title: Mutations in two regions of FLNB result in atelosteogenesis I and III.
abstract: 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.
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Farrington-Rock
authors.forename: Marc H
authors.initials: MH
authors.lastname: Firestein
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.forename: Joelle
authors.initials: J
authors.lastname: Roume
authors.forename: Patrick
authors.initials: P
authors.lastname: Rump
authors.forename: Joke B G M
authors.initials: JB
authors.lastname: Verheij
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sweeney
authors.forename: David L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
mesh_terms: 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
chemical_list: D003285:Contractile Proteins; C578662:FLNB protein, human; D064448:Filamins; D008840:Microfilament Proteins