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: 5.64). 03/2007; 44(2):89-98. DOI: 10.1136/jmg.2006.043687
Source: PubMed

ABSTRACT 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, Aug 13, 2015
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    • "The clinical and radiographic phenotypes were reviewed by one of us (SR) to ensure the diagnoses were correctly assigned according to previously published criteria [Bicknell et al., 2007; Farrington-Rock et al., 2006]. The exon and intron– exon boundaries of FLNB were amplified by polymerase chain reaction (PCR) using previously published primers [Krakow et al., 2004] and subjected to denaturing high performance liquid chromatography (DHPLC) using the WAVE platform (Transgenomic, Omaha, NE) or using direct sequencing on an ABI3100 capillary sequencer as previously described [Bicknell et al., 2007]. Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence NM_001457.3. "
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    • "Moreover, they interact directly with a plethora of cellular proteins of great functional diversity, indicating that they are multifunctional signalling adapter proteins (Stossel et al., 2001; van der Flier et al., 2002 Feng and Walsh, 2004; Popowicz et al., 2006;). The human filamin family consists of three isoforms, filamins A, B and C. Mutations in filamin A and B have been reported to cause a broad range of congenital malformations, affecting brain, bone and other organs (Robertson et al., 2003; Bicknell et al., 2007). Filamin C (formerly also called filamin 2, g-filamin or ABP-L) is the muscle-specific filamin isoform. "
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