title: Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta.
abstract: Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis.
authors.affiliation: Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Becker
authors.forename: Oliver
authors.initials: O
authors.lastname: Semler
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Hanno Jörn
authors.initials: HJ
authors.lastname: Bolz
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.forename: Friederike
authors.initials: F
authors.lastname: Koerber
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Petra
authors.initials: P
authors.lastname: de Vries
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
authors.forename: Eckhard
authors.initials: E
authors.lastname: Schoenau
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Christian
authors.initials: C
authors.lastname: Netzer
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009414:Nerve Growth Factors / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000235:genetics*; D011859:Radiography; 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