Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1994 April; 93(4): 1860–1863.
PMCID: PMC294267

A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds.


To determine the molecular defect accounting for the deficiency of pulmonary surfactant protein B (SP-B) in full-term neonates who died from respiratory failure associated with alveolar proteinosis, the sequence of the SP-B transcript in affected infants was ascertained. A frameshift mutation consisting of a substitution of GAA for C in codon 121 of the SP-B cDNA was identified. The three affected infants in the index family were homozygous for this mutation, which segregated in a fashion consistent with autosomal recessive inheritance of disease. The same mutation was found in two other unrelated infants who died from alveolar proteinosis, one of whom was also homozygous, and in the parents of an additional unrelated, affected infant, but was not observed in 50 control subjects. We conclude that this mutation is responsible for SP-B deficiency and neonatal alveolar proteinosis in multiple families and speculate that the disorder is more common than was recognized previously.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (944K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Farrell PM, Avery ME. Hyaline membrane disease. Am Rev Respir Dis. 1975 May;111(5):657–688. [PubMed]
  • Nogee LM, de Mello DE, Dehner LP, Colten HR. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med. 1993 Feb 11;328(6):406–410. [PubMed]
  • Coleman M, Dehner LP, Sibley RK, Burke BA, L'Heureux PR, Thompson TR. Pulmonary alveolar proteinosis: an uncommon cause of chronic neonatal respiratory distress. Am Rev Respir Dis. 1980 Mar;121(3):583–586. [PubMed]
  • Knight DP, Knight JA. Pulmonary alveolar proteinosis in the newborn. Arch Pathol Lab Med. 1985 Jun;109(6):529–531. [PubMed]
  • Schumacher RE, Marrogi AJ, Heidelberger KP. Pulmonary alveolar proteinosis in a newborn. Pediatr Pulmonol. 1989;7(3):178–182. [PubMed]
  • Moulton SL, Krous HF, Merritt TA, Odell RM, Gangitano E, Cornish JD. Congenital pulmonary alveolar proteinosis: failure of treatment with extracorporeal life support. J Pediatr. 1992 Feb;120(2 Pt 1):297–302. [PubMed]
  • Pilot-Matias TJ, Kister SE, Fox JL, Kropp K, Glasser SW, Whitsett JA. Structure and organization of the gene encoding human pulmonary surfactant proteolipid SP-B. DNA. 1989 Mar;8(2):75–86. [PubMed]
  • Glasser SW, Korfhagen TR, Weaver T, Pilot-Matias T, Fox JL, Whitsett JA. cDNA and deduced amino acid sequence of human pulmonary surfactant-associated proteolipid SPL(Phe). Proc Natl Acad Sci U S A. 1987 Jun;84(12):4007–4011. [PubMed]
  • Jacobs KA, Phelps DS, Steinbrink R, Fisch J, Kriz R, Mitsock L, Dougherty JP, Taeusch HW, Floros J. Isolation of a cDNA clone encoding a high molecular weight precursor to a 6-kDa pulmonary surfactant-associated protein. J Biol Chem. 1987 Jul 15;262(20):9808–9811. [PubMed]
  • Revak SD, Merritt TA, Degryse E, Stefani L, Courtney M, Hallman M, Cochrane CG. Use of human surfactant low molecular weight apoproteins in the reconstitution of surfactant biologic activity. J Clin Invest. 1988 Mar;81(3):826–833. [PMC free article] [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PubMed]
  • Rogers BB, Alpert LC, Hine EA, Buffone GJ. Analysis of DNA in fresh and fixed tissue by the polymerase chain reaction. Am J Pathol. 1990 Mar;136(3):541–548. [PubMed]
  • Todd S, Naylor SL. Dinucleotide repeat polymorphism in the human surfactant-associated protein 3 gene (SFTP3). Nucleic Acids Res. 1991 Jul 11;19(13):3756–3756. [PMC free article] [PubMed]
  • Baserga SJ, Benz EJ., Jr Nonsense mutations in the human beta-globin gene affect mRNA metabolism. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2056–2060. [PubMed]
  • Satoh K, Nukiwa T, Brantly M, Garver RI, Jr, Hofker M, Courtney M, Crystal RG. Emphysema associated with complete absence of alpha 1- antitrypsin in serum and the homozygous inheritance [corrected] of a stop codon in an alpha 1-antitrypsin-coding exon. Am J Hum Genet. 1988 Jan;42(1):77–83. [PubMed]
  • Hamosh A, Trapnell BC, Zeitlin PL, Montrose-Rafizadeh C, Rosenstein BJ, Crystal RG, Cutting GR. Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis. J Clin Invest. 1991 Dec;88(6):1880–1885. [PMC free article] [PubMed]
  • Dietz HC, Valle D, Francomano CA, Kendzior RJ, Jr, Pyeritz RE, Cutting GR. The skipping of constitutive exons in vivo induced by nonsense mutations. Science. 1993 Jan 29;259(5095):680–683. [PubMed]
  • Kadowaki T, Kadowaki H, Rechler MM, Serrano-Rios M, Roth J, Gorden P, Taylor SI. Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest. 1990 Jul;86(1):254–264. [PMC free article] [PubMed]
  • Urlaub G, Mitchell PJ, Ciudad CJ, Chasin LA. Nonsense mutations in the dihydrofolate reductase gene affect RNA processing. Mol Cell Biol. 1989 Jul;9(7):2868–2880. [PMC free article] [PubMed]
  • Belgrader P, Cheng J, Maquat LE. Evidence to implicate translation by ribosomes in the mechanism by which nonsense codons reduce the nuclear level of human triosephosphate isomerase mRNA. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):482–486. [PubMed]
  • Cheng J, Maquat LE. Nonsense codons can reduce the abundance of nuclear mRNA without affecting the abundance of pre-mRNA or the half-life of cytoplasmic mRNA. Mol Cell Biol. 1993 Mar;13(3):1892–1902. [PMC free article] [PubMed]
  • Fisher CW, Fisher CR, Chuang JL, Lau KS, Chuang DT, Cox RP. Occurrence of a 2-bp (AT) deletion allele and a nonsense (G-to-T) mutant allele at the E2 (DBT) locus of six patients with maple syrup urine disease: multiple-exon skipping as a secondary effect of the mutations. Am J Hum Genet. 1993 Feb;52(2):414–424. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation