Article

Mutations in FLNB cause boomerang dysplasia.

Journal of Medical Genetics (Impact Factor: 5.64). 08/2005; 42(7):e43. DOI: 10.1136/jmg.2004.029967
Source: PubMed

ABSTRACT Boomerang dysplasia (BD) is a perinatal lethal osteochondrodysplasia, characterised by absence or underossification of the limb bones and vertebrae. The BD phenotype is similar to a group of disorders including atelosteogenesis I, atelosteogenesis III, and dominantly inherited Larsen syndrome that we have recently shown to be associated with mutations in FLNB, the gene encoding the actin binding cytoskeletal protein, filamin B. We report the identification of mutations in FLNB in two unrelated individuals with boomerang dysplasia. The resultant substitutions, L171R and S235P, lie within the calponin homology 2 region of the actin binding domain of filamin B and occur at sites that are evolutionarily well conserved. These findings expand the phenotypic spectrum resulting from mutations in FLNB and underline the central role this protein plays during skeletogenesis in humans.

Download full-text

Full-text

Available from: Louise S Bicknell, Aug 23, 2015
0 Followers
 · 
138 Views
  • Source
    • "A range of autosomal dominant diseases is caused by missense mutations or small in-frame deletions or insertions in FLNB. These phenotypes include atelosteogenesis I and III (AOI; MIM# 108720 and AOIII; MIM# 108721) and boomerang dysplasia (BD; MIM# 112310) that are severe disorders in which bones are either undermodeled or have failed to initiate ossification [Bicknell et al., 2005; Farrington-Rock et al., 2006]. Whereas AOIII is survivable in a minority of individuals, AOI and BD invariably present with in utero lethality. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dominant missense mutations in FLNB, encoding the actin-cross linking protein filamin B (FLNB), cause a broad range of skeletal dysplasias with varying severity by an unknown mechanism. Here these FLNB mutations are shown to cluster in exons encoding the actin-binding domain (ABD) and filamin repeats surrounding the flexible hinge 1 region of the FLNB rod domain. Despite being positioned in domains that bind actin, it is unknown if these mutations perturb cytoskeletal structure. Expression of several full-length FLNB constructs containing ABD mutations resulted in the appearance of actin-containing cytoplasmic focal accumulations of the substituted protein to a degree that was correlated with the severity of the associated phenotypes. In contrast, study of mutations leading to substitutions in the FLNB rod domain that result in the same phenotypes as ABD mutations demonstrated that with only one exception disease-associated substitutions, surrounding hinge 1 demonstrated no tendency to form actin-filamin foci. The exception, a substitution in filamin repeat 6, lies within a region previously implicated in filamin-actin binding. These data are consistent with mutations in the ABD conferring enhanced actin-binding activity but suggest that substitutions affecting repeats near the flexible hinge region of FLNB precipitate the same phenotypes through a different mechanism.
    Human Mutation 04/2012; 33(4):665-73. DOI:10.1002/humu.22012 · 5.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Boomerang dysplasia (BD) was first described by Kozlowski et al in 1981; and is a form of neonatally lethal chondrodysplasia. The name itself vividly described its characteristic radiographic features, and the importance of recognising these features has major implication in genetic counselling. All, except two reported cases of BD were males. We here reported the third female case of Boomerang dysplasia in literature.
  • Article: Case Report
    [Show abstract] [Hide abstract]
    ABSTRACT: We treated a patient with multiple congenital joint dislocations and facial dysmorphisms consistent with Larsen syndrome. Sequencing of the FLNB gene resulted in identification of a novel, de novo 508G>C point mutation resulting in substitution of proline for a highly conserved alanine (A170P). This mutation has not been described previously but is likely causative because this alanine is highly conserved and is located in the calponin homology domain where other mutations have been described. We also report the successful use of a minimally invasive technique in achieving initial correction of bilateral congenital knee dislocations in this patient. The technique consists of serial manipulations and castings followed by an open quadriceps tenotomy. Longer followup is needed to ensure maintenance of correction and to avoid the need for more extensive surgery, which has been the traditional treatment for congenital knee dislocation associated with Larsen syndrome.
    Clinical Orthopaedics and Related Research 06/2008; 466(6):1503-1509. DOI:10.1007/s11999-008-0196-5 · 2.88 Impact Factor
Show more