ABCMdb

ABCA3 p.Leu212Met

Predicted by SNAP2:	A: N (61%), C: N (78%), D: D (63%), E: N (61%), F: N (82%), G: D (63%), H: D (75%), I: N (93%), K: N (53%), M: N (61%), N: N (53%), P: D (53%), Q: D (75%), R: D (53%), S: N (57%), T: N (72%), V: N (87%), W: D (59%), Y: N (72%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] An intronic ABCA3 mutation that is responsible for... Pediatr Res. 2012 Jun;71(6):633-7. doi: 10.1038/pr.2012.21. Epub 2012 Feb 15. Agrawal A, Hamvas A, Cole FS, Wambach JA, Wegner D, Coghill C, Harrison K, Nogee LM
An intronic ABCA3 mutation that is responsible for respiratory disease.
Pediatr Res. 2012 Jun;71(6):633-7. doi: 10.1038/pr.2012.21. Epub 2012 Feb 15., [PMID:22337229]

Abstract [show]
INTRODUCTION: Member A3 of the ATP-binding cassette family of transporters (ABCA3) is essential for surfactant metabolism. Nonsense, missense, frameshift, and splice-site mutations in the ABCA3 gene (ABCA3) have been reported as causes of neonatal respiratory failure (NRF) and interstitial lung disease. We tested the hypothesis that mutations in noncoding regions of ABCA3 may cause lung disease. METHODS: ABCA3-specific cDNA was generated and sequenced from frozen lung tissue from a child with fatal lung disease with only one identified ABCA3 mutation. ABCA3 was sequenced from genomic DNA prepared from blood samples obtained from the proband, parents, and other children with NRF. RESULTS: ABCA3 cDNA from the proband contained sequences derived from intron 25 that would be predicted to alter the structure and function of the ABCA3 protein. Genomic DNA sequencing revealed a heterozygous C>T transition in intron 25 trans to the known mutation, creating a new donor splice site. Seven additional infants with an ABCA3-deficient phenotype and inconclusive genetic findings had this same variant, which was not found in 2,132 control chromosomes. DISCUSSION: These findings support that this variant is a disease-causing mutation that may account for additional cases of ABCA3 deficiency with negative genetic studies.

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80 However, the mechanism to account for this larger aberrant transcript with an additional 249 bases Table 1. Characteristics of subjects with one ABCA3 mutation Patient Ethnicity Presentation Allele 1 mutation Allele 2 mutation Findings consistent with ABCA3 deficiency Outcome A Caucasian Newborn, RDS p.E690K IVS25-98T Case patient; lung histopathology and EM Died B Caucasian RDS p.L941P IVS25-98T Family history of sibling with fatal RDS Died C Caucasian 8 y/old, ILD L212M ? Login to comment

[hide] Identification of early interstitial lung disease ... Chest. 2010 Apr;137(4):969-73. Crossno PF, Polosukhin VV, Blackwell TS, Johnson JE, Markin C, Moore PE, Worrell JA, Stahlman MT, Phillips JA 3rd, Loyd JE, Cogan JD, Lawson WE
Identification of early interstitial lung disease in an individual with genetic variations in ABCA3 and SFTPC.
Chest. 2010 Apr;137(4):969-73., [PMID:20371530]

Abstract [show]
A man with usual interstitial pneumonia (age of onset 58 years) was previously found to have an Ile73Thr (I73T) surfactant protein C (SFTPC) mutation. Genomic DNA from the individual and two daughters (aged 39 and 43 years) was sequenced for the I73T mutation and variations in ATP-binding cassette A3 (ABCA3). All three had the I73T SFTPC mutation. The father and one daughter (aged 39 years) also had a transversion encoding an Asp123Asn (D123N) substitution in ABCA3. The daughters were evaluated by pulmonary function testing and high-resolution CT (HRCT). Neither daughter had evidence of disease, except for focal subpleural septal thickening on HRCT scan in one daughter (aged 39 years). This daughter underwent bronchoscopy with transbronchial biopsies revealing interstitial fibrotic remodeling. These findings demonstrate that subclinical fibrotic changes may be present in family members of patients with SFTPC mutation-associated interstitial lung disease and suggest that ABCA3 variants could affect disease pathogenesis.

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88 Previously, Bullard and Nogee7 analyzed children with I73T SFTPC mutation-associated ILD and found heterozygous ABCA3 mutations in three of four individuals-two with E292V (glutamic acid-to-valine) and one with L212M (leucine-to-methionine). Login to comment

[hide] Familial interstitial disease with I73T mutation: ... Pediatr Pulmonol. 2009 Feb;44(2):167-75. Abou Taam R, Jaubert F, Emond S, Le Bourgeois M, Epaud R, Karila C, Feldmann D, Scheinmann P, de Blic J
Familial interstitial disease with I73T mutation: A mid- and long-term study.
Pediatr Pulmonol. 2009 Feb;44(2):167-75., [PMID:19148933]

