Mutations in FLNB cause boomerang dysplasia

Article (PDF Available)inJournal of Medical Genetics 42(7):e43 · August 2005with45 Reads
DOI: 10.1136/jmg.2004.029967 · Source: PubMed
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.

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Available from: Louise S Bicknell
    • "The actin-binding domain of FlnB consists of two calponin homology domains (CH1 and CH2) in its N-terminus [21] . Most of the causative mutations of AO-I are located in exons 2 and 3, which encode CH2 [21]. The novel c.517G > A (p.Ala173Thr) variant in the present case occurs in exon 2 and is predicted to interrupt actin binding. "
    [Show abstract] [Hide abstract] ABSTRACT: Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows. AO-I is caused by mutations in the filamin B (FLNB) gene; however, several other genes can cause AO-like lethal skeletal dysplasias. In order to screen all possible genes associated with AO-like lethal skeletal dysplasias simultaneously, we performed whole-exome sequencing in a female newborn having clinical features of AO-I. Exome sequencing identified a novel missense variant (c.517G>A; p.Ala173Thr) in exon 2 of the FLNB gene in the patient. Sanger sequencing validated this variant, and genetic analysis of the patient's parents suggested a de novo occurrence of the variant. This study shows that exome sequencing can be a useful tool for the identification of causative mutations in lethal skeletal dysplasia patients.
    Full-text · Article · Mar 2014
    • "LS features joint dislocations, cervical spine malformations, and supernumerary carpal and tarsal ossification centers [1]. AOI, AOIII, and BD exhibit more severe phenotypes including undermodeled bones or ossification initiation failure [2,3,4]. A minority of individuals survive in AOIII, while AOI and BD present with fetal/perinatal lethality. "
    [Show abstract] [Hide abstract] ABSTRACT: Humans who harbor loss of function mutations in the actin-associated filamin B (FLNB) gene develop spondylocarpotarsal syndrome (SCT), a disorder characterized by dwarfism (delayed bone formation) and premature fusion of the vertebral, carpal and tarsal bones (premature differentiation). To better understand the cellular and molecular mechanisms governing these seemingly divergent processes, we generated and characterized FlnB knockdown ATDC5 cell lines. We found that FlnB knockdown led to reduced proliferation and enhanced differentiation in chondrocytes. Within the shortened growth plate of postnatal FlnB(-/-) mice long bone, we observed a similarly progressive decline in the number of rapidly proliferating chondrocytes and premature differentiation characterized by an enlarged prehypertrophic zone, a widened Col2a1(+)/Col10a1(+) overlapping region, but relatively reduced hypertrophic zone length. The reduced chondrocyte proliferation and premature differentiation were, in part, attributable to enhanced G2/M phase progression, where fewer FlnB deficient ATDC5 chondrocytes resided in the G2/M phase of the cell cycle. FlnB loss reduced Cdk1 phosphorylation (an inhibitor of G2/M phase progression) and Cdk1 inhibition in chondrocytes mimicked the null FlnB, premature differentiation phenotype, through a β1-integrin receptor- Pi3k/Akt (a key regulator of chondrocyte differentiation) mediated pathway. In this context, the early prehypertrophic differentiation provides an explanation for the premature differentiation seen in this disorder, whereas the progressive decline in proliferating chondrocytes would ultimately lead to reduced chondrocyte production and shortened bone length. These findings begin to define a role for filamin proteins in directing both cell proliferation and differentiation through indirect regulation of cell cycle associated proteins.
    Full-text · Article · Feb 2014
    • "Although providing more support of a role for the FLNB gene in osteoporosis, comparisons with this study and our previous study must be done with caution due to differences in study design as well as differences in the ethnicity of the study subjects. In addition to the evidence suggesting a role for the human FLNB gene in bone development171819202122, there is increasing evidence to suggest that the murine Flnb gene also has a role in bone. Flnb expression has been detected in vertebral bodies obtained from mouse embryos, and it has been suggested that the gene plays a role in vertebral segmentation, joint formation and endochondral ossification [18]. "
    [Show abstract] [Hide abstract] ABSTRACT: Low bone mineral density (BMD) is a primary risk factor for osteoporosis and is a highly heritable trait, but appears to be influenced by many genes. Genome-wide linkage studies have highlighted the chromosomal region 3p14-p22 as a quantitative trait locus for BMD (LOD 1.1 - 3.5). The FLNB gene, which is thought to have a role in cytoskeletal actin dynamics, is located within this chromosomal region and presents as a strong candidate for BMD regulation. We have previously identified significant associations between four SNPs in the FLNB gene and BMD in women. We have also previously identified associations between five SNPs located 5[prime] of the transcription start site (TSS) and in intron 1 of the FLNB gene and expression of FLNB mRNA in osteoblasts in vitro. The latter five SNPs were genotyped in this study to test for association with BMD parameters in a family-based population of 769 Caucasian women. Using FBAT, significant associations were seen for femoral neck BMD Z-score with the SNPs rs11720285, rs11130605 and rs9809315 (P = 0.004 -- 0.043). These three SNPs were also found to be significantly associated with total hip BMD Z-score (P = 0.014 -- 0.026). We then combined the genotype data for these three SNPs with the four SNPs we previously identified as associated with BMD and performed a conditional analysis to determine whether they represent multiple independent associations with BMD. The results from this analysis suggested that these variants represent a single association signal. The SNPs identified in our studies as associated with BMD appear to be part of a single association signal between the FLNB gene and BMD in our data. FLNB is one of several genes located in 3p14-p22 that has been identified as significantly associated with BMD in Caucasian women.
    Full-text · Article · Oct 2013
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