A molecular and clinical study of Larsen syndrome caused by mutations in FLNB.
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.
Bicknell
Louise S
LS
Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand.
Farrington-Rock
Claire
C
Shafeghati
Yousef
Y
Rump
Patrick
P
Alanay
Yasemin
Y
Alembik
Yves
Y
Al-Madani
Navid
N
Firth
Helen
H
Karimi-Nejad
Mohammad Hassan
MH
Kim
Chong Ae
CA
Leask
Kathryn
K
Maisenbacher
Melissa
M
Moran
Ellen
E
Pappas
John G
JG
Prontera
Paolo
P
de Ravel
Thomy
T
Fryns
Jean-Pierre
JP
Sweeney
Elizabeth
E
Fryer
Alan
A
Unger
Sheila
S
Wilson
L C
LC
Lachman
Ralph S
RS
Rimoin
David L
DL
Cohn
Daniel H
DH
Krakow
Deborah
D
Robertson
Stephen P
SP
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*
D003285:Contractile Proteins; C578662:FLNB protein, human; D064448:Filamins; D008840:Microfilament Proteins; D004247:DNA