A molecular and clinical study of Larsen syndrome caused by mutations in FLNB

Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand.
Journal of Medical Genetics (Impact Factor: 6.34). 03/2007; 44(2):89-98. DOI: 10.1136/jmg.2006.043687
Source: PubMed


Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied.
Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated.
The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.

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Available from: Louise S Bicknell, Oct 06, 2015
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    • "Congenital bowing of the long bones is a hallmark feature of STWS [1], but it is not unique to STWS and manifests in other syndromes including type IX Ehlers-Danlos syndrome, Campomelic Displasia, Larsen syndrome and other conditions. [109-112]. Some have suggested that prenatal bowing of the long bones results from the mechanical forces of imbalanced muscles acting on structurally weak bones in utero[113-115]. "
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    ABSTRACT: Stuve-Wiedemann syndrome (STWS; OMIM #610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes. STWS usually results in infant mortality, yet some STWS patients survive into and, in some cases, beyond adolescence. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomally recessive pattern. Most LIFR mutations resulting in STWS are null mutations which cause instability of the mRNA and prevent the formation of LIFR, impairing the signaling pathway. LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines. STWS is managed on a symptomatic basis since there is no treatment currently available.
    Orphanet Journal of Rare Diseases 03/2014; 9(1):34. DOI:10.1186/1750-1172-9-34 · 3.36 Impact Factor
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    • "Autosomal dominant mutations of FLNB (missense mutations, small in-frame deletions or insertions) cause a group of skeletal dysplasias, including Larsen syndrome (LS; OMIM 150250), atelosteogenesis I and III (AOI and AOIII; OMIM 108720 and 108721), and boomerang dysplasia (BD; OMIM 112310) [1], [2], [3]. 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]. "
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    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.
    PLoS ONE 02/2014; 9(2):e89352. DOI:10.1371/journal.pone.0089352 · 3.23 Impact Factor
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    • "The Filamin B (FLNB) gene, which is thought to have a role in cytoskeletal actin dynamics [16], is located within this chromosomal region and presents as a strong candidate for BMD regulation. Mutations within the FLNB gene have been implicated in a variety of genetic disorders characterised by skeletal malformation, some of which include: spondylocarpotarsal synostosis syndrome [17-19], Larsen syndrome [18,20], atelosteogenesis types I and III [18,21] and boomerang dysplasia [22]. Associations have also been identified between polymorphism in FLNB and human stature variation in a genome-wide association study [23]. "
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    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.
    BMC Genetics 10/2013; 14(1):107. DOI:10.1186/1471-2156-14-107 · 2.40 Impact Factor
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