ABCA3 p.Leu579Pro
| Predicted by SNAP2: | A: D (66%), C: D (53%), D: D (80%), E: D (66%), F: D (53%), G: D (80%), H: D (63%), I: N (82%), K: D (71%), M: N (82%), N: D (71%), P: D (75%), Q: D (59%), R: D (71%), S: D (66%), T: D (53%), V: N (66%), W: D (75%), Y: D (53%), |
| 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] Alteration of the pulmonary surfactant system in f... Am J Respir Crit Care Med. 2006 Sep 1;174(5):571-80. Epub 2006 May 25. Brasch F, Schimanski S, Muhlfeld C, Barlage S, Langmann T, Aslanidis C, Boettcher A, Dada A, Schroten H, Mildenberger E, Prueter E, Ballmann M, Ochs M, Johnen G, Griese M, Schmitz G
Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency.
Am J Respir Crit Care Med. 2006 Sep 1;174(5):571-80. Epub 2006 May 25., [PMID:16728712]
Abstract [show]
RATIONALE: ABCA3 mutations are known to cause fatal surfactant deficiency. OBJECTIVE: We studied ABCA3 protein expression in full-term newborns with unexplained respiratory distress syndrome (URDS) as well as the relevance of ABCA3 mutations for surfactant homeostasis. METHODS: Lung tissue of infants with URDS was analyzed for the expression of ABCA3 in type II pneumocytes. Coding exons of the ABCA3 gene were sequenced. Surfactant protein expression was studied by immunohistochemistry, immunoelectron microscopy, and Western blotting. RESULTS: ABCA3 protein expression was found to be greatly reduced or absent in 10 of 14 infants with URDS. Direct sequencing revealed distinct ABCA3 mutations clustering within vulnerable domains of the ABCA3 protein. A strong expression of precursors of surfactant protein B (pro-SP-B) but only low levels and aggregates of mature surfactant protein B (SP-B) within electron-dense bodies in type II pneumocytes were found. Within the matrix of electron-dense bodies, we detected precursors of SP-C (pro-SP-C) and cathepsin D. SP-A was localized in small intracellular vesicles, but not in electron-dense bodies. SP-A and pro-SP-B were shown to accumulate in the intraalveolar space, whereas mature SP-B and SP-C were reduced or absent, respectively. CONCLUSION: Our data provide evidence that ABCA3 mutations are associated not only with a deficiency of ABCA3 but also with an abnormal processing and routing of SP-B and SP-C, leading to severe alterations of surfactant homeostasis and respiratory distress syndrome. To identify infants with hereditary ABCA3 deficiency, we suggest a combined diagnostic approach including immunohistochemical, ultrastructural, and mutation analysis.
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No. Sentence Comment
123 MUTATIONS OF THE ABCA3 GENE IN THE STUDY GROUP AND ABCA3 PROTEIN EXPRESSION IN TYPE II PNEUMOCYTES IN INDEX PATIENTS ABCA3 Protein Expression in Type II Pneumocytes in Index Patients Family Localization* Nucleotide Deviation Structural Relevance Affected Domain (immunohistochemical score)† 1 Exon 15 c1755C Ͼ G Silent polymorphism - Weak (1) Exon 15 c1814G Ͼ A R605Q (Arg Ͼ Gln) NBD 1 Exon 31 c4877-8delAG Frameshift/Stop C-terminus 2 Exon 10 c1058C Ͼ T Silent polymorphism - Weak (1) Intron 15 c1897-1G Ͼ C Acceptor splice-site mutation NBD 1 3 Exon 8 c643C Ͼ A Q215K (Gln Ͼ Lys) First extracellular loop Absent (0) Exon 8 c863G Ͼ A R288K (Arg Ͼ Lys) First extracellular loop 4 Intron 21 c3005-1G Ͼ A Acceptor splice-site mutation Second half-size transporter Weak (1) 5 Exon 5 c128G Ͼ T (het) R43L (Arg Ͼ Leu) First extracellular loop Absent (0) Exon 8 c863G Ͼ A (het) R288K (Arg Ͼ Lys) First extracellular loop Exon 15 c1755C Ͼ G (het) Silent polymorphism - Exon 31 c4751delT (het) Frameshift/Stop C-terminus 6 Exon 14 c1736T Ͼ C (het) L579P (Leu Ͼ Pro) NBD 1 Weak (1) Exon 25 c3812delG (het) Frameshift/Stop Last extracellular loop, C-terminus 7 Exon 30 c4681 C Ͼ T R1561X (Arg Ͼ Stop) C-terminus Weak (1) 8 Exon 19 c2429-30delTT Frameshift/Stop Second half-size transporter Weak (1) Definition of abbreviation: NBD ϭ nucleotide-binding domain.
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ABCA3 p.Leu579Pro 16728712:123:1143
status: NEW