ABCMdb

PMID: 22145626

Hartel C, Felderhoff-Muser U, Gebauer C, Hoehn T, Kribs A, Laux R, Moller J, Segerer H, Teig N, von der Wense A, Wieg C, Stichtenoth G, Herting E, Gopel W
ATP-binding cassette member A3 (E292V) gene mutation and pulmonary morbidity in very-low-birth-weight infants.
Acta Paediatr. 2012 Apr;101(4):380-3. doi: 10.1111/j.1651-2227.2011.02553.x. Epub 2012 Jan 9., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCA3 p.Glu292Val Term infants carrying the E292V missense mutation of the gene encoding ABCA3 are likely to develop respiratory distress syndrome, and the mutation has also been linked to interstitial lung disease in paediatric patients. Login to comment 6 ABCA3 p.Glu292Val The aim of this study was to investigate the association of the E292V genotype with pulmonary morbidity in a large cohort of very-low-birth-weight (VLBW) infants. Methods: We performed a genetic association study with a prospective, population-based multi-centre cohort of 3177 VLBW infants born in 16 German study centres between 2003 and 2009 (German Neonatal Network). Login to comment 8 ABCA3 p.Glu292Val Results: In a large cohort of 3177 VLBW infants, 11 individuals were found to be heterozygote for the E292V mutation (0.34%). Login to comment 10 ABCA3 p.Glu292Val Conclusions: Within the size limits of our study cohort, the ABCA3 missense mutation E292V had no remarkable effect on pulmonary outcome in VLBW infants. Login to comment 11 ABCA3 p.Glu292Val Present results do not rule out the possibility that E292V phenotype is associated with minor difference in the morbidity. Login to comment 16 ABCA3 p.Glu292Val Recently, several studies have linked ABCA3 gene mutations with lung disease in neonates and 1 Key notes • ATP-binding cassette member A 3 (ABCA3) plays a critical role for the transport of surfactant phospholipids, and the E292V missense mutation of the ABCA3 gene has been linked to pulmonary morbidity. Login to comment 18 ABCA3 p.Glu292Val • 11 individuals were found to be heterozygote for the E292V mutation (0.34%); however, no remarkable effect on pulmonary outcome was noted. Login to comment 20 ABCA3 p.Glu292Val The E292V missense mutation was found to be over-represented in a cohort of term infants with RDS (7). Login to comment 21 ABCA3 p.Glu292Val This particular mutation consists of a thymine for adenine substitution at cDNA position 875 (first codon of exon 9) and causes substitution of valine (mutation) for glutamic acid (wildtype) in codon 292 (E292V, new recognition site for the restriction endonuclease BsrG1; 8). Login to comment 22 ABCA3 p.Glu292Val Bullard et al. (8) also noted an association between the E292V mutation and interstitial lung disease in children. Login to comment 26 ABCA3 p.Glu292Val In this study, we hypothesized that the ABCA3 E292V is a potential candidate mutation to influence short-term pulmonary outcome in a multi-centre cohort of 3177 VLBW infants. METHODS Genetic association study We prospectively studied the influence of the ABCA3 E292 V on pulmonary outcome in 3177 VLBW infants enrolled in a multi-centre trial involving 16 neonatal intensive care units in Germany from April 2003 until December 2009. Login to comment 33 ABCA3 p.Glu292Val BsrG1 restriction enzyme analysis was used to detect the E292V mutation according to previously published reports by means of restriction fragment length polymorphism-PCR (7,8). Login to comment 37 ABCA3 p.Glu292Val ABCA3 p.Glu292Val Table 1 Clinical characteristics of the very-low-birth-weight cohort stratified to ABCA3 genotype ABCA3 E292E (total) ABCA3 E292V (total) p ABCA3 E292E (<30 weeks) ABCA3 E292V (<30 weeks) p Number of infants 3166 11 2048 6 Gestational age (mean / median / range weeks) 28.8 / 28.8 / 22.0-36.4 28.9 / 28.6 / 24.1-33.1 0.52 27.2 / 27.4 / 22.0-29.8 26.6 / 26.6 / 24.1-28.6 0.32 Birth weight (mean / median, g) 1073 / 1100 / 295-1495 1042 / 1020 / 615-1490 0.71 951 / 940 / 295-1495 866 / 825 / 615-1170 0.42 Gender (male, %) 51.0 54.5 1.0 52.4 66.7 0.7 Multiples (%) 27.3 32.6 1.0 29.8 33.3 1.0 Inborn (%) 92.7 88.8 0.49 92.4 80.0 0.33 Antenatal steroids (%) 86.4 100 0.38 88.7 100 1.0 Death (%) 2.4 9.1 0.24 3.4 16.7 0.18 IVH (%) 17.7 36.3 0.08 23.8 66.7 0.03 Grade I 7.2 10.0 8.8 16.7 Grade II 4.1 10.0 6.0 16.7 Grade III 2.8 10.0 4.0 16.7 Grade IV 3.6 10.0 5.0 16.7 Sepsis (%) 16.5 18.2 0.7 22.1 33.3 0.62 OP (%) 13.4 9.1 1.0 19.2 16.7 1.0 Duration hospital stay (mean / median / range, days) 71.8 / 66 / 1-387 67.3 / 64 / 3-125 0.74 84.4 / 80 / 1-387 85.2 / 103 / 3-125 0.46 Maternal descendence Germany (%) 74.5 90.9 0.84 71.6 83.3 0.9 Europe / Russia (%) 10.7 9.1 11.5 16.7 Middle East / Turkey (%) 10.0 0 11.1 0 IVH intraventricular haemorrhage; sepsis: clinical sepsis with positive blood culture; OP: any surgical intervention for necrotizing enterocolitis or focal intestinal perforation, retinopathy of prematurity, persistent Ductus arteriosus, hydrocephalus. Login to comment 38 ABCA3 p.Glu292Val RESULTS In a large cohort of 3177 VLBW infants, 11 individuals carried the E292V mutation (0.34%). Login to comment 42 ABCA3 p.Glu292Val When we analysed a subgroup of infants <30 weeks of gestation, infants carrying the E292V mutation had a higher risk for development of IVH and tended to be more frequently and longer ventilated than infants without the mutation. Login to comment 45 ABCA3 p.Glu292Val DISCUSSION This is the first large-scale cohort of VLBW infants studied for the influence of the ABCA3 E292V mutation on pulmonary morbidity. Login to comment 53 ABCA3 p.Glu292Val ABCA3 (E292V) and pulmonary morbidity in VLBW infants Ha¨rtel et al. ª2011 The Author(s)/Acta Pædiatrica ª2011 Foundation Acta Pædiatrica 2012 101, pp. 380-383 infants were born after Caesarean section. Login to comment 57 ABCA3 p.Glu292Val We would like to illustrate this by a post hoc power analysis: If the rate of 'death or BPD`, which was 15% in infants not carrying the ABCA3-E292V, would have been 50% in carriers of the mutation, 3000 infants would have been sufficient to test the difference. Login to comment 59 ABCA3 p.Glu292Val Therefore present results do not rule out the possibility that E292V phenotype is associated with some difference in the morbidity. Login to comment 60 ABCA3 p.Glu292Val Besides statistical limitations of our study, there may be ethnic differences relating to other interactive genes expressed in alveolar epithelium or to haplotypes associated with E292V genotype that influence the risk. Login to comment 65 ABCA3 p.Glu292Val Garmany et al. (7) noted a high incidence of respiratory dysfunction (BPD, mechanical ventilation >1 year) in the two most immature infants (26 and 29 gestational weeks) with E292V; however, this was not confirmed in our cohort (Tables 2 and 3). Login to comment 70 ABCA3 p.Glu292Val In conclusion, we were not able to confirm an attributable risk of the genetically disruptive ABCA3 mutation E292V on pulmonary outcome in VLBW infants. Login to comment