ABCMdb

PMID: 15044640

Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M
ABCA3 gene mutations in newborns with fatal surfactant deficiency.
N Engl J Med. 2004 Mar 25;350(13):1296-303., [PubMed]

Sentences

No. Mutations Sentence Comment

43 ABCA3 p.Asn568Asp ABCA3 p.Gly1221Ser ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1553Pro ABCA3 p.Leu1553Pro ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Leu1580Pro ABCA3 p.Gln1591Pro ABCA3 p.Arg106* ABCA3 p.Arg106* ABCA3 p.Trp1142* ABCA3 p.Trp1142* ABCA3 p.Trp1142* ABCA3 p.Trp1142* ABCA3 p.Leu982Pro ABCA3 p.Leu982Pro Family History/ Consanguinity Outcome Histologic Findings ABCA3 Mutation 1 White F 1 Yes/Yes Death within 3 mo after birth DIP, PAP W1142X/W1142X 2 White F 1 Yes/Yes Death during neonatal period DIP, PAP W1142X/W1142X 3 Black M 2 Yes/Yes Death during neonatal period NA L101P/L101P 4 Black M 2 Yes/Yes Death during neonatal period NA L101P/L101P 5 White F 3 Yes/No Death during neonatal period NA 4552insT/L1580P 6 White F 3 Yes/No Death during neonatal period NA 4552insT/L1580P 7 White M 4 Yes/No Death within 3 mo after birth PAP G1221S/L982P 8 White M 4 Yes/No Death during neonatal period PAP G1221S/L982P 9 Middle Eastern M 5 Yes/Yes Death during neonatal period DIP, PAP L1553P/L1553P 10 Middle Eastern M 5 Yes/Yes Death during neonatal period NA L1553P/L1553P 11 White M 6 Yes/No Recovery from RDS NA None found 12 White M 6 Yes/No Recovery from RDS NA None found 13 Middle Eastern M 7 No/Yes Unknown NA 1644delC/1644delC 14 Middle Eastern M 8 Yes/No Death during neonatal period DIP, PAP R106X/R106X 15 Asian F 9ߤ Yes/Yes Death during neonatal period NA 4909+1G>A/4909+1G>A 16 White M 10 Yes/Yes Death during neonatal period NA None found 17 White M 11 No/No Recovery from RDS NA None found 18 White F 12 No/No Death during neonatal period NA None found 19 White M 13 Yes/No Chronic lung disease CPI, DIP Q1591P/-ߥ 20 Hispanic M 14 No/No Death after lung transplantation PAP N568D/-ߥ 21 Asian F 9ߤ Yes/Yes Death during neonatal period PAP 4909+1G>A/4909+1G>A entorganisms,weusedthededucedaminoacidse- quence of ABCA3 (GenBank accession number NP_001080) to search the sequence data base using the BLAST program (http://www.ncbi.nlm.nih. Login to comment 44 ABCA3 p.Asn568Asp ABCA3 p.Asn568Asp ABCA3 p.Gly1221Ser ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1553Pro ABCA3 p.Leu1553Pro ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Leu1580Pro ABCA3 p.Gln1591Pro ABCA3 p.Gln1591Pro ABCA3 p.Arg106* ABCA3 p.Arg106* ABCA3 p.Trp1142* ABCA3 p.Trp1142* ABCA3 p.Trp1142* ABCA3 p.Trp1142* ABCA3 p.Leu982Pro ABCA3 p.Leu982Pro Family History/ Consanguinity Outcome Histologic Findings ABCA3 Mutation 1 White F 1 Yes/Yes Death within 3 mo after birth DIP, PAP W1142X/W1142X 2 White F 1 Yes/Yes Death during neonatal period DIP, PAP W1142X/W1142X 3 Black M 2 Yes/Yes Death during neonatal period NA L101P/L101P 4 Black M 2 Yes/Yes Death during neonatal period NA L101P/L101P 5 White F 3 Yes/No Death during neonatal period NA 4552insT/L1580P 6 White F 3 Yes/No Death during neonatal period NA 4552insT/L1580P 7 White M 4 Yes/No Death within 3 mo after birth PAP G1221S/L982P 8 White M 4 Yes/No Death during neonatal period PAP G1221S/L982P 9 Middle Eastern M 5 Yes/Yes Death during neonatal period DIP, PAP L1553P/L1553P 10 Middle Eastern M 5 Yes/Yes Death during neonatal period NA L1553P/L1553P 11 White M 6 Yes/No Recovery from RDS NA None found 12 White M 6 Yes/No Recovery from RDS NA None found 13 Middle Eastern M 7 No/Yes Unknown NA 1644delC/1644delC 14 Middle Eastern M 8 Yes/No Death during