ABCMdb

PMID: 23166334

Wambach JA, Wegner DJ, Depass K, Heins H, Druley TE, Mitra RD, An P, Zhang Q, Nogee LM, Cole FS, Hamvas A
Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome.
Pediatrics. 2012 Dec;130(6):e1575-82. doi: 10.1542/peds.2012-0918. Epub 2012 Nov 19., [PubMed]

Sentences

No. Mutations Sentence Comment

52 ABCA3 p.Glu292Val ABCA3 p.Arg288Lys Two mutations previously associated with respiratory disease in newborns and children, p.R288K (c.863G.A) and p.E292V (c.875A.T),22-24 accounted for 13 of the 16 mutated alleles among RDS infants. Login to comment 57 ABCA3 p.Glu292Val ABCA3 p.Arg1474Trp ABCA3 p.Arg288Lys ABCA3 p.Leu212Met ABCA3 p.Arg43Cys ABCA3 p.Arg280Cys ABCA3 p.Arg208Trp ABCA3 p.Arg280His ABCA3 p.Arg1561Gln ABCA3 p.Arg20Trp ABCA3 p.Ser1516Asn ABCA3 p.Ile1117Met ABCA3 p.Val133Met ABCA3 p.Arg1081Trp ABCA3 p.Val129Met ABCA3 p.Val480Met ABCA3 p.Thr761Lys ABCA3 p.Ile561Phe ABCA3 p.Gly594Arg ABCA3 p.Glu522Lys ABCA3 p.Ser693Leu ABCA3 p.Ala132Thr ABCA3 p.Val1588Met ABCA3 p.Arg671Cys ABCA3 p.Ile1382Met ABCA3 p.Ala1466Thr ABCA3 p.Met1428Leu ABCA3 p.Ala1297Thr ABCA3 p.Leu654Val ABCA3 p.Glu725Lys ABCA3 p.Pro246Leu ABCA3 p.Val1495Met ABCA3 p.Thr1424Met ABCA3 p.Gly668Asp ABCA3 p.Arg1457Gln ABCA3 p.Ala1119Glu Although the European-descent RDS infants had a lower mean gestational age than non-RDS infants (Table 1), there was no statistical difference in mean gestational age or birth weight for European-descent infants with or without ABCA3 mutations, thereby suggesting that ABCA3 mutations are associated with RDS rather than TABLE 3 Rare Mutations Identified Among Infants of European Descent Gene Mutation RDS (n = 112) Non-RDS (n = 161) Missouri Population (n = 871) ESP (n = 3510) ABCA3 R20W 2 R43C 1 V129M 1 A132T 1 V133M 1 R208W 1 L212M 3 14 P246L 1 R280C 1 R280H 12 R288K 6 (5.3%)a 2 (1.2%)a 14 (1.6%)a 54 (1.5%)a E292V 7 (6.2%)a 1 (0.6%)a 1 (0.1%)a 32 (0.9%)a V480M 1 E522K 1 I561F 1 G594R 1 L654V 2 G668D 1 R671C 1 S693L 1 7 E725K 1 T761K 1 R1081W 1 I1117M 1 A1119E 1 A1297T 1 I1382M 1 T1424M 1 M1428L 2 R1457Q 1 A1466T 1 R1474W 1 3 8 29 V1495M 1 S1516N 1 R1561Q 1 V1588M 1 c.3863-98 C.T 1 ABCA3 allele (carrier) frequency 16 (14.3%)a 6 (3.7%)a 31 (3.6%)a 176 (5.0%)a SFTPC D15N 1 I26V 1 A53T 1 1 L110R 1 SFTPC allele (carrier) frequency 1 (0.1%)a 4 (0.1%)a CHPT1 S40W 4 W60C 1 D132E 2 CHPT1 allele (carrier) frequency 7 (0.2%)a LPCAT1 G110S 1 P230S 1 R237Q 1 M298V 1 E312K 1 F460V 1 R526W 1 LPCAT1 allele (carrier) frequency 1 (0.1%)a 6 (0.2%)a PCYT1B V192F 1(0.03%)a Identified mutations are predicted to be damaging according to both SIFT and PolyPhen (accessed March 2012) or previous association with pediatric respiratory disease. Blank boxes indicate the mutations were not observed in that specific cohort. Login to comment 64 ABCA3 p.Arg1474Trp With 1 exception (c.4420C.T, p. R1474W), the ABCA3 mutations were unique to the African-descent disease-based infants (Tables 3 and 4). Login to comment 67 ABCA3 p.Glu292Val ABCA3 p.Pro933Leu Only 1 of these infants was compound heterozygous for ABCA3 mutations (p.E292V/p.P933L) and therefore had ABCA3 deficiency. Login to comment 74 ABCA3 p.Glu292Val ABCA3 p.Arg1474Trp ABCA3 p.Arg288Lys ABCA3 p.Arg280Cys ABCA3 p.Asn1418Ser ABCA3 p.Arg280His ABCA3 p.Arg20Trp ABCA3 p.Val129Met ABCA3 p.Gly739Ala ABCA3 p.Phe245Leu ABCA3 p.Thr574Ile ABCA3 p.Phe353Leu ABCA3 p.Leu707Phe ABCA3 p.Ala1660Val ABCA3 p.Gly571Arg ABCA3 p.Val968Met ABCA3 p.Pro585Ser ABCA3 p.Asn555Ser ABCA3 p.Phe1164Val TABLE 4 Rare Mutations Identified Among Infants of African Descent Gene Mutations RDS (n = 44) Non-RDS (n = 196) Missouri Population (n = 195) ESP (n = 1869) ABCA3 R20W 2 V129M 12 F245L 1 R280C 1 R280H 2 R288K 7 (0.4%)a E292V 4 (0.2%)a F353L 3 N555S 5 G571R 1 T574I 1 2 P585S 1 L707F 14 G739A 2 15 V968M 1 1 F1164V 1 N1418S 1 R1474W 1 1 A1660V 1 Infants with variant 2 (4.5%)a 3 (1.5%)a 3 (1.5%)a 72 (3.9%)a SFTPC R35C 1 V39M 1 G57S 1 R81C 1 SFTPC allele (carrier) frequency 4 (0.2%)a CHPT1 G70R 2 T87M 1 G115A 1 Y365H 3 CHPT1 allele (carrier) frequency 7 (0.4%)a LPCAT1 A194V 6 L255Q 2 D392H 1 R526W 1 LPCAT1 allele (carrier) frequency 10 (0.5%)a PCYT1B G199D 1 (0.05%)a Identified mutations are predicted to be damaging according to both SIFT and PolyPhen (accessed March 2012) or previous association with pediatric respiratory disease. Blank boxes indicate the mutations were not observed in that specific cohort. Login to comment 89 ABCA3 p.Arg1474Trp For example, although p.R1474W is predicted to be deleterious according to both SIFTand PolyPhen and has been detected in children with respiratory disease, its high carrier frequency (~1%) and similar frequencies among infants with and without RDS suggest lower penetrance than estimated by the prediction algorithms. Login to comment 91 ABCA3 p.Arg288Lys For example, p.R288K is predicted to be benign (tolerated) by both prediction algorithms and would not have been included in our analysis had it not been previously associated with pediatric respiratory disease.22 Its threefold to fourfold enrichment among the European-descent RDS infants suggests an important role in the genetic pathogenesis of RDS. Login to comment 94 ABCA3 p.Glu292Val ABCA3 p.Arg280Cys Only 2 of these mutations were found in our study: p.R280C, which disrupts ABCA3 folding and trafficking, and p.E292V, which disrupts ATP hydrolysis and decreases phospholipid transport across the lamellar body membrane.29,30 Our combined genomic, computational, and disease-based variant discovery strategy permits prioritization of mutations for further functionalinvestigation,whichiscritical for understanding disease pathogenesis. Login to comment