Bardetbiedl Syndrome
Bardet-Biedl syndrome (BBS) is an autosomal recessive condition characterized by rod-cone dystrophy (atypical retinitis pigmentosa), postaxial polydactyly, central obesity, mental retardation, hypogonadism, and renal dysfunction. Other features, not always present, include hepatic fibrosis, diabetes mellitus, reproductive abnormalities, endocrinological disturbances, short stature, developmental delay, and speech deficits. BBS is distinguished from the much rarer Laurence-Moon syndrome, in which retinal pigmentary degeneration, mental retardation, and hypogonadism occur in conjunction with progressive spastic paraparesis and distal muscle weakness, but without poly-dactyly (76). BBS was first described in 1920 (77), and the cardinal manifestations were described as retinal pigmentary dystrophy (retinitis pigmentosa), postaxial poly-
dactyly, central obesity, mental retardation, and hypogenitalism (78). The prevalence of BBS is about 1 in 125,000, and criteria for diagnosis have been published (79). In this large survey of 109 BBS patients in the United Kingdom and their families, the average age at diagnosis was 9 yr, although parents first noticed abnormalities in their children at a mean age of 3 yr. Obesity only began to develop at around 2-3 yr, and retinal degeneration did not become apparent until a mean age of 8.5 yr. Only seven patients (6%) had non-insulin-dependent diabetes mellitus. However, only a minority of patients surveyed had undergone a fasting glucose measurement or glucose tolerance test, so the prevalence of diabetes may be much higher. Diabetes presented in adulthood and was thought to be the result of insulin resistance.
Recently, genetic heterogeneity has been confirmed with the finding of five gene loci, on chromosomes 11 (BBS1) (80), 16 (BBS2) (81), 3 (BBS3) (82) 15 (BBS4) (83), and 2 (BBS5) (84), each associated with a similar phenotype. Recently, Bardet-Biedl families from Newfoundland who had genetic linkage excluded from the known loci were found to be linked to markers on chromosome 2q31 (BBS6) (85). Mutations were identified in a chaperonin-like gene, McKusick-Kaufman syndrome (MKKS). Most were frame-shift mutations that were likely to result in a severely truncated, nonfunctional protein. The MKKS protein shows similarity to type II chaperonins, which are responsible for folding a wide range of proteins. Spatial conformation is likely to be critical to this molecule and disruptions may reduce the efficiency or abolish the ability to fold target peptides. Presumably there are other BBS genes that encode proteins that interact with MKKS to form a multimeric chaperone unit. Molecules that require MKKS for correct folding may also be candidates for different aspects of the BBS phenotype.
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