title: 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.
authors.affiliation: Laboratoire de Genetique Medicale, Faculte de Medecine, Hopitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Stoetzel
authors.forename: Jean
authors.initials: J
authors.lastname: Muller
authors.forename: Virginie
authors.initials: V
authors.lastname: Laurier
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.forename: Norann A
authors.initials: NA
authors.lastname: Zaghloul
authors.forename: Serge
authors.initials: S
authors.lastname: Vicaire
authors.forename: Cecile
authors.initials: C
authors.lastname: Jacquelin
authors.forename: Frederic
authors.initials: F
authors.lastname: Plewniak
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Leitch
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarda
authors.forename: Christian
authors.initials: C
authors.lastname: Hamel
authors.forename: Thomy J L
authors.initials: TJ
authors.lastname: de Ravel
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: Evelyne
authors.initials: E
authors.lastname: Friederich
authors.forename: Christelle
authors.initials: C
authors.lastname: Thibault
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Danse
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Olivier
authors.initials: O
authors.lastname: Poch
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.forename: Helene
authors.initials: H
authors.lastname: Dollfus
mesh_terms: D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D018833:Chaperonins / Q000235:genetics* / Q000502:physiology; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000002:abnormalities; D056385:Group II Chaperonins; D006720:Homozygote; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D015027:Zebrafish / Q000002:abnormalities / Q000196:embryology / Q000235:genetics
chemical_list: C517002:BBS12 protein, human; D018833:Chaperonins; D056385:Group II Chaperonins