title: Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred.
abstract: Familial pulmonary fibrosis is a heterogeneous group of interstitial lung diseases of unknown cause that is associated with multiple pathologic subsets. Mutations in the surfactant protein C (SP-C) gene (SFTPC) are associated with familial desquamative and nonspecific interstitial pneumonitis. Genetic studies in familial usual interstitial pneumonitis have been inconclusive. Using a candidate gene approach, we found a heterozygous exon 5 + 128 T-->A transversion of SFTPC in a large familial pulmonary fibrosis kindred, including adults with usual interstitial pneumonitis and children with cellular nonspecific interstitial pneumonitis. The mutation is predicted to substitute a glutamine for a conserved leucine residue and may hinder processing of SP-C precursor protein. SP-C precursor protein displayed aberrant subcellular localization by immunostaining. Electron microscopy of affected lung revealed alveolar type II cell atypia, with numerous abnormal lamellar bodies. Mouse lung epithelial cells transfected with the SFTPC mutation were notable for similar electron microscopy findings and for exaggerated cellular toxicity. We show that an SFTPC mutation segregates with the pulmonary fibrosis phenotype in this kindred and may cause type II cellular injury. The presence of two different pathologic diagnoses in affected relatives sharing this mutation indicates that in this kindred, these diseases may represent pleiotropic manifestations of the same central pathogenesis.
authors: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-2650, USA. alan.thomas@mcmail.vanderbilt.edu
authors: Alan Q
authors: AQ
authors: Thomas
authors: Kirk
authors: K
authors: Lane
authors: John
authors: J
authors: Phillips
authors: Melissa
authors: M
authors: Prince
authors: Cheryl
authors: C
authors: Markin
authors: Marcy
authors: M
authors: Speer
authors: David A
authors: DA
authors: Schwartz
authors: Radhika
authors: R
authors: Gaddipati
authors: Annis
authors: A
authors: Marney
authors: Joyce
authors: J
authors: Johnson
authors: Richard
authors: R
authors: Roberts
authors: Jonathan
authors: J
authors: Haines
authors: Mildred
authors: M
authors: Stahlman
authors: James E
authors: JE
authors: Loyd
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D017563:Lung Diseases, Interstitial / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011510:Proteolipids / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D011663:Pulmonary Surfactants / Q000235:genetics*
chemical_list: D011510:Proteolipids; D011663:Pulmonary Surfactants