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.

Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia

“…Moreover, none of the alterations appeared unique to one specific Bbs mutation. Although difficult to quantify, we noticed more abnormalities in epithelia that had been cultured for a longer period, a result consistent with reports of age-dependent effects in Bbs phenotypes (27). Interestingly, in all of the Bbs mutants, most of the cilia appeared morphologically normal.…”

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

“…To test for a role of cilia in diabetes, we examined a ciliopathy model for prediabetic phenotypes. At birth, Bardet-Biedl-Syndrome 4 (Bbs4) mutant mice are runted compared with their wild-type littermates and manifest obesity later on 15 . Penetrance is dependent on sex and age of the animals both in this and another Bbs4 À / À mutant strain 16 .…”

“…Generally, female mutants are more severely affected than age-matched male mutants. At 4-6 months of age, both sexes exhibit diabetic phenotypes including hyperglycemia and mild hyperinsulinemia 15 . Because we could not exclude a role for Bbs4 during pancreas development, we assessed pancreatic islet morphology in 4-week-old male mutant mice and wild-type littermates (n ¼ 3, Fig.…”

“…Before the measurements, animals were fasted for 12 h. Because of the anxiety phenotype of Bbs4 À / À animals 15 , we sedated both wildtype and knockout animals with very low doses of Hypnorm (VetaPharma Ltd.)/ Dormicum (F.Hofmann-LaRoche Ltd; 1/16 of the dose to induce surgical anaesthesia; 5 mg ml À 1 fentanyl, 156 mg ml À 1 fluanison, 250 mg ml À 1 midazolam in water; 100 ml per 10 g bodyweight) 60-90 min before the procedure 57 . Animals were calm but responsive and moving in their cages during the procedure.…”

“…In addition, we observed that as many as twothirds of the T2DM susceptibility genes have entries in the ciliary proteome database (see ref. 15), suggesting a direct relationship between ciliary dysfunction and T2DM susceptibility.…”