Mutations in two regions of FLNB result in atelosteogenesis I and III.
The filamins are a family of cytoplasmic proteins that bind to and organize actin filaments, link membrane proteins to the cytoskeleton, and provide a scaffold for signaling molecules. Mutations in the gene encoding filamin B (FLNB) cause a spectrum of osteochondrodysplasias, including atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII). AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations. Previous studies have shown that heterozygosity for missense mutations that alter the CH2 domain and repeat 6 region of filamin B produce AOI and AOIII. In this study, 14 novel missense mutations in FLNB were found in 15 unrelated patients with AOI and AOIII. The majority of the mutations resided in exon 2 and exon 3, which encode the CH2 domain of the actin-binding region of filamin B. The remaining mutations were found in exon 28 and exon 29, which encode repeats 14 and 15 of filamin B. These results show that clustering of mutations in two regions of FLNB produce AOI/AOIII, and highlight the important role of this cytoskeletal protein in normal skeletogenesis.
Farrington-Rock
Claire
C
Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Firestein
Marc H
MH
Bicknell
Louise S
LS
Superti-Furga
Andrea
A
Bacino
Carlos A
CA
Cormier-Daire
Valerie
V
Le Merrer
Martine
M
Baumann
Clarisse
C
Roume
Joelle
J
Rump
Patrick
P
Verheij
Joke B G M
JB
Sweeney
Elizabeth
E
Rimoin
David L
DL
Lachman
Ralph S
RS
Robertson
Stephen P
SP
Cohn
Daniel H
DH
Krakow
Deborah
D
D000595:Amino Acid Sequence; D003285:Contractile Proteins / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005315:Fetal Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D064448:Filamins; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D011247:Pregnancy; D011296:Prenatal Diagnosis; D017434:Protein Structure, Tertiary; D011859:Radiography; D016415:Sequence Alignment
D003285:Contractile Proteins; C578662:FLNB protein, human; D064448:Filamins; D008840:Microfilament Proteins