Abstract [show]
OBJECTIVES: To describe the long-term course and the management in children of chronic interstitial lung disease associated with I73T mutation. MATERIALS AND METHODS: Clinical, radiological, and histological data from one family including five children and two adults were analyzed retrospectively for three patients and prospectively for the others. RESULTS: Mean age of onset of respiratory symptoms for children was 6 months (2-15 months). The follow up was 14 months to 15 years (mean 55 months). The children were treated by intravenous high dose methylprednisolone pulses (6-15, mean 12). Four received oral prednisolone (mean 16 months) and hydroxychloroquine, one of these had additional mycophenolate mofetil. One adult with mild respiratory symptoms in infancy and another who was symptom free were also diagnosed. Both of them received no treatment. BAL fluids were obtained in all children: pro-SPC and SPB were positive in all. Lung biopsies were performed in two children respectively at 7 months, showing interstitial pneumonia features with endoluminal macrophage and type II alveolar cells hyperplasia, and at 33 months, showing subpleural microbullae, areas of interstitial pneumonia and type II alveolar cells hyperplasia. Immunohistochemistry showed for both an increased SPB and TTF1 staining in type II cells nuclei and a faint staining for pro-SPC and for ABCA3. Genetic diagnosis obviated the need for biopsy in other cases. The clinical status progressively improved and oxygen supplementation could be stopped after 3-14 months (mean 9 months). The CT scans initially showed ground glass opacities, then reduction in the ground glass pattern associated with clinical improvement and development of cysts. CONCLUSION: This kindred illustrates the variability of respiratory involvement and prognosis. It confirms the value of genetic screening for surfactant protein genes mutations.

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118 Recently Bullard and Nogee2 reported an additional heterozygous ABCA3 mutation in three of four infants with SFTPC I73T mutation, all of whom developed a respiratory disease by 2 months of age (E292Vin two patients and L212M in one patient). Login to comment

[hide] Heterozygosity for ABCA3 mutations modifies the se... Pediatr Res. 2007 Aug;62(2):176-9. Bullard JE, Nogee LM
Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation.
Pediatr Res. 2007 Aug;62(2):176-9., [PMID:17597647]

Abstract [show]
Heterozygous SFTPC mutations have been associated with adult and pediatric interstitial lung disease (pILD). Inheritance is autosomal dominant, but de novo mutations may cause sporadic disease. SFTPC mutations have been associated with variable onset of symptoms, ranging from early infancy to late adulthood. The underlying mechanisms for this variability are unknown. Recently, mutations in ABCA3 (encoding member A3 of the adenosine triphosphate-binding cassette family of transporters) were identified as a cause of pILD. To test the hypothesis that ABCA3 mutations modify the severity of lung disease in individuals with SFTPC mutations, we sequenced ABCA3 from four symptomatic infants with the same SFTPC mutation, a substitution of isoleucine by threonine in codon 73 (I73T). Each infant developed respiratory symptoms by 2 mo of age and inherited the mutation from an asymptomatic parent. Three of the four infants were also heterozygous for an ABCA3 mutation, which was inherited from the parent without SFTPC I73T. The finding of heterozygosity for ABCA3 mutations in severely affected infants with SFTPC I73T, and independent inheritance from disease-free parents supports that ABCA3 acts as a modifier gene for the phenotype associated with an SFTPC mutation.

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54 Patient 3 was heterozygous for a missense mutation in exon 8, a substitution of methionine for leucine at codon 212, L212M. Login to comment
67 Circle, female; square, male; shaded quarter symbol, SFTPC I73T; solid quarter symbol, ABCA3 E292V; check- ered quarter symbol, ABCA3 L212M; slash through symbol, deceased; IPF, idiopathic pulmonary fibrosis; RSV, respiratory syncytial virus. Login to comment
75 The third infant had a different missense mutation, ABCA3 L212M, which results in a conservative neutral substitution. Login to comment
76 It is possible that L212M represents a rare but benign polymorphism. Login to comment
77 However, two siblings with significant respiratory symptoms and who had lung histopathology findings consistent with surfactant dysfunction were compound heterozygotes for a previously identified ABCA3 nonsense mutation (R106X) and L212M, suggesting that L212M is a disease-causing mutation (L.M. Nogee, unpublished data). Login to comment
78 However, two siblings with significant respiratory symptoms and who had lung histopathology findings consistent with surfactant dysfunction were compound heterozygotes for a previously identified ABCA3 nonsense mutation (R106X) and L212M, suggesting that L212M is a disease-causing mutation (L.M. Nogee, unpublished data). Login to comment

[hide] Single ABCA3 mutations increase risk for neonatal ... Pediatrics. 2012 Dec;130(6):e1575-82. doi: 10.1542/peds.2012-0918. Epub 2012 Nov 19. 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., [PMID:23166334]

Abstract [show]
BACKGROUND AND OBJECTIVE: Neonatal respiratory distress syndrome (RDS) due to pulmonary surfactant deficiency is heritable, but common variants do not fully explain disease heritability. METHODS: Using next-generation, pooled sequencing of race-stratified DNA samples from infants >/=34 weeks' gestation with and without RDS (n = 513) and from a Missouri population-based cohort (n = 1066), we scanned all exons of 5 surfactant-associated genes and used in silico algorithms to identify functional mutations. We validated each mutation with an independent genotyping platform and compared race-stratified, collapsed frequencies of rare mutations by gene to investigate disease associations and estimate attributable risk. RESULTS: Single ABCA3 mutations were overrepresented among European-descent RDS infants (14.3% of RDS vs 3.7% of non-RDS; P = .002) but were not statistically overrepresented among African-descent RDS infants (4.5% of RDS vs 1.5% of non-RDS; P = .23). In the Missouri population-based cohort, 3.6% of European-descent and 1.5% of African-descent infants carried a single ABCA3 mutation. We found no mutations among the RDS infants and no evidence of contribution to population-based disease burden for SFTPC, CHPT1, LPCAT1, or PCYT1B. CONCLUSIONS: In contrast to lethal neonatal RDS resulting from homozygous or compound heterozygous ABCA3 mutations, single ABCA3 mutations are overrepresented among European-descent infants >/=34 weeks' gestation with RDS and account for ~10.9% of the attributable risk among term and late preterm infants. Although ABCA3 mutations are individually rare, they are collectively common among European- and African-descent individuals in the general population.

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57 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