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Filamins (FLNs) play important roles in integrating
extracellular signals with the cellular cytoskeleton. More specifically, they
regulate the organization of actin networks beneath the cell surface and
influence events affected by these networks, such as cell-cell and cell matrix
interactions and signal transduction. Mammals have three filamin genes – FLNA,
FLNB and FLNC that encode proteins that contain an amino-terminal
actin binding domain and a series of repeats that bind to cytoplasmic and
membrane proteins. Mutations of FLNA have recently been shown to cause
a spectrum of X-linked malformation syndromes.
Spondylocarpotarsal syndrome (SCT) (OMIM 272460), an
autosomal recessive condition with short stature and vertebral, carpal and
tarsal fusion, was recently mapped to a 4.7 cM candidate region on chromosome
3p14 that contained 14 genes, one of which is FLNB. Given that
mutations of FLNA disrupt skeletogenesis, Krakow et al detected
mutations of FLNB in four families with SCT. The patients were either
homozygous or compound heterozygotes for FLNB mutations predicted to
cause loss or truncation of filamin B. Larsen syndrome (OMIM 150250) is
a genetically heterogeneous disorder with joint dislocations, craniofacial
abnormalities and accessory carpal bones that in some cases has been mapped to
chromosome 3p14. FLNB heterozygous were identified in five families,
some of which mapped to the actin binding domain and others to the repeats
region of filamin B. Atelosteogenesis types I and III (AOI – OMIM 108720 and
AOIII –OMIM 109721) are also candidates for FLNB mutations because of
their vertebral abnormalities and radiographic overlap with Larsen syndrome . These
autosomal dominant lethal skeletal dysplasias present disharmonius skeletal
maturation, poorly modeled long bones and joint dislocations. Heterozygous FNB
mutations were found in 3 of 3 patients with AOI and in 2 of 2 patients with
AOIII.
To gain insight into how mutations of FNB cause
a range of skelelal malformations, they examined the distribution of filamin B
in mid gestation mouse embryos. The most abundant filamin B was
detected in vertebral bodies. Immunostaining of growth plate tissues revealed a
uniform distribution with most intense staining at the cleavage furrow between
dividing chondrocytes in the proliferative zone. The authors discussed possible
mechanisms that would explain how different types of mutations lead to the different
clinical phenotypes. For example, they note that 3 of the 4 mutations found in
AOI and AOIII map to the actin binding domain, whereas three mutations that
produce Larsen syndrome map to the repeat region of the protein, although too
little is known about the biology of filamin B to draw any firm conclusions.
Of note, they identified the same mutation in patients with AOI and AOIII that
had previously been considered to be different entities on radiographic and
growth plate histologic grounds.
Krakow D, Robertson SP, King LM, et al. Mutation in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet 2004;36:405-410.
Editor’s comment: Not long ago, mutations of the gene
encoding filamin A were shown to cause a broad array of malformation syndromes
including otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia
and Melnick-Needles syndrome.1 The report by Krakow is like deju vu
with regard to the diversity of syndromes caused by mutations of another gene
in this family. Presumably both reflect the multidomain nature of these
molecules, which allows them to interact functionally with many different
molecules and for mutations which adversely affect different cellular functions
depending on which specific interactions they disrupt. The reports also
underscore the importance of the cytoskeleton in building a skeleton.
William A. Horton, MD
References - (linked to  )
- Robertson SR, Twigg SR, Sutherland-Smith AJ, et al. Nat Genet 2003;33:487-491.
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Current GGH - Vol. 24 No. 1
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