Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred.
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.
Thomas
Alan Q
AQ
Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-2650, USA. alan.thomas@mcmail.vanderbilt.edu
Lane
Kirk
K
Phillips
John
J
Prince
Melissa
M
Markin
Cheryl
C
Speer
Marcy
M
Schwartz
David A
DA
Gaddipati
Radhika
R
Marney
Annis
A
Johnson
Joyce
J
Roberts
Richard
R
Haines
Jonathan
J
Stahlman
Mildred
M
Loyd
James E
JE
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*
D011510:Proteolipids; D011663:Pulmonary Surfactants