neonatal period DIP, PAP R106X/R106X 15 Asian F 9† Yes/Yes Death during neonatal period NA 4909+1G>A/4909+1G>A 16 White M 10 Yes/Yes Death during neonatal period NA None found 17 White M 11 No/No Recovery from RDS NA None found 18 White F 12 No/No Death during neonatal period NA None found 19 White M 13 Yes/No Chronic lung disease CPI, DIP Q1591P/-‡ 20 Hispanic M 14 No/No Death after lung transplantation PAP N568D/-‡ 21 Asian F 9† Yes/Yes Death during neonatal period PAP 4909+1G>A/4909+1G>A entorganisms,weusedthededucedaminoacidse- quence of ABCA3 (GenBank accession number NP_001080) to search the sequence data base using the BLAST program (http://www.ncbi.nlm.nih. Login to comment 58 ABCA3 p.Leu101Pro ABCA3 p.Asn568Asp ABCA3 p.Asn568Asp ABCA3 p.Gly1221Ser ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Leu1580Pro ABCA3 p.Gln1591Pro ABCA3 p.Gln1591Pro ABCA3 p.Leu982Pro ABCA3 p.Leu982Pro ABCA4 p.Pro982Leu Seven missense muta- tionswereidentifiedinconservedaminoacids(Fig. 2), including homozygous substitutions of proline for leucine in codons 101 and 1553 (L101P and L1553P, respectively) and heterozygous substitutions of aspartic acid for asparagine at position 568 (N568D), proline for leucine at position 982 (L982P), serine for glycine at position 1221 (G1221S), proline for leucine at position 1580 (L1580P), and proline for glutamine at position 1591 (Q1591P). Login to comment 59 ABCA3 p.Leu101Pro ABCA3 p.Asn568Asp ABCA3 p.Asn568Asp ABCA3 p.Gly1221Ser ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Leu1580Pro ABCA3 p.Gln1591Pro ABCA3 p.Gln1591Pro ABCA3 p.Leu982Pro ABCA3 p.Leu982Pro ABCA4 p.Pro982Leu Seven missense muta- tionswereidentifiedinconservedaminoacids(Fig. 2), including homozygous substitutions of proline for leucine in codons 101 and 1553 (L101P and L1553P, respectively) and heterozygous substitutions of aspartic acid for asparagine at position 568 (N568D), proline for leucine at position 982 (L982P), serine for glycine at position 1221 (G1221S), proline for leucine at position 1580 (L1580P), and proline for glutamine at position 1591 (Q1591P). Login to comment 76 ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Trp1142* ABCA3 p.Leu982Pro Electron micrographs of lung tissue from Patient 21 (who was homozygous for the 4909+1G>A mutation) revealed lamellarbodies(Fig.3)thatweresmallerthanthose from control lung tissue, with more densely packed membranes and eccentrically placed, dense inclusion bodies, similar to those previously described in Patients 1 and 2, who were homozygous for the W1142X mutation.17 Similarly abnormal lamellar bodies were observed in lung tissue from Patient 8 (who was heterozygous for the G1221S and L982P mutations) and Patient 9 (who was homozygous for the L1553P mutation). Login to comment 77 ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Trp1142* ABCA3 p.Leu982Pro Electron micrographs of lung tissue from Patient 21 (who was homozygous for the 4909+1G>A mutation) revealed lamellarbodies(Fig.3)thatweresmallerthanthose from control lung tissue, with more densely packed membranes and eccentrically placed, dense inclusion bodies, similar to those previously described in Patients 1 and 2, who were homozygous for the W1142X mutation.17 Similarly abnormal lamellar bodies were observed in lung tissue from Patient 8 (who was heterozygous for the G1221S and L982P mutations) and Patient 9 (who was homozygous for the L1553P mutation). Login to comment 84 ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Leu982Pro ABCA3 p.Leu1552Pro The sequences of the puffer fish and the zebra fish are not