PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
 
J Clin Invest. 1993 November; 92(5): 2291–2302.
PMCID: PMC288410

Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype.

Abstract

We examined the genetic basis for adenosine deaminase (ADA) deficiency in seven patients with late/delayed onset of immunodeficiency, an underdiagnosed and relatively unstudied condition. Deoxyadenosine-mediated metabolic abnormalities were less severe than in the usual, early-onset disorder. Six patients were compound heterozygotes; 7 of 10 mutations found were novel, including one deletion (delta 1019-1020), three missense (Arg156 > His, Arg101 > Leu, Val177 > Met), and three splicing defects (IVS 5, 5'ss T+6 > A; IVS 10, 5'ss G+1 > A; IVS 10, 3'ss G-34 > A). Four of the mutations generated stop signals at codons 131, 321, 334, and 348; transcripts of all but the last, due to delta 1019-1020, were severely reduced. delta 1019-1020 (like delta 955-959, found in one patient and apparently recurrent) is at a short deletional hot spot. Arg156 > His, the product of which had detectable activity, was found in three patients whose second alleles were unlikely to yield active ADA. The oldest patient diagnosed was homozygous for a single base change in intron 10, which activates a cryptic splice acceptor, resulting in a protein with 100 extra amino acids. We speculate that this "macro ADA," as well as the Arg156 > His, Arg101 > Leu, Ser291 > Leu, and delta 1019-1020 products, may contribute to mild phenotype. Tissue-specific variation in splicing efficiency may also ameliorate disease severity in patients with splicing mutations.

