Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome

Corinne Stoetzel, Jean Muller, Virginie Laurier, Erica Ellen Davis, Norann A. Zaghloul, Serge Vicaire, Cécile Jacquelin, Frédéric Plewniak, Carmen C. Leitch, Pierre Sarda, Christian Hamel, Thomy J.L. De Ravel, Richard Alan Lewis, Evelyne Friederich, Christelle Thibault, Jean Marc Danse, Alain Verloes, Dominique Bonneau, Elias Nicholas Katsanis, Olivier PochJean Louis Mandel, Hélène Dollfus*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

178 Scopus citations

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 ∼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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalAmerican journal of human genetics
Volume80
Issue number1
DOIs
StatePublished - Jan 2007

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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