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The Bardet-Biedl syndrome (BBS) is
characterized by obesity and increased incidence of diabetes mellitus,
polydactyly, retinopathy, hypogonadism, renal dysfunction, congenital heart
disease, and developmental delay.1 BBS is genetically heterogeneous;
to date 8 chromosomal loci have been associated with BBS (BBS1-BBS8) and
mutations in 6 genes identified. The relationship of these genes to one
another (either as a multi-subunit complex or a sequence of genetically
controlled reactions) is not understood as yet. The locus of the gene termed BBS4
has been placed at chromosome 15q22.3-q23. Kim et al reported that BBS4
encodes a protein that affects the function of centrosomes, nuclear structures
that regulate spindle formation and cell division. It also affects the movement
of cytoplasmic organelles, cell shape, and morphogenesis and functions, in
part, by serving as a base for the organization of microtubules. The studies
demonstrated that the protein encoded by BBS4 serves as an adaptor
between pericentriolar material (PCM)1 and other proteins. The investigators
showed that BBS4 binds to the carboxyl terminal of PCM1 and is co-localized
with PCM1 in the pericentriolar protein as a component of the centriolar
satellite (and within cilia). They also demonstrated that BBS4 serves as a
bridge or adaptor linking PCM1 to dynein-dynactin, specifically to the p150glued
subunit of dynactin, the complex then permitting transport of PCM1 to its
proper pericentriolar location. (Dynein is a microtubule based motor protein
that complexes with dynactin, a macromolecule with 10 protein subunits, the
combination aiding the movement of proteins and organelles within cells.) The
truncated products produced by mutations in BBS4: 1) do not support
normal movement of PCM1 and lead to its dispersion within cytosol, and result
in 2) disorganization of the microtubule network due to errors in anchoring, 3)
impaired cell cycling and division, and 4) increased rate of cell apoptosis.
BBS4 was co-expressed with PCM1 in hippocampal neurons, bronchioles, olfactory
epithelium, retina, pericardium and interdigital epithelium. The investigators
conclude that the molecular defect in BBS4 (and possibly the other BBS genetic
defects) results in "improper targeting of PCM1 and its associated proteins to
centriolar satellites and (in) microtubule disorganization."
Kim JC, Badano JL, Sibold S, et al. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 2004;36:462-470.
Editor's Comment: BBS constitutes a "treasure trove“ of
information about basic cellular function alterations and unusual mechanisms of
genetic transmission of disease. Although BBS is usually transmitted as an
autosomal recessive disorder, on occasion it is conveyed by triallelic inheritance
in which mutations in 3 alleles of 2 genes are necessary for disease
expression. The product of BBS4 is a chaperone that aids in the movement,
folding, or assembling of other proteins into larger structures.1 The
product of BBS8 is also found in ciliated cells as is that of BBS4, suggesting
that the cluster of gene products whose disruption results in BBS is involved
with intracellular movement of indispensable cellular components.
Allen W. Root, MD
References - (linked to  )
- Sheffield VA. Pediatr Res 2004;55:908-911.
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Current GGH - Vol. 24 No. 1
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