title: Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene.
abstract: Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy. After performing X-exome capture and sequencing, we identified a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the disease. The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) and was not found in 400 control X chromosomes, pilot data from the 1000 Genomes Project, or the FLNA gene variant database. In the families, the variant segregated with the disease, and it was transmitted four times from a mildly affected mother to a more seriously affected daughter. We show that, because of nonrandom X chromosome inactivation, the mutant allele was not expressed in patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15. Our data show that TOD is caused by this single recurrent mutation in the FLNA gene.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Rowida
authors.initials: R
authors.lastname: Almomani
authors.forename: Emmelien
authors.initials: E
authors.lastname: Aten
authors.forename: Jacopo
authors.initials: J
authors.lastname: Celli
authors.forename: Jaap
authors.initials: J
authors.lastname: van der Heijden
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: Anna
authors.initials: A
authors.lastname: Baroncini
authors.forename: Brunella
authors.initials: B
authors.lastname: Franco
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Emiko
authors.initials: E
authors.lastname: Horii
authors.forename: Ricardo
authors.initials: R
authors.lastname: Drut
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Ariyurek
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
mesh_terms: D000328:Adult; D001848:Bone Diseases, Developmental / Q000150:complications / Q000235:genetics*; D001859:Bone Neoplasms / Q000150:complications / Q000235:genetics*; D002675:Child, Preschool; D003285:Contractile Proteins / Q000235:genetics*; D005260:Female; D005350:Fibroma / Q000150:complications / Q000235:genetics*; D064448:Filamins; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D010375:Pedigree; D010859:Pigmentation Disorders / Q000150:complications / Q000235:genetics*; D012880:Skin Pigmentation
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins