Testing for triallelism: analysis of six BBS genes in a Bardet-Biedl syndrome family cohort.
The phenotype of Bardet-Biedl syndrome (BBS) is defined by the association of retinitis pigmentosa, obesity, polydactyly, hypogenitalism, renal disease and cognitive impairement. The significant genetic heterogeneity of this condition is supported by the identification, to date, of eight genes (BBS1-8) implied with cilia assembly or function. Triallelic inheritance has recently been suggested on the basis of the identification of three mutated alleles in two different genes for the same patient. In a cohort of 27 families, six BBS genes (namely BBS1, BBS2, BBS4, BBS6, BBS7 and BBS8) have been studied. Mutations were identified in 14 families. Two mutations within the same gene have been identified in seven families. BBS1 is most frequently implied with the common M390R substitution at the homozygous state (n=2), or associated with another mutation at BBS1 (n=3). Compound heterozygous mutations have been found in BBS2 (one family) and BBS6 (one family). In seven other families, only one heterozygous mutation has been identified (once in BBS1, twice for BBS2 and three times in BBS6). Although our study did not reveal any families with bona fide mutations in two BBS genes, consistent with a triallelic hypothesis, we have found an excess of heterozygous single mutations. This study underlines the genetic heterogeneity of the BBS and the involvement of possibly unidentified genes.
Hichri
Haifa
H
Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Stoetzel
Corinne
C
Laurier
Virginie
V
Caron
Solenne
S
Sigaudy
Sabine
S
Sarda
Pierre
P
Hamel
Christian
C
Martin-Coignard
Dominique
D
Gilles
Morin
M
Leheup
Bruno
B
Holder
Mureille
M
Kaplan
Josseline
J
Bitoun
Pierre
P
Lacombe
Didier
D
Verloes
Alain
A
Bonneau
Dominique
D
Perrin-Schmitt
Fabienne
F
Brandt
Christian
C
Besancon
Anne-Françoise
AF
Mandel
Jean-Louis
JL
Cossée
Mireille
M
Dollfus
Hélène
H
D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000595:Amino Acid Sequence; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D015331:Cohort Studies; D003598:Cytoskeletal Proteins; D005260:Female; D005602:France; D006580:Genetic Carrier Screening; D018740:Genetic Heterogeneity; D005820:Genetic Testing / Q000379:methods; D056385:Group II Chaperonins; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D011506:Proteins / Q000737:chemistry / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C429655:BBS4 protein, human; C464790:Bbs1 protein, human; C473309:Bbs2 protein, human; C473308:Bbs7 protein, human; D003598:Cytoskeletal Proteins; C414726:MKKS protein, human; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; D011506:Proteins; D056385:Group II Chaperonins