title: 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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: I
authors.initials: I
authors.lastname: Santisteban
authors.forename: F X
authors.initials: FX
authors.lastname: Arredondo-Vega
authors.forename: S
authors.initials: S
authors.lastname: Kelly
authors.forename: A
authors.initials: A
authors.lastname: Mary
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: D S
authors.initials: DS
authors.lastname: Hummell
authors.forename: A
authors.initials: A
authors.lastname: Lawton
authors.forename: R U
authors.initials: RU
authors.lastname: Sorensen
authors.forename: E R
authors.initials: ER
authors.lastname: Stiehm
authors.forename: L
authors.initials: L
authors.lastname: Uribe
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics*; D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D003839:Deoxyadenosines / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D013601:T-Lymphocytes / Q000201:enzymology
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D003839:Deoxyadenosines; D000243:Adenosine Deaminase