title: Mutations in SERPINF1 cause osteogenesis imperfecta type VI.
abstract: Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism. In a large consanguineous family with OI type VI, we performed homozygosity mapping and next-generation sequencing of the candidate gene region to isolate and identify the causative gene. We describe loss of function mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF1) in two affected members of this family and in an additional unrelated patient with OI type VI. SERPINF1 encodes pigment epithelium-derived factor. Hence, loss of pigment epithelium-derived factor function constitutes a novel mechanism for OI and shows its involvement in bone mineralization.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Erica P
authors.initials: EP
authors.lastname: Homan
authors.forename: Frank
authors.initials: F
authors.lastname: Rauch
authors.forename: Ingo
authors.initials: I
authors.lastname: Grafe
authors.forename: Caressa
authors.initials: C
authors.lastname: Lietman
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doll
authors.forename: Brian
authors.initials: B
authors.lastname: Dawson
authors.forename: Terry
authors.initials: T
authors.lastname: Bertin
authors.forename: Dobrawa
authors.initials: D
authors.lastname: Napierala
authors.forename: Roy
authors.initials: R
authors.lastname: Morello
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.forename: Lisa
authors.initials: L
authors.lastname: White
authors.forename: Rika
authors.initials: R
authors.lastname: Miki
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.forename: Susan
authors.initials: S
authors.lastname: Crawford
authors.forename: Rose
authors.initials: R
authors.lastname: Travers
authors.forename: Francis H
authors.initials: FH
authors.lastname: Glorieux
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009414:Nerve Growth Factors / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010375:Pedigree; D015203:Reproducibility of Results; D015843:Serpins / Q000235:genetics*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor