title: A molecular and clinical study of Larsen syndrome caused by mutations in FLNB.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.forename: Claire
authors.initials: C
authors.lastname: Farrington-Rock
authors.forename: Yousef
authors.initials: Y
authors.lastname: Shafeghati
authors.forename: Patrick
authors.initials: P
authors.lastname: Rump
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Yves
authors.initials: Y
authors.lastname: Alembik
authors.forename: Navid
authors.initials: N
authors.lastname: Al-Madani
authors.forename: Helen
authors.initials: H
authors.lastname: Firth
authors.forename: Mohammad Hassan
authors.initials: MH
authors.lastname: Karimi-Nejad
authors.forename: Chong Ae
authors.initials: CA
authors.lastname: Kim
authors.forename: Kathryn
authors.initials: K
authors.lastname: Leask
authors.forename: Melissa
authors.initials: M
authors.lastname: Maisenbacher
authors.forename: Ellen
authors.initials: E
authors.lastname: Moran
authors.forename: John G
authors.initials: JG
authors.lastname: Pappas
authors.forename: Paolo
authors.initials: P
authors.lastname: Prontera
authors.forename: Thomy
authors.initials: T
authors.lastname: de Ravel
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sweeney
authors.forename: Alan
authors.initials: A
authors.lastname: Fryer
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: L C
authors.initials: LC
authors.lastname: Wilson
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.forename: David L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D003285:Contractile Proteins / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D064448:Filamins; D050278:Finger Phalanges / Q000002:abnormalities; D006801:Humans; D007738:Kyphosis / Q000235:genetics*; D008297:Male; D008663:Metacarpus / Q000002:abnormalities; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D013131:Spine / Q000002:abnormalities*
chemical_list: D003285:Contractile Proteins; C578662:FLNB protein, human; D064448:Filamins; D008840:Microfilament Proteins; D004247:DNA