS6 and BBS10. We found pathogenic 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. BBS12 is vertebrate specific and, together with BBS6 and BBS10, defines a novel branch of the type II chaperonin superfamily. These three 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-movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all three members resulted in severely affected embryos, possibly hinting at partial functional redundancy within this protein family.

MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination

“…Thus, rhodopsin is a candidate protein that would be transported with assistance of BBS proteins, including MKKS, although other target proteins also must exist. In addition to MKKS , BBS10 (Stoetzel et al, 2006), and BBS12 (Stoetzel et al, 2007) are now known to share weak but significant sequence similarity to the group II chaperonins, including CCT. These proteins might assist protein transport by performing chaperone-like activities, although the exact molecular mechanisms of MKKS-dependent transport remain to be investigated.…”

“…Amino acid sequence similarity between MKKS protein and group II chaperonins suggests that MKKS function may have evolved from the chaperonin family . In addition to MKKS, two other BBS proteins, BBS10 (Stoetzel et al, 2006) and BBS12 (Stoetzel et al, 2007), were recently shown to share weak but significant sequence similarities with group II chaperonins. Interestingly, none of the three chapeonin-like BBS proteins were found in the BBSome (Nachury et al, 2007), suggesting that these chaperonin like proteins have a distinctive role in BBS-associated functions.…”

Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation

“…Indeed, an up-regulation of several BBS genes during the early phase of adipogenic differentiation in culture has been recently reported (25). In the present study we focused on 2 chaperonine-like BBS proteins that we recently identified: BBS10 (26) and BBS12 (27). This led us to discover the transient formation of a primary cilium that carries Wnt and Hh receptors, during preadipocyte differentiation.…”

Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome

“…Genotypes were specified by the Genotyping Console Software (GTYPE v4.0, Affymetrix) and were displayed by the HomoSNP linkage program. 7 Additional information regarding methods used for histological analyses, cell culture and endocytosis assays, imaging, in vitro GTPase and membrane tubulation assays, and characterization of zebrafish models can be found in the Methods section of the Supplementary Information).…”