ABCMdb

ABCA3 p.Thr761Met

Predicted by SNAP2:	A: N (66%), C: N (61%), D: N (61%), E: N (66%), F: D (59%), G: N (57%), H: N (72%), I: N (57%), K: N (72%), L: N (53%), M: N (57%), N: N (78%), P: N (57%), Q: N (61%), R: N (61%), S: N (82%), V: N (61%), W: D (75%), Y: D (53%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: D, F: N, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: N, V: N, W: D, Y: D,

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[hide] Hereditary interstitial lung diseases manifesting ... Pediatr Res. 2014 Nov;76(5):453-8. doi: 10.1038/pr.2014.114. Epub 2014 Aug 8. Akimoto T, Cho K, Hayasaka I, Morioka K, Kaneshi Y, Furuta I, Yamada M, Ariga T, Minakami H
Hereditary interstitial lung diseases manifesting in early childhood in Japan.
Pediatr Res. 2014 Nov;76(5):453-8. doi: 10.1038/pr.2014.114. Epub 2014 Aug 8., [PMID:25105258]

Abstract [show]
BACKGROUND: Genetic variations associated with interstitial lung diseases (ILD) have not been extensively studied in Japanese infants. METHODS: Forty-three infants with unexplained lung dysfunction were studied. All 43, 22, and 17 infants underwent analyses of surfactant protein (SP)-C gene (SFTPC) and ATP-binding cassette A3 gene (ABCA3), SP-B gene (SFTPB), and SP-B western blotting, respectively. Two and four underwent assessment of granulocyte macrophage colony-stimulating factor-stimulating phosphorylation of signal transducer and activator of transcription-5 (pSTAT-5) and analyses of FOXF1 gene (FOXF1), respectively. RESULTS: ILD were diagnosed clinically in nine infants: four, three, and two had interstitial pneumonitis, hereditary pulmonary alveolar proteinosis (hPAP), and alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), respectively. Genetic variations considered responsible were detected in six (67%) of the nine infants with ILD: three with hPAP (SFTPC p.Leu45Arg and p.Gln145fs, and ABCA3 p.Arg1583Trp/p.Val1495CysfsX21), two with interstitial pneumonitis (SFTPC p.Lys63Glu and p.Ser72Asn/p.Gly100Ala), and one with ACD/MPV (FOXF1 p.Leu300ArgfsX79). None showed SFTPB mutations or defects in pSTAT-5. The 17 bronchoalveolar lavage or tracheal aspirates contained enough SP-B protein. CONCLUSION: The SP-C abnormality was most prevalent, and SP-B deficiency was rare in Japanese infants with hereditary ILD.

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No. Sentence Comment
33 Two other compound heterozygous ABCA3 mutations, i.e., ABCA3 p.Pro73Leu/p.Gly1205Arg and ABCA3 p.Thr761Met/p.Ala1362Val, were detected in two (cases 7 and 8 in Table 3) of the 34 infants without ILD: one full-term infant with p.Pro73Leu/p.Gly1205Arg manifested lung dysfunction immediately after birth, but recovered with transient assisted ventilation only, and another with p.Thr761Met/p.Ala1362Val born at gestational week 27 weighing 778ߙg manifested lung dysfunction at 8 mo after birth and is being treated currently with vasodilators and home oxygen. Login to comment
64 To our knowledge, 10 other mutations in six cases (cases 2-5, 7, and 8) have not been reported to date, i.e., four SFTPC mutations of heterozygous p.Gln145fs, heterozygous p.Lys63Glu, p.Ser72Asn, and p.Gly100Ala, and six ABCA3 mutations of p.Arg1583Trp, p.Val1495CysfsX21, p.Pro73Leu, p.Gly1205Arg, p.Thr761Met, and p.Ala1362Val. Login to comment
67 Frameshift mutations were detected in case 2 Table 3.ߒ Eight patients in whom genetic variations were found Case BW/GW Onset Diagnosis AV iNO Genotype SIFT/ polyphen-2 Origin of variations Treatment Outcome 1 3,204/40 0 d hPAP Yes No SFTPC c.134T>C: p.Leu45Arg (het) Damaging/ damaging Denovo Surfactant, steroids, and Hch Undergoing treatment, 43 mo 2 2,600/40 6 d hPAP Yes No SFTPC c.433delC: p.Gln145fs (het) Not done Unknownc Surfactant, steroids, and Hch Died, 77 d 3 3,230/40 0 d hPAP Yes Yes ABCA3 c.4747C>T: p.Arg1583Trp, Damaging/ damaging Mother (asymptomatic) Surfactant, steroids, and Hch Died, 7 mo ABCA3 c.4483_4507del25: p.Val1495CysfsX21 Not done Father (asymptomatic) 4 3,060/41 5 mo IPa No No SFTPC c.187A>G: p.Lys63Glu (het) Damaging/ damaging Mother (asymptomatic) and mother`s father (pulmonary fibrosis) Steroids and Hch Undergoing treatment, 54 mo 5 3,520/38 2 wk IP Yes No SFTPC c.215G>A: p.Ser72Asn Damaging/ damaging Unknownc Steroids, CsA, CPM, and AZP Undergoing treatment, 13 y SFTPC c.299G>C: p.Gly100Ala Damaging/ benign 6 3,344/41 3 mo ACD/MPV Yes Yes FOXF1 c.899delT: p.Leu300ArgfsX79 (het) Not done Denovo Steroids, vasodilator Undergoing treatment, 24 mo 7 3,194/40 0 d URD Yes No ABCA3 c.218C>T: p.Pro73Leu Tolerated/ benignb Unknownc None Recovered ABCA3 c.3613G>A: p.Gly1205Arg Tolerated/ benignb 8 778/27 8 mo CLD, PH Yes No ABCA3 c.2282C>T: p.Thr761Met, Damaging/ damaging Mother (asymptomatic) Vasodilator Undergoing treatment, 17 mo ABCA3 c.4085C>T: p.Ala1362Val Tolerated/ benignb Father (asymptomatic) ACD/MPV, alveolar capillary dysplasia with misalignment of pulmonary veins; AV, assisted ventilation; AZP, azathioprine; BW/GW, birth weight/gestational week at delivery; CLD, chronic lung disease; CPM, cyclophosphamide; CsA, cyclosporine A; Hch, hydroxychloroquine; hPAP, hereditary pulmonary alveolar proteinosis; iNO, inhaled nitric oxide; IP, interstitial pneumonitis; PH, pumonary hypertension; URD, unexplained respiratory distress. Login to comment
76 Whether the three variations in cases 7 and 8 except ABCA3 p.Thr761Met were causative for lung dysfunction is undetermined. Login to comment
77 The ABCA3 p.Thr761Met in case 8 was judged as "damaging" with both SIFT and polyphen-2 occurring in one in 6,500 European and Americans according to the Exome Sequencing Project. Login to comment
78 Thus, the ABCA3 p.Thr761Met may be responsible for lung dysfunction in case 8. Login to comment