ABCMdb

PMID: 15976379

Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM
ABCA3 mutations associated with pediatric interstitial lung disease.
Am J Respir Crit Care Med. 2005 Oct 15;172(8):1026-31. Epub 2005 Jun 23., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCA3 p.Glu292Val All three had the same missense mutation (E292V) and a second unique mutation. Login to comment 7 ABCA3 p.Glu292Val ABCA3 p.Glu292Val The E292V mutation was not found on 200 control alleles from adults without lung disease, but seven additional patients of the remaining study patients had the E292V mutation on one allele. Login to comment 69 ABCA3 p.Glu292Val ABCA3 p.Glu292Val This mutation results in the substitution of valine for glutamic acid in codon 292 (E292V) and introduces a new recognition site for the restriction endonuclease BsrG1. Login to comment 70 ABCA3 p.Glu292Val The E292V mutation was not found on any of the 200 alleles examined from 100 adults without lung disease and who were matched for ethnic background by restriction analysis of polymerase chain reaction products spanning exon 9. Login to comment 71 ABCA3 p.Glu292Val DNA samples from 153 of the remaining study patients, for whom the cause of lung disease remained undetermined, were then examined for the E292V mutations by restriction analysis. Login to comment 73 ABCA3 p.Glu292Val Seven additional patients with the E292V mutation on one allele were identified by restriction analysis and confirmed by DNA sequence analysis, including one pair of siblings (Table 2). Login to comment 82 ABCA3 p.Trp12* A similar pattern of robust staining for proSP-B with reduced staining for mature SP-B, which was recovered after antigen retrieval, was observed in Patients 3 and 8 (not shown), as well as in lung tissue from a full-term neonate who was a compound heterozygote for two ABCA3 mutations (W12X/ 3997delAG; Figure 2). Login to comment 86 ABCA3 p.Glu292Val All 10 patients had the identical ABCA3 mutation on one allele, E292V, a nonconservative amino acid substitution in a region of the protein that has been highly conserved during evolution (Figure 3). Login to comment 87 ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Asn1076Lys The E292V mutation was not found on 200 control alleles, indicating that it is TABLE 1. CHARACTERISTICS OF OLDER CHILDREN WITH CHRONIC LUNG DISEASE Patient 1 Patient 2 Patient 3 Patient 4 Race White White White White Age of symptoms Birth Ͻ 1 yr Ͻ 1 yr Birth Sex Female Female Male Male Lung biopsy DIP DIP DIP DIP Age at enrollment 23 yr 14 yr 10 yr 11 yr Current age 32 yr 16 yr 12 yr 11 yr Family history No Yes No No Outcome Lung transplant Alive Alive Alive ABCA3 mutations E292V/N1076K E292V/c3704-1 GϾT E292V/c1742-9 GϾA None Maternal allele NA c3704-1 GϾT E292V NA Paternal allele NA NA c1742-9 GϾA NA Definition of abbreviations: DIP ϭ desquamative interstitial pneumonitis; NA ϭ not available. Login to comment 90 ABCA3 p.Glu292Val The early onset of disease, similar lung histopathology, and finding of a common mutation all support the idea that ABCA3 mutations in general, and the E292V mutation in particular, are responsible for the genetic etiology of pILD related to abnormal surfactant function. Login to comment 104 ABCA3 p.Glu292Val ABCA3 p.Glu292Val phenotype had the same variant supports the hypothesis that E292V is deleterious and not a neutral variant, although we cannot exclude the possibility that E292V is linked functionally to a more significant mutation in a region of the ABCA3 gene that we have not analyzed. Login to comment 105 ABCA3 p.Glu292Val ABCA3 p.Glu690Lys ABCA3 p.Thr1114Met ABCA3 p.Asn1076Lys ABCA3 p.Gly1302Glu ABCA3 p.Pro1301Leu In addition to the E292V mutation, five additional missense variants (N1076K, G1302E, P1301L, T1114M, E690K) and three splice junction site mutations (c3704-1 GϾT, c1742-9 GϾA, c1612-2 AϾG) that would likely alter RNA splicing were identified. Login to comment 110 ABCA3 p.Glu292Val A second mutation affecting ABCA3 expression or mRNA splicing may have been present in a region of the gene we did not examine, or other genetic or environmental factors in combination with the E292V mutation on one allele may have accounted for their lung disease. Login to comment 121 ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu292Val ABCA3 p.Glu690Lys ABCA3 p.Glu690Lys ABCA3 p.Thr1114Met ABCA3 p.Gly1302Glu ABCA3 p.Pro1301Leu Some of this variability may reflect different stages of the disease and/or patchy distribution of disease within the lung, as well as TABLE 2. CHARACTERISTICS OF CHILDREN WITH CHRONIC LUNG DISEASE WHO SCREENED POSITIVE FOR E292V MUTATION Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Race White White White White White Hispanic White Age of symptoms Neonate Neonate Neonate 7 yr 5 yr Neonate Neonate Sex Female Female Male Male Male Male Male Lung biopsy Not done Not done Not done IP/PF Not done BO/fibrosis Normal Current age NA 11 yr 11 yr 11 yr 9 yr NA 6 yr Family history Yes No Yes Yes Yes No No Outcome Died at 11 yr Alive Alive Alive Alive Died at 6 mo Alive ABCA3 mutations E292V/c1612-2 E292V/G1302E E292V/T1114M E292V/E690K E292V/E690K E292V/none E292V/none AϾG/P1301L identified identified Definition of abbreviations: BO ϭ bronchiolitis obliterans; IP ϭ interstitial pneumonitis; NA ϭ not available; PF ϭ pulmonary fibrosis. Login to comment 124 ABCA3 p.Glu292Val ABCA3 p.Glu690Lys However, both siblings with the E292V/E690K mutations reportedly did not develop symptoms of lung disease until 5 to 7 years of age. Login to comment 128 ABCA3 p.Glu292Val Lung tissue from Patient 1, with ABCA3 mutations (E292V/N1076) and prolonged survival (left column: A, D, G, J, M; original magnification, ϫ20). Login to comment 130 ABCA3 p.Trp12* A similar pattern is seen in lung tissue from a full-term neonate with fatal lung disease who was a compound heterozygote for ABCA3 null mutations (W12X/3997delAG; middle column: B, E, H, K, N; original magnification, ϫ20). Login to comment 137 ABCA3 p.Glu292Val ABCA3 amino acid sequence is highly conserved in region of E292V mutation. Login to comment 144 ABCA3 p.Glu292Val The immunohistochemical staining pattern for the surfactant proteins in three of our E292V patients was abnormal, with robust staining for proSP-B but markedly reduced staining for mature SP-B, which was recovered with antigen retrieval. Login to comment 158 ABCA3 p.Glu292Val The relative contribution of ABCA3 mutations to lung disease may be even greater than we currently appreciate, because the majority of patients in our study group were screened only for the E292V mutation and have not yet had their ABCA3 gene sequenced or screened for other mutations. Login to comment 162 ABCA3 p.Glu292Val Thus, there is significant ascertainment bias that limits interpretation of the relative frequency of these genetic causes of lung disease, and the unusual nature of the lung disease in these patients may exaggerate the apparent contribution of E292V and other ABCA3 mutations to pILD. Login to comment