TY - JOUR
T1 - Recombination as a mechanism for sporadic mutation in the surfactant protein-C gene
AU - McBee, Amy D.
AU - Wegner, Daniel J.
AU - Carlson, Christopher S.
AU - Wambach, Jennifer A.
AU - Yang, Ping
AU - Heins, Hillary B.
AU - Saugstad, Ola D.
AU - Trusgnich, Michelle A.
AU - Watkins-Torry, Julie
AU - Nogee, Lawrence M.
AU - Henderson, Howard
AU - Cole, F. Sessions
AU - Hamvas, Aaron
PY - 2008/5
Y1 - 2008/5
N2 - Objective: To determine haplotype background of common mutations in the genes encoding surfactant proteins B and C (SFTPB and SFTPC) and to assess recombination in SFTPC. Study Design: Using comprehensive resequencing of SFTPC and SFTPB, we assessed linkage disequilibrium (LD) (D′), and computationally inferred haplotypes. We computed average recombination rates and Bayes factors (BFs) within SFTPC in a population cohort and near SFTPC (±50 kb) in HapMap cohorts. We then biochemically confirmed haplotypes in families with sporadic SFTPC mutations (n = 11) and in individuals with the common SFTPB mutation (121ins2, n = 30). Results: We detected strong evidence (weak LD and BFs > 1,400) for an intragenic recombination hot spot in both genes. The 121ins2 SFTPB mutation occurred predominantly (89%) on 2 common haplotypes. In contrast, no consistent haplotypes were associated with mutated SFTPC alleles. Sporadic SFTPC mutations arose on the paternal allele in four of five families; the remaining child had evidence for somatic recombination on the mutated allele. Conclusions: In contrast to SFTPB, disease alleles at SFTPC do not share a common haplotype background. Most sporadic mutations in SFTPC occurred on the paternal allele, but somatic recombination may be an important mechanism of mutation in SFTPC.
AB - Objective: To determine haplotype background of common mutations in the genes encoding surfactant proteins B and C (SFTPB and SFTPC) and to assess recombination in SFTPC. Study Design: Using comprehensive resequencing of SFTPC and SFTPB, we assessed linkage disequilibrium (LD) (D′), and computationally inferred haplotypes. We computed average recombination rates and Bayes factors (BFs) within SFTPC in a population cohort and near SFTPC (±50 kb) in HapMap cohorts. We then biochemically confirmed haplotypes in families with sporadic SFTPC mutations (n = 11) and in individuals with the common SFTPB mutation (121ins2, n = 30). Results: We detected strong evidence (weak LD and BFs > 1,400) for an intragenic recombination hot spot in both genes. The 121ins2 SFTPB mutation occurred predominantly (89%) on 2 common haplotypes. In contrast, no consistent haplotypes were associated with mutated SFTPC alleles. Sporadic SFTPC mutations arose on the paternal allele in four of five families; the remaining child had evidence for somatic recombination on the mutated allele. Conclusions: In contrast to SFTPB, disease alleles at SFTPC do not share a common haplotype background. Most sporadic mutations in SFTPC occurred on the paternal allele, but somatic recombination may be an important mechanism of mutation in SFTPC.
KW - Children
KW - Genetics
KW - Haplotype
KW - Interstitial lung disease
KW - Linkage disequilibrium
UR - http://www.scopus.com/inward/record.url?scp=43249098873&partnerID=8YFLogxK
U2 - 10.1002/ppul.20782
DO - 10.1002/ppul.20782
M3 - Article
C2 - 18383112
AN - SCOPUS:43249098873
SN - 8755-6863
VL - 43
SP - 443
EP - 450
JO - Pediatric Pulmonology
JF - Pediatric Pulmonology
IS - 5
ER -