title: Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity.
abstract: Bardet-Biedl syndrome (BBS) is a rare oligogenic disorder exhibiting both clinical and genetic heterogeneity. Although the BBS phenotype is variable both between and within families, the syndrome is characterized by the hallmarks of developmental and learning difficulties, post-axial polydactylia, obesity, hypogenitalism, renal abnormalities, retinal dystrophy, and several less frequently observed features. Eleven genes mutated in BBS patients have been identified, and more are expected to exist, since about 20-30% of all families cannot be explained by the known loci. To investigate the etiopathogenesis of BBS, we created a mouse null for one of the murine homologues, Bbs4, to assess the contribution of one gene to the pleiotropic murine Bbs phenotype. Bbs4 null mice, although initially runted compared to their littermates, ultimately become obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal lipid profiles, signs of liver dysfunction, and elevated insulin and leptin levels reminiscent of metabolic syndrome. As in patients with BBS, we found age-dependent retinal dystrophy. Behavioral assessment revealed that mutant mice displayed more anxiety-related responses and reduced social dominance. We noted the rare occurrence of birth defects, including neural tube defects and hydrometrocolpos, in the null mice. Evaluations of these null mice have uncovered phenotypic features with age-dependent penetrance and variable expressivity, partially recapitulating the human BBS phenotype.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza Room 604B, Houston, TX 77030, USA.
authors.forename: Erica R
authors.initials: ER
authors.lastname: Eichers
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Abd-El-Barr
authors.forename: Richard
authors.initials: R
authors.lastname: Paylor
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Lin
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Meehan
authors.forename: David W
authors.initials: DW
authors.lastname: Stockton
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Wu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lindsay
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000375:Aging; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000473:pathology; D020788:Bardet-Biedl Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D007328:Insulin / Q000097:blood; D007438:Introns; D020738:Leptin / Q000097:blood; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D016254:Mutagenesis, Insertional; D009765:Obesity / Q000235:genetics / Q000473:pathology; D019683:Penetrance; D010641:Phenotype; D012160:Retina / Q000473:pathology; D012930:Social Dominance
chemical_list: C506281:BBS4 protein, mouse; D007328:Insulin; D020738:Leptin; D008869:Microtubule-Associated Proteins