RGD Reference Report - 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.

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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.
Authors:	Santisteban, I Arredondo-Vega, FX Kelly, S Mary, A Fischer, A Hummell, DS Lawton, A Sorensen, RU Stiehm, ER Uribe, L
Citation:	Santisteban I, etal., J Clin Invest 1993 Nov;92(5):2291-302.
RGD ID:	1300353
Pubmed:	PMID:8227344 (View Abstract at PubMed)
PMCID:	PMC288410 (View Article at PubMed Central)
DOI:	DOI:10.1172/JCI116833 (Journal Full-text)
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.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
ADA	Human	severe combined immunodeficiency		IAGP			RGD
Ada	Rat	severe combined immunodeficiency		ISO	ADA (Homo sapiens)		RGD
Ada	Mouse	severe combined immunodeficiency		ISO	ADA (Homo sapiens)		RGD

Objects Annotated

Genes (Rattus norvegicus)

Ada (adenosine deaminase)

Genes (Mus musculus)

Ada (adenosine deaminase)

Genes (Homo sapiens)

ADA (adenosine deaminase)

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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.