Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer.
Idiopathic pulmonary fibrosis (IPF) is a lethal scarring lung disease that affects older adults. Heterozygous rare mutations in the genes encoding telomerase are found in approximately 15% of familial cases. We have used linkage to map another disease-causing gene in a large family with IPF and adenocarcinoma of the lung to a 15.7 Mb region on chromosome 10. We identified a rare missense mutation in a candidate gene, SFTPA2, within the interval encoding surfactant protein A2 (SP-A2). Another rare mutation in SFTPA2 was identified in another family with IPF and lung cancer. Both mutations involve invariant residues in the highly conserved carbohydrate-recognition domain of the protein and are predicted to disrupt protein structure. Recombinant proteins carrying these mutations are retained in the endoplasmic reticulum and are not secreted. These data are consistent with SFTPA2 germline mutations that interfere with protein trafficking and cause familial IPF and lung cancer.
Wang
Yongyu
Y
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Kuan
Phillip J
PJ
Xing
Chao
C
Cronkhite
Jennifer T
JT
Torres
Fernando
F
Rosenblatt
Randall L
RL
DiMaio
J Michael
JM
Kinch
Lisa N
LN
Grishin
Nick V
NV
Garcia
Christine Kim
CK
D000230:Adenocarcinoma / Q000150:complications / Q000235:genetics*; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000150:complications / Q000235:genetics*; D008175:Lung Neoplasms / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics*
D037662:Pulmonary Surfactant-Associated Protein A; C445843:SFTPA2 protein, human