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 (3.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hirschhorn R, Vawter GF, Kirkpatrick JA, Jr, Rosen FS. Adenosine deaminase deficiency: frequency and comparative pathology in autosomally recessive severe combined immunodeficiency. Clin Immunol Immunopathol. 1979 Sep;14(1):107–120. [PubMed]
  • Hirschhorn R. Adenosine deaminase deficiency. Immunodefic Rev. 1990;2(3):175–198. [PubMed]
  • Coleman MS, Donofrio J, Hutton JJ, Hahn L, Daoud A, Lampkin B, Dyminski J. Identification and quantitation of adenine deoxynucleotides in erythrocytes of a patient with adenosine deaminase deficiency and severe combined immunodeficiency. J Biol Chem. 1978 Mar 10;253(5):1619–1626. [PubMed]
  • Cohen A, Hirschhorn R, Horowitz SD, Rubinstein A, Polmar SH, Hong R, Martin DW., Jr Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. Proc Natl Acad Sci U S A. 1978 Jan;75(1):472–476. [PubMed]
  • Hershfield MS. Apparent suicide inactivation of human lymphoblast S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine and adenine arabinoside. A basis for direct toxic effects of analogs of adenosine. J Biol Chem. 1979 Jan 10;254(1):22–25. [PubMed]
  • Hershfield MS, Kredich NM, Ownby DR, Ownby H, Buckley R. In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients. J Clin Invest. 1979 Apr;63(4):807–811. [PMC free article] [PubMed]
  • Hirschhorn R. Overview of biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res. 1993 Jan;33(1 Suppl):S35–S41. [PubMed]
  • Geffner ME, Stiehm ER, Stephure D, Cowan MJ. Probable autoimmune thyroid disease and combined immunodeficiency disease. Am J Dis Child. 1986 Nov;140(11):1194–1196. [PubMed]
  • Levy Y, Hershfield MS, Fernandez-Mejia C, Polmar SH, Scudiery D, Berger M, Sorensen RU. Adenosine deaminase deficiency with late onset of recurrent infections: response to treatment with polyethylene glycol-modified adenosine deaminase. J Pediatr. 1988 Aug;113(2):312–317. [PubMed]
  • Hershfield MS, Buckley RH, Greenberg ML, Melton AL, Schiff R, Hatem C, Kurtzberg J, Markert ML, Kobayashi RH, Kobayashi AL, et al. Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N Engl J Med. 1987 Mar 5;316(10):589–596. [PubMed]
  • Hershfield MS, Chaffee S, Sorensen RU. Enzyme replacement therapy with polyethylene glycol-adenosine deaminase in adenosine deaminase deficiency: overview and case reports of three patients, including two now receiving gene therapy. Pediatr Res. 1993 Jan;33(1 Suppl):S42–S48. [PubMed]
  • Arredondo-Vega FX, Kurtzberg J, Chaffee S, Santisteban I, Reisner E, Povey MS, Hershfield MS. Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combine immunodeficiency. J Clin Invest. 1990 Aug;86(2):444–452. [PMC free article] [PubMed]
  • Badley JE, Bishop GA, St John T, Frelinger JA. A simple, rapid method for the purification of poly A+ RNA. Biotechniques. 1988 Feb;6(2):114–116. [PubMed]
  • Wiginton DA, Adrian GS, Hutton JJ. Sequence of human adenosine deaminase cDNA including the coding region and a small intron. Nucleic Acids Res. 1984 Mar 12;12(5):2439–2446. [PMC free article] [PubMed]
  • Wiginton DA, Kaplan DJ, States JC, Akeson AL, Perme CM, Bilyk IJ, Vaughn AJ, Lattier DL, Hutton JJ. Complete sequence and structure of the gene for human adenosine deaminase. Biochemistry. 1986 Dec 16;25(25):8234–8244. [PubMed]
  • Ammann AJ, Cowan MJ, Martin DW, Wara DW. Dipyridamole and intravenous deoxycytidine therapy in a patient with adenosine deaminase deficiency. Birth Defects Orig Artic Ser. 1983;19(3):117–120. [PubMed]
  • Cowan MJ, Wara DW, Ammann AJ. Deoxycytidine therapy in two patients with adenosine deaminase deficiency and severe immunodeficiency disease. Clin Immunol Immunopathol. 1985 Oct;37(1):30–36. [PubMed]
  • Girault D, Le Deist F, Debré M, Pérignon JL, Herbelin C, Griscelli C, Sciudery D, Hershfield M, Fischer A. Traitement du déficit en adénosine désaminase par l'adénosine désaminase couplée au polyéthylène glycol. Arch Fr Pediatr. 1992 Apr;49(4):339–343. [PubMed]
  • Ochs HD, Buckley RH, Kobayashi RH, Kobayashi AL, Sorensen RU, Douglas SD, Hamilton BL, Hershfield MS. Antibody responses to bacteriophage phi X174 in patients with adenosine deaminase deficiency. Blood. 1992 Sep 1;80(5):1163–1171. [PubMed]
  • Padgett RA, Grabowski PJ, Konarska MM, Seiler S, Sharp PA. Splicing of messenger RNA precursors. Annu Rev Biochem. 1986;55:1119–1150. [PubMed]
  • Shapiro MB, Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987 Sep 11;15(17):7155–7174. [PMC free article] [PubMed]
  • Losson R, Lacroute F. Interference of nonsense mutations with eukaryotic messenger RNA stability. Proc Natl Acad Sci U S A. 1979 Oct;76(10):5134–5137. [PubMed]
  • Baumann B, Potash MJ, Köhler G. Consequences of frameshift mutations at the immunoglobulin heavy chain locus of the mouse. EMBO J. 1985 Feb;4(2):351–359. [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]
  • Mashima Y, Murakami A, Weleber RG, Kennaway NG, Clarke L, Shiono T, Inana G. Nonsense-codon mutations of the ornithine aminotransferase gene with decreased levels of mutant mRNA in gyrate atrophy. Am J Hum Genet. 1992 Jul;51(1):81–91. [PubMed]
  • Hirschhorn R. Identification of two new missense mutations (R156C and S291L) in two ADA- SCID patients unusual for response to therapy with partial exchange transfusions. Hum Mutat. 1992;1(2):166–168. [PubMed]
  • Hirschhorn R, Chakravarti V, Puck J, Douglas SD. Homozygosity for a newly identified missense mutation in a patient with very severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). Am J Hum Genet. 1991 Oct;49(4):878–885. [PubMed]
