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Genetic Defects in Surfactant Protein A2 Are Associated with Pulmonary Fibrosis and Lung Cancer

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Genetic Defects in Surfactant Protein A2 Are Associated with Pulmonary Fibrosis and Lung Cancer View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT Genetic Defects in Surfactant Protein A2 Are Associated with Pulmonary Fibrosis and Lung Cancer Yongyu Wang,1 Phillip J. Kuan,1,2 Chao Xing,1 Jennifer T. Cronkhite,1 Fernando Torres,2 Randall L. Rosenblatt,2 J. Michael DiMaio,3 Lisa N. Kinch,4 Nick V. Grishin,4,5 and Christine Kim Garcia1,2,* 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 ~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 endo- plasmic 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. Idiopathic pulmonary fibrosis (IPF, MIM 178500) is a scar- In family F27, multiple members have early-onset ring lung disease that presents in older adults with short- pulmonary fibrosis and lung cancer cosegregating in an ness of breath and cough. The mean length of time from autosomal-dominant pattern, suggesting that these two disease diagnosis to death is only 3 years. IPF is distin- diseases share a common etiology. The proband of the guished by its progressive course, radiographic features, family, subject IV:8 (Figure 1), is a 51-year-old white man and pathologic evidence of patchy injury with foci of repli- who has ten relatives with pulmonary fibrosis; five of the cating fibroblasts at the interface of normal and scarred ten died before age 50. Four individuals (III:8, III:12, IV:2, lung tissue.1 Approximately 2% of subjects with IPF have and IV:7) also had adenocarcinoma of the lung with a familial disease form characterized by an autosomal- features of bronchioloalveolar cell carcinoma (BAC). Three dominant pattern of inheritance with incomplete pene- other related individuals had pulmonary adenocarcinoma trance.2 In ~15% of these families, the disease is caused or BAC in the absence of known fibrosis. Photomicro- by mutations in the genes encoding the protein (TERT, graphs of hematoxylin and eosin-stained slides of resected MIM 187270) or RNA component (TERC, MIM 602322) lung tissue from affected family members are shown in of telomerase,3,4 an enzyme that maintains the integrity Figure 2. Seven individuals, including the proband, were of the chromosomal ends. An additional 25% of individ- evaluated with pulmonary function testing and high-reso- uals who have either familial or sporadic pulmonary lution CT scans of the chest; medical records or death fibrosis but who do not have a mutation in TERT or certificates were obtained when possible. Additional clin- TERC have evidence of telomere shortening of circulating ical information is provided in Table S1. leukocytes.5 Although evidence of telomerase dysfunction We performed a whole genome linkage analysis of 29 is present in a large proportion of IPF cases, other genetic family members by using the Illumina Linkage IVb SNP defects probably cause disease. panel of >6,000 SNPs. Call rates varied from 97.2% to We have 59 kindreds who have familial pulmonary 98.5% for Autopure-purified DNA and from 56.4% to fibrosis and no identifiable mutations in the coding 73.9% for whole-genome-amplified DNA extracted from regions of TERT or TERC. To identify other genes that are archived samples. Individuals with pulmonary fibrosis defective in IPF, we performed a whole-genome linkage and/or lung cancer were classified as ‘‘affected,’’ and all study in one of the largest of these families in our collec- others were assigned an unknown affectation status. We tion. The study was approved by the Institutional Review used the software MERLIN6 to screen the entire genome Board of the University of Texas Southwestern Medical by using multipoint model-free linkage analysis,7 and we Center at Dallas. Kindreds were described previously.5 then evaluated the regions with the highest signals by Written informed consent was obtained from all subjects. using a model-based method. Figure S1 in the Supple- Genomic DNA was isolated from either circulating leuko- mental Data shows the analysis of family F27 with the cytes or paraffin-embedded archived tissue.4 highest peak on chromosome 10; the model-free LOD 1Eugene McDermott Center for Human Growth and Development, 2Department of Internal Medicine, 3Department of Cardiovascular and Thoracic Surgery, 4Department of Biochemistry, 5Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. *Correspondence: [email protected] DOI 10.1016/j.ajhg.2008.11.010. ª2009 by The American Society of Human Genetics. All rights reserved. 52 The American Journal of Human Genetics 84, 52–59, January 9, 2009 A F27: c.692G>T G231V CKG810: c.593T>C F198S D 65 62 55 35 I. Neck (1) (2) (1) (2) 72 85 72 38 61 70 68 68 68 II. 6 (1) (2) (3) (4) (5) (6) (7) (8) (1) (2) (3) (4) (5) (+) (+) (+) 36 64 52 82 49 54 73 79 51 47 56 66 49 55 51 46 35 III. (1) (2) (3)(4) (5) 6 (7) (8) (9) 10 11 12 13 14 (1) (2) (3) 4 (5) (+) (+) (+) + + + F198 41 56 57 53 50 48 41 56 53 45 IV. Lung Cancer 1 23456 78910 + + + + + + + Pulmonary Fibrosis Undefined Lung Disease G231 CRD B C F198 G231 rs877783 D10S580D10S1730 D10S201 D10S1786 D10S1686 D10S5523 rs4869 Human SFTPA2 185 AYVGLTEGPSPGDFRYSDGTPVNYTNWYRGEPAGRGKEQCVEMYTDGQWNDRNCLYSRLTICDF 248 72Mb 89Mb Human SFTPA1 AYVGLTEGPSPGDFRYSDGTPVNYTNWYRGEPAGRGKEQCVEMYTDGQWNDRNCLYSRLTICEF Chimpanzee SFTPA2 AYVGLTEGPSPGDFRYSDGTPVNYTNWYRGEPAGRGKEQCVEMYTDGQWNDRNCLYSRLTICEF Chimpanzee SFTPA1 AYVGLTEGPSPGDFRYSDGTPVNYTNWYRGEPAGRGKEQCVEMYTDGQWNDRNCLYSRLTICEF Rhesus monkey SFTPA2 AYVGLTEGPSPGDFRYSDGTPVNYTNWYPGEPAGRGTEQCVEMYTDGRWNDRNCLYNRLTICEF SFTPD Rhesus monkey SFTPA1 AYVGLTEGPSPGDFRYSDGTPVNYTNWYPGEPAGRGTEQCVEMYTDGRWNDRNCLYNRLTICEF SFTPA2 SFTPA1 Lemur AYLGLAEGPTPGDFRYLDGAPVNYSNWYPGEPGGRGKEKCVEMYADGQWNDKNCLQYRLAICEF Elephant AYLGLAEGSTPGEFYYLDGAPVNYTNWYLGEPRGLGKERCVEMYTDGQWNDKNCLQHRLTICEF 80.9Mb 81.7Mb Armadillo AYLGLAEGPTPGEFRQLDGAPVNYTNWYPGEPRGRGKERCVDMYTDGQWNDKNCLQYRLAICEF Cow AYLGLVEGPTAGDFYYLDGAPVNYTNWYPGEPRGRGKEKCVEIYTDGQWNDKNCLQYRLAICEF Sheep AYLGLAEGPTAGDFYYLDGAPVNYTNWYPGEPRGRGKEKCVEIYTDGQWNDKNCLQYRLAICEF Horse AYLGLEEGPTAGDFYYLDGAPVNYTNWYPGEPRGRGKEKCVEMYTDGQWNDRSCLQYRLAICEF 20 100 134 248 Pig AYLGLVEGPTAGDFFYLDGTPVNYTNWYPGEPRGRGKEKCVEMYTDGQWNDRNCQQYRLAICEF Collagen-like region Neck Carbohydrate recognition domain Cat AYLGLEEGPSPGDFCYLDGAPVNYTNWYPGEPRGGGKEKCVEMYTDGQWNNKNCLQYRLAICEF Dog AYLGLVESPDSGDFQYMDGAPVNYTNWYPGEPRGRGKEQCVEMYTDGQWNNKNCLQYRLAICEF Rabbit AYLGLAEGPTAGDFYYLDGDPVNYTNWYPGEPRGQGREKCVEMYTDGKWNDKNCLQYRLVICEF Bat AYLGLSESPTPGVFHYLDDTPVNYTKWYPGEPRGRGKEKCVEMYTDGQWNDKSCHQYRLTVCEF E shrew AYLGLEEGSEPGDFYSIDGTQVNYTNWYPGEPRGRGKEKCVEMYTDGKWNDKNCLQYRLTICEF Mouse PYLGVIEGQTPGDFHYLDGASVNYTNWYPGEPRGRGKEKCVEMYTDGKWNDKGCLQYRLAICEF Rat VYLGMIEDQTPGDFHYLDGASVNYTNWYPGEPRGQGKEKCVEMYTDGTWNDRGCLQYRLAVCEF Guinea pig SYLGLTEGHTPGDFHYLDGSPLNYTNWYPGEPRGRGKEKCAEMYLDGTWNDKNCLQSRLTICEF F198S Ground squirrel AYLGLVESNTPGDFRYLDETPVNYTNWYPGEPRGRGREKCVEMYTDGTWNDRNCLQYRLAICEF G231V E hedgehog AYLGLEEGSTLGDFYNLDGAPLNYTNWYPGEPSGQGKEKCVEMYTDGKWNDKGCLQYRLAICEF P G D F/S R Y S YT DG/VQW N M hedgehog AYLGLTEGTTPGEFNDLDRTPVNYTNWYPGEPKGMGTERCVEMYTNGQWNDRNCLQYRLTICEF CCT GGA GAC TYC CGC TAC TCA TAC ACA GAT GKG CAG TGG AAT Short-tailed opossum AYLGLTEGKTPGKFYHLNGSPMNYTNWYSGEPAGKGREPCVEMYKDGTWNDKSCLQYRLTVCEF Brushtail opossum AFLGLREGKTPGKFYYLDGSPVNYTNWYEGSPDGGGTENCVEMYTDGTWNDRYCYKSRLAVCEF Platypus AYLGIVEGKDPGKFYYLDETPVNYTNWYQREPRGGGKENCVEMYTDGTWNDKNCQQYRLTICEF Chicken AYLGIKESLIPGTFQFLNGGELSYTNWYSHEPSGKGEEECVEMYTDGTWNDRRCNQNRLVVCQF Chicken AYLGIKESDTAGQFKYVNNQPLNYTSWQQYEPNGKGTEKCVEMYTDGNWKDRKCNLYRLTVCEY Frog AYLGIKVGDIADQFHYLDGTSVNYTNWGKNEPSGKGKEPCVEIYTDGHWNDKVCNQYRLTVCEF Frog AYLGIKVGDIADQFHYLNGTSVNYTNWGNNEPSSKGKEPCVEMYTDGHWNDKVCNQYRLTVCEF Figure 1. Mutations in SFTPA2 Segregate with Familial Lung Cancer and Pulmonary Fibrosis (A) Abridged pedigrees are shown. The arrow indicates the index case. Circles represent females; squares represent males. Symbols with a slash through them indicate deceased subjects. Individuals with pulmonary fibrosis, lung cancer, or undefined lung disease are indi- cated by blue, red, and green symbols, respectively. Numbers below each symbol correspond to the individuals described in Table S1; numbers in parentheses indicate individuals for whom no DNA sample was available. The presence or absence of a mutation in SFTPA2 is indicated by plus or minus signs, respectively. When the mutation was inferred based upon the pattern of inheritance, the plus sign is placed in parentheses. The current age or the age at death is indicated to the upper right of each symbol. The SFTPA2 mutations and predicted amino acid changes are listed above each family. (B) A region of chromosome 10 cosegregates with pulmonary fibrosis and lung cancer. The genes that encode paralogs of both surfactant protein A and surfactant protein D lie within the linked
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