Filamin B Mutations Disrupt Skeletogenesis in Bone Dysplasias
© 2004 Prime Health Consultants, Inc.
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.
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
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