  • Treisman R, Proudfoot NJ, Shander M, Maniatis T. A single-base change at a splice site in a beta 0-thalassemic gene causes abnormal RNA splicing. Cell. 1982 Jul;29(3):903–911. [PubMed]
  • Wieringa B, Meyer F, Reiser J, Weissmann C. Unusual splice sites revealed by mutagenic inactivation of an authentic splice site of the rabbit beta-globin gene. Nature. 1983 Jan 6;301(5895):38–43. [PubMed]
  • Kuivaniemi H, Kontusaari S, Tromp G, Zhao MJ, Sabol C, Prockop DJ. Identical G+1 to A mutations in three different introns of the type III procollagen gene (COL3A1) produce different patterns of RNA splicing in three variants of Ehlers-Danlos syndrome. IV. An explanation for exon skipping some mutations and not others. J Biol Chem. 1990 Jul 15;265(20):12067–12074. [PubMed]
  • Coulondre C, Miller JH, Farabaugh PJ, Gilbert W. Molecular basis of base substitution hotspots in Escherichia coli. Nature. 1978 Aug 24;274(5673):775–780. [PubMed]
  • Cooper DN, Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet. 1988 Feb;78(2):151–155. [PubMed]
  • Bonthron DT, Markham AF, Ginsburg D, Orkin SH. Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency. J Clin Invest. 1985 Aug;76(2):894–897. [PMC free article] [PubMed]
  • Uberti J, Lightbody JJ, Wolf JW, Anderson JA, Reid RH, Johnson RM. The effect of adenosine on mitogenesis of ADA-deficient lymphocytes. Clin Immunol Immunopathol. 1978 Aug;10(4):446–458. [PubMed]
  • Uberti J, Peterson WD, Jr, Lightbody JJ, Johnson RM. A phenotypically normal revertant of an adenosine deaminase-deficient lymphoblast cell line. J Immunol. 1983 Jun;130(6):2866–2870. [PubMed]
  • Akeson AL, Wiginton DA, Dusing MR, States JC, Hutton JJ. Mutant human adenosine deaminase alleles and their expression by transfection into fibroblasts. J Biol Chem. 1988 Nov 5;263(31):16291–16296. [PubMed]
  • Daar IO, Maquat LE. Premature translation termination mediates triosephosphate isomerase mRNA degradation. Mol Cell Biol. 1988 Feb;8(2):802–813. [PMC free article] [PubMed]
  • Chang ZY, Nygaard P, Chinault AC, Kellems RE. Deduced amino acid sequence of Escherichia coli adenosine deaminase reveals evolutionarily conserved amino acid residues: implications for catalytic function. Biochemistry. 1991 Feb 26;30(8):2273–2280. [PubMed]
  • Wilson DK, Rudolph FB, Quiocho FA. Atomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations. Science. 1991 May 31;252(5010):1278–1284. [PubMed]
  • Krawczak M, Cooper DN. Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum Genet. 1991 Mar;86(5):425–441. [PubMed]
  • Green MR. Biochemical mechanisms of constitutive and regulated pre-mRNA splicing. Annu Rev Cell Biol. 1991;7:559–599. [PubMed]
  • Goguel V, Rosbash M. Splice site choice and splicing efficiency are positively influenced by pre-mRNA intramolecular base pairing in yeast. Cell. 1993 Mar 26;72(6):893–901. [PubMed]
  • McInnes B, Potier M, Wakamatsu N, Melancon SB, Klavins MH, Tsuji S, Mahuran DJ. An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds. J Clin Invest. 1992 Aug;90(2):306–314. [PMC free article] [PubMed]
  • Berkvens TM, Schoute F, van Ormondt H, Meera Khan P, van der Eb AJ. Adenosine deaminase gene expression is regulated posttranscriptionally in the nucleus. Nucleic Acids Res. 1988 Apr 25;16(8):3255–3268. [PMC free article] [PubMed]
  • Carstens RP, Fenton WA, Rosenberg LR. Identification of RNA splicing errors resulting in human ornithine transcarbamylase deficiency. Am J Hum Genet. 1991 Jun;48(6):1105–1114. [PubMed]
  • Marvit J, DiLella AG, Brayton K, Ledley FD, Robson KJ, Woo SL. GT to AT transition at a splice donor site causes skipping of the preceding exon in phenylketonuria. Nucleic Acids Res. 1987 Jul 24;15(14):5613–5628. [PMC free article] [PubMed]
  • Weil D, Bernard M, Combates N, Wirtz MK, Hollister DW, Steinmann B, Ramirez F. Identification of a mutation that causes exon skipping during collagen pre-mRNA splicing in an Ehlers-Danlos syndrome variant. J Biol Chem. 1988 Jun 25;263(18):8561–8564. [PubMed]
  • Kishimoto TK, O'Conner K, Springer TA. Leukocyte adhesion deficiency. Aberrant splicing of a conserved integrin sequence causes a moderate deficiency phenotype. J Biol Chem. 1989 Feb 25;264(6):3588–3595. [PubMed]
  • Hidaka Y, Palella TD, O'Toole TE, Tarlé SA, Kelley WN. Human adenine phosphoribosyltransferase. Identification of allelic mutations at the nucleotide level as a cause of complete deficiency of the enzyme. J Clin Invest. 1987 Nov;80(5):1409–1415. [PMC free article] [PubMed]
  • Andrews LG, Markert ML. Exon skipping in purine nucleoside phosphorylase mRNA processing leading to severe immunodeficiency. J Biol Chem. 1992 Apr 15;267(11):7834–7838. [PubMed]
  • Grandchamp B, Picat C, de Rooij F, Beaumont C, Wilson P, Deybach JC, Nordmann Y. A point mutation G----A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria. Nucleic Acids Res. 1989 Aug 25;17(16):6637–6649. [PMC free article] [PubMed]
  • Robberson BL, Cote GJ, Berget SM. Exon definition may facilitate splice site selection in RNAs with multiple exons. Mol Cell Biol. 1990 Jan;10(1):84–94. [PMC free article] [PubMed]
  • Treisman R, Orkin SH, Maniatis T. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591–596. [PubMed]
  • Krainer AR, Maniatis T, Ruskin B, Green MR. Normal and mutant human beta-globin pre-mRNAs are faithfully and efficiently spliced in vitro. Cell. 1984 Apr;36(4):993–1005. [PubMed]
  • Hirschhorn R, Ellenbogen A, Tzall S. Five missense mutations at the adenosine deaminase locus (ADA) detected by altered restriction fragments and their frequency in ADA--patients with severe combined immunodeficiency (ADA-SCID). Am J Med Genet. 1992 Jan 15;42(2):201–207. [PubMed]

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