complete, resulting in some gaps in this information in the case of L982P, G1221S, L1552P, L1553P, and L1580P. Login to comment 85 ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Leu982Pro ABCA3 p.Leu1552Pro The sequences of the puffer fish and the zebra fish are not complete, resulting in some gaps in this information in the case of L982P, G1221S, L1552P, L1553P, and L1580P. Login to comment 86 ABCA3 p.Leu101Pro ABCA3 p.Leu101Pro ABCA3 p.Asn568Asp ABCA3 p.Asn568Asp ABCA3 p.Gly1221Ser ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Leu1580Pro ABCA3 p.Gln1591Pro ABCA3 p.Gln1591Pro ABCA3 p.Arg106* ABCA3 p.Trp1142* ABCA3 p.Leu982Pro ABCA3 p.Leu982Pro Human Mouse Rat Puffer fish ETVRRALVIN ETVKREFMIK EAVRREFMIK EDVRGKLELS QDVQQNLVRG L101P NGAGKTT NGAGKTT NGAGKTT NGAGKTT NGAGKTT N568D VARRLL VARRLL VARRLL VARRLL L1553P Q1591P T301C(L101P) C316T(R106X) A1702G(N568D) 1644delC G3426A(W1142X) G3661A(G1221S) T4657C(L1553P) 4552insT A4771C(Q1591P) 4909+1G>A G1221S LSGIAT LSGIAT LSGIAT ATP-binding domains L982P QQLSEHL QQLSENL QQLSEHL T2945C(L982P) ECEALC LAIMVQGQFKC ECEALC ECEALC L1580P T4739C(L1580P) Nonsense Missense Splice Frameshift LAIMVQGQFKC LAIMVQGQFKC LAVMVNGQFKC Zebra fish LAVMVNGQFKC tified occur in residues that are highly conserved (Fig.2).Theaminoacidalignmentwasusedtopro- duce a phylogenetic tree of the ABCA3-related proteins showing the relation of the proteins from different organisms (see Supplementary Appendix 2, available with the full text of this article at www. nejm.org).ThefishABCA3proteinsclusterwiththe mammalian ABCA3 proteins and are distinct from other, more distant ABCA-family proteins, such as the mouse Abca14, Abca15, and Abca16 proteins and the sea-urchin ABCA proteins (see Supplementary Appendix 2. Login to comment 87 ABCA3 p.Leu101Pro ABCA3 p.Leu101Pro ABCA3 p.Asn568Asp ABCA3 p.Asn568Asp ABCA3 p.Gly1221Ser ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Leu1580Pro ABCA3 p.Gln1591Pro ABCA3 p.Gln1591Pro ABCA3 p.Arg106* ABCA3 p.Trp1142* ABCA3 p.Leu982Pro ABCA3 p.Leu982Pro Human Mouse Rat Puffer fish ETVRRALVIN ETVKREFMIK EAVRREFMIK EDVRGKLELS QDVQQNLVRG L101P NGAGKTT NGAGKTT NGAGKTT NGAGKTT NGAGKTT N568D VARRLL VARRLL VARRLL VARRLL L1553P Q1591P T301C(L101P) C316T(R106X) A1702G(N568D) 1644delC G3426A(W1142X) G3661A(G1221S) T4657C(L1553P) 4552insT A4771C(Q1591P) 4909+1G>A G1221S LSGIAT LSGIAT LSGIAT ATP-binding domains L982P QQLSEHL QQLSENL QQLSEHL T2945C(L982P) ECEALC LAIMVQGQFKC ECEALC ECEALC L1580P T4739C(L1580P) Nonsense MissenseSpliceFrameshift LAIMVQGQFKC LAIMVQGQFKC LAVMVNGQFKC Zebra fish LAVMVNGQFKC tified occur in residues that are highly conserved (Fig.2).Theaminoacidalignmentwasusedtopro- duce a phylogenetic tree of the ABCA3-related proteins showing the relation of the proteins from different organisms (see Supplementary Appendix 2, available with the full text of this article at www. nejm.org).ThefishABCA3proteinsclusterwiththe mammalian ABCA3 proteins and are distinct from other, more distant ABCA-family proteins, such as the mouse Abca14, Abca15, and Abca16 proteins and the sea-urchin ABCA proteins (see Supplementary Appendix 2. Login to comment 96 ABCA3 p.Leu101Pro ABCA3 p.Leu1553Pro In the case of the L101P and L1553P mutations, each of which affected one pair of siblings from two different families, the two pairs of siblings were both homozygous for the variant and homozygous for all other polymorphisms that we found in the gene - findings that are consistent with the occurrence of a recessive mutation in these consanguineous families. Login to comment 97 ABCA3 p.Leu101Pro ABCA3 p.Asn568Asp ABCA3 p.Leu1553Pro In the case of the L101P and L1553P mutations, each of which affected one pair of siblings from two different families, the two pairs of siblings were both homozygous for the variant and homozygous for all other polymorphisms that we found in the gene - findings that are consistent with the occurrence of a recessive mutation in these consanguineous families. Login to comment 98 ABCA3 p.Asn568Asp The N568D mutation is in a highly conserved residue in the ATP-binding domain, and it almost certainly disrupts the function of the protein. Login to comment 105 ABCA3 p.Asn568Asp ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Gln1591Pro ABCA3 p.Leu982Pro Nucleotide Affected* Site Affected or Outcome SNP No.ߤ Mutation Exon 5 3, 4 T301C L101Pߥ Exon 5 14 C316T R106Xߥ Exon 14 20 A1702G N568D Exon 14 13 1644delC Frameshiftߥ Exon 21 7, 8 T2945C L982P Exon 23 1, 2 G3426A W1142Xߥ Exon 24 7, 8 G3661A G1221S Exon 30 9, 10 T4657C L1553P Exon 30 5, 6 4552insT Frameshift Exon 31 15, 21 4909+1G>A Splice siteߥ Exon 31 5, 6 T4739C L1580P Exon 31 19 A4772C Q1591P Polymorphism Exon 5 Multiple Exon 5+50A/G Intron rs46725 Exon 6 20 393C/T A131A Exon 6 18 Exon 6+119G/A Intron rs323059 Exon 7 19 Exon 7-14C/G Intron Exon 8 14 681C/T A227A Exon 10 Multiple Exon 10-105C/A Intron rs323066 Exon 10 Multiple Exon 10-20C/T Intron Exon 10 Multiple 1058C/T F353F Exon 14 Multiple Exon 14+33G/A Intron rs170447 Exon 15 Multiple 1755C/G P585P rs323043 Exon 18 13 Exon 18-17G/A Intron Exon 18 1 2340C/T H780H Exon 21 Multiple Exon 21-20C/G Intron rs313908 Exon 21 Multiple Exon 21+34C/T Intron rs313909 Exon 27 Multiple 4116C/T S1372S rs149532 Exon 32 11 4944C/T V1648V In two patients, a mutation was identified on only one allele. Login to comment 106 ABCA3 p.Asn568Asp ABCA3 p.Asn568Asp ABCA3 p.Gly1221Ser ABCA3 p.Gly1221Ser ABCA3 p.Leu1553Pro ABCA3 p.Leu1553Pro ABCA3 p.Leu1580Pro ABCA3 p.Leu1580Pro ABCA3 p.Gln1591Pro ABCA3 p.Gln1591Pro ABCA3 p.Leu982Pro ABCA3 p.Leu982Pro Nucleotide Affected* Site Affected or Outcome SNP No.† Mutation Exon 5 3, 4 T301C L101P‡ Exon 5 14 C316T R106X‡ Exon 14 20 A1702G N568D Exon 14 13 1644delC Frameshift‡ Exon 21 7, 8 T2945C L982P Exon 23 1, 2 G3426A W1142X‡ Exon 24 7, 8 G3661A G1221S Exon 30 9, 10 T4657C L1553P Exon 30 5, 6 4552insT Frameshift Exon 31 15, 21 4909+1G>A Splice site‡ Exon 31 5, 6 T4739C L1580P Exon 31 19 A4772C Q1591P Polymorphism Exon 5 Multiple Exon 5+50A/G Intron rs46725 Exon 6 20 393C/T A131A Exon 6 18 Exon 6+119G/A Intron rs323059 Exon 7 19 Exon 7-14C/G Intron Exon 8 14 681C/T A227A Exon 10 Multiple Exon 10-105C/A Intron rs323066 Exon 10 Multiple Exon 10-20C/T Intron Exon 10 Multiple 1058C/T F353F Exon 14 Multiple Exon 14+33G/A Intron rs170447 Exon 15 Multiple 1755C/G P585P rs323043 Exon 18 13 Exon 18-17G/A Intron Exon 18 1 2340C/T H780H Exon 21 Multiple Exon 21-20C/G Intron rs313908 Exon 21 Multiple Exon 21+34C/T Intron rs313909 Exon 27 Multiple 4116C/T S1372S rs149532 Exon 32 11 4944C/T V1648V In two patients, a mutation was identified on only one allele. Login to comment 109 ABCA3 p.Gln1591Pro One patient, who had a missense mutation (Q1591P) on one allele and an unknown mutation on the other allele, is still alive at six years of age and has chronic lung disease, suggesting that some ABCA3 mutations are not fatal. Login to comment 110 ABCA3 p.Gln1591Pro One patient, who had a missense mutation (Q1591P) on one allele and an unknown mutation on the other allele, is still alive at six years of age and has chronic lung disease, suggesting that some ABCA3 mutations are not fatal. Login to comment