title: Surfactant protein C G100S mutation causes familial pulmonary fibrosis in Japanese kindred.
abstract: Several mutations in the surfactant protein C (SP-C) gene (SFTPC) have been reported as causing familial pulmonary fibrosis (FPF). However, the genetic background and clinical features of FPF are still not fully understood. We identified one Japanese kindred, in which at least six individuals over three generations were diagnosed with pulmonary fibrosis. We examined the patients radiologically and histopathologically and sequenced their SFTPC and ABCA3 genes. We also established a cell line stably expressing the mutant gene. All the patients had similar radiological and histopathological characteristics. Their histopathological pattern was that of usual interstitial pneumonia, showing numerous fibroblastic foci even in areas without abnormal radiological findings on chest high-resolution computed tomography. No child had respiratory symptoms in the kindred. Sequencing of SFTPC showed a novel heterozygous mutation, c.298G>A (G100S), in the BRICHOS domain of proSP-C, which co-segregated with the disease. However, in the ABCA3 gene, no mutation was found. In vitro expression of the mutant gene revealed that several endoplasmic reticulum stress-related proteins were strongly expressed. The mutation increases endoplasmic reticulum stress and induces apoptotic cell death compared with wild-type SP-C in alveolar type II cells, supporting the significance of this mutation in the pathogenesis of pulmonary fibrosis.
authors.affiliation: Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Ishida
authors.forename: A
authors.initials: A
authors.lastname: Kinoshita
authors.forename: J
authors.initials: J
authors.lastname: Fukuoka
authors.forename: M
authors.initials: M
authors.lastname: Takaki
authors.forename: N
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Ishimatsu
authors.forename: S
authors.initials: S
authors.lastname: Kohno
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: M
authors.initials: M
authors.lastname: Senba
authors.forename: M
authors.initials: M
authors.lastname: Yasunami
authors.forename: Y
authors.initials: Y
authors.lastname: Kubo
authors.forename: L M
authors.initials: LM
authors.lastname: Yoshida
authors.forename: H
authors.initials: H
authors.lastname: Kubo
authors.forename: K
authors.initials: K
authors.lastname: Ariyoshi
authors.forename: K
authors.initials: K
authors.lastname: Yoshiura
authors.forename: K
authors.initials: K
authors.lastname: Morimoto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D019943:Amino Acid Substitution / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D001706:Biopsy; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005192:Family Health; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics*
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human