ABCMdb

PMID: 22438829

Henderson LB, Doshi VK, Blackman SM, Naughton KM, Pace RG, Moskovitz J, Knowles MR, Durie PR, Drumm ML, Cutting GR
Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis.
PLoS Genet. 2012;8(3):e1002580. Epub 2012 Mar 15., [PubMed]

Sentences

No. Mutations Sentence Comment

24 ABCC7 p.Gly551Asp For example, the amino acid substitution p.Gly551Asp (''G551D``) has been associated with reduced risk of MI compared to the most common CFTR mutation that causes a deleterious in-frame deletion of one amino acid (p.Phe508del, ''delta F508``) [15,16]. Login to comment 57 ABCC7 p.Gly551Asp b CFTR mutation-specific analysis (i.e. p.Gly551Asp vs. p.Phe508del) utilized the entire TSS sample. Login to comment 103 ABCC7 p.Gly551Asp However, there is a finer correlation between CFTR genotype and MI as two CFTR mutations that are highly correlated with PI, p.Gly551Asp and p.Gly542X, have been shown to decrease or increase MI risk, respectively, from that conferred by the common mutation p.Phe508del [14-16]. Login to comment 104 ABCC7 p.Gly551Asp As p.Gly551Asp is present at a relatively high frequency among European CF alleles (,2% [41]), we evaluated the association between this mutation and MI in the TSS and CGS cohorts. Login to comment 105 ABCC7 p.Gly551Asp The incidence of MI in p.Gly551Asp- bearing subjects was 7.8% in the TSS (n = 51) and 5.9% in the CGS (n = 51), compared to 20.5% (n = 507) and 17.9% (n = 851) in p.Phe508del homozygotes (P = 0.026, 0.033), respectively. Login to comment 106 ABCC7 p.Gly551Asp Combining these two samples of CF subjects demonstrated that the odds of MI in subjects with p.Gly551Asp was about a third of that in p.Phe508del homozygotes (OR = 0.32, 95% CI [0.130.76]; P = 0.010), comparable to the report by Hamosh, et al [15]. Login to comment 112 ABCC7 p.Arg117His ABCC7 p.Arg117His Intestinal obstruction in a null CF mouse model (C57BL/ 6J Cftr2/2 ) leads to high mortality (.80% [17]) by 40 days of age while lower rates of mortality [44] occur in a CF mouse model (C57BL/ 6JR117H/R117H ) with a targeted knock-in of a missense mutation (p.Arg117His) associated with residual CFTR function [45,46] and very low rates of MI in humans with CF [47]. Login to comment 113 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His Mice heterozygous for the Cftr null (Cftr+/2 ) or p.Arg117His allele (Cftr+/R117H ) were crossed to mice with one or two Msra null alleles to produce CF mice (Cftr2/2 or CftrR117H/R117H ) with wild-type (+/+), heterozygous (+/2), and null (2/2) Msra genotypes. Login to comment 119 ABCC7 p.Arg117His As anticipated, CftrR117H/ R117H mice displayed reduced mortality, notably through the weaning period, compared to Cftr-null mice (64.3% of Msra+/+ mice alive at 40 days, n = 14; Figure 3B). Login to comment 126 ABCC7 p.Arg117His B. CF mice homozygous for a missense Cftr allele (CftrR117H/R117H ) and wild-type for Msra display a low rate of mortality due to intestinal obstruction around the time of weaning (n = 14). Login to comment 127 ABCC7 p.Arg117His Survival is not affected in CftrR117H/R117H mice lacking one (n = 51) or two (n = 51) Msra alleles compared to wild-type. Login to comment 148 ABCC7 p.Arg117His Our hypothesis was that the CF null model (with high rates of obstruction) would reveal whether loss of Msra function decreased obstruction while the p.Arg117His model (with lower rates of obstruction) would reveal whether loss of Msra function increased obstruction. Login to comment 150 ABCC7 p.Arg117His ABCC7 p.Arg117His The lack of effect in the p.Arg117His CF mice suggested that the modifying effect of Msra did not exceed the reduction in obstruction conferred by residual function of CFTR bearing p.Arg117His. Login to comment 220 ABCC7 p.Gly551Asp Rates of MI in subjects carrying the CFTR p.Gly551Asp mutation (c.1652G.A) or who were homozygous for p.Phe508del were evaluated in the entire TSS sample and the CGS sample. Login to comment 221 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys ABCC7 p.Val520Phe Subjects with p.Gly551Asp carried this mutation in trans with another PI-associated mutation: p.Cys343X (c.1029delC), c.1585-1G.A, p.Lys1177SerfsX15 (c.3528delC), c.489+1G.T, p.Glu585X (c.1753G.T), p.Phe508del, p.Gly542X (c.1624G.T), p.Gly551Asp, p.Asn1303Lys (c.3909C .G), p.Arg553X (c.1657C.T), p.Val520Phe (c.1558G.T), or p.Trp1282X (c.3846G.A). Login to comment 222 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys ABCC7 p.Val520Phe Subjects with p.Gly551Asp carried this mutation in trans with another PI-associated mutation: p.Cys343X (c.1029delC), c.1585-1G.A, p.Lys1177SerfsX15 (c.3528delC), c.489+1G.T, p.Glu585X (c.1753G.T), p.Phe508del, p.Gly542X (c.1624G.T), p.Gly551Asp, p.Asn1303Lys (c.3909C .G), p.Arg553X (c.1657C.T), p.Val520Phe (c.1558G.T), or p.Trp1282X (c.3846G.A). Login to comment 245 ABCC7 p.Arg117His Mouse studies Mice heterozygous for a Cftr null allele, B6.129P2-Cftrtm1Unc [17] or for the Cftr missense allele p.Arg117His, B6.129S6-Cftrtm2Uth [44], and either homozygous or heterozygous for a null allele of Msra [51] were generated as breeders to produce CF mice carrying the three genotypes of Msra (+/+, +/2, and 2/2) used in this study. Login to comment 246 ABCC7 p.Arg117His Mouse studies Mice heterozygous for a Cftr null allele, B6.129P2-Cftrtm1Unc [17] or for the Cftr missense allele p.Arg117His, B6.129S6-Cftrtm2Uth [44], and either homozygous or heterozygous for a null allele of Msra [51] were generated as breeders to produce CF mice carrying the three genotypes of Msra (+/+, +/2, and 2/2) used in this study. Login to comment