GM04258

GM04258 LCL from B-Lymphocyte

Description:

SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY
ADENOSINE DEAMINASE; ADA

Affected:

Yes

Sex:

Male

Age:

4 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Nucleotide and Nucleic Acid Metabolism

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

Black/African American

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; admitted to hospital at age 4 months with pneumonia, a history of recurrent infections, and failure to thrive; severe combined immunodeficiency was diagnosed based on lymphopenia, decreased immunoglobins, and minimal response of peripheral lymphocytes to mitogens and allogenic cells; at age 4 months, prior to blood transfusions, only trace amounts of adenosine deaminase activity were present in erythrocytes and activity was greatly decreased in lymphocytes and granulocytes; concentrations of dATP and dADP were over 100-fold higher than normal in lymphocytes and erythrocytes; excretion of deoxyadenosine was increased in the urine; no thymic shadow seen on chest x-ray; incompetent humoral and cellular immunity; both parents have heterozygous ADA levels; at age 2.5 years subject was free of infection, at the 10th percentile for height and weight, and had normal psychomotor development; produces normal ADA mRNA; donor subject is a compound heterozygote: one allele has a C>T transition at nucleotide 1081 in exon 11 of the ADA gene [1081C>T] resulting in a substitution of valine for alanine at codon 329 [Ala329Val(A329V)] and a second allele has a C>T transition at nucleotide 872 in exon 10 of the ADA gene [872C>T] resulting in a substitution of leucine for serine at codon 291 [Ser291Leu (S291L)].

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase Isoenzyme Electrophoresis

messenger RNA

Adrian et al (Mol Cell Biol 4:1712-1717 1984) performed S1 endonuclease cleavage of ADA cDNA-mRNA hybrids to show that the ADA mRNA from this culture yielded fragments that were indistinguishable from ADA mRNA fragments from normal controls. The ADA cDNA utilized for these experiments represented the complete mRNA sequence with the possible exception of some of the 5 prime untranslated region.

GENE MAPPING & DOSAGE STUDIES - Y CHROMOSOME

PCR analysis of DNA from this cell culture gave a positive result with a primer for Yq11, DYS227.

adenosine deaminase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.5.4.4

Gene

ADA

Chromosomal Location

20q13.11

Allelic Variant 1

608958.0006; SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY

Identified Mutation

ALA329VAL; In GM02756, Akeson et al. [Proc Natl Acad Sci U S A 84: 5947 (1987)] demonstrated 2 different mutant alleles: one was ala329 to val; the other was a 632G-A transition in the ADA gene, resulting in the replacement of the arginine residue by histidine at codon 211 (102700.0004). In addition, Akeson et al. [Proc Natl Acad Sci U S A 84: 5947 (1987)] and [J Biol Chem 263:16291 (1988)] found that cell line GM02825A was a genetic compound. One allele had an ala329-to-val change (102700.0006); the other allele had a point mutation from A to G in the 3-prime splice site of intron 3 (102700.0017), resulting in elimination of exon 4 from the mature mRNA.

Gene

ADA

Chromosomal Location

20q13.11

Allelic Variant 2

608958.0019; SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY

Identified Mutation

SER291LEU; Hirschhorn [Hum Mutat 1: 166 (1992)] found the missense mutation, S291L, in cell line GM04258.

Phenotypic Data

Remarks

Publications

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 Mutat1:166-8 1992

PubMed ID: 1284479

Hirschhorn R, Ellenbogen A, Tzall SHirschhorn, 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 Hum Genet42:201-7 1992

PubMed ID: 1346349

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 Genet49:878-85 1991

PubMed ID: 1680289

Tzall S, Ellenbogen A, Eng F, Hirschhorn R, Identification and characterization of nine RFLPs at the adenosine deaminase (ADA) locus. Am J Hum Genet44:864-75 1989

PubMed ID: 2567118

Berkvens TM, Gerritsen EJ, Oldenburg M, Breukel C, Wijnen JT, van Ormondt H, Vossen JM, van der Eb AJ, Meera Khan P, Severe combined immune deficiency due to a homozygous 3.2-kb deletion spanning the promoter and first exon of the adenosine deaminase gene. Nucleic Acids Res15:9365-78 1987

PubMed ID: 3684597

Kantoff PW, Kohn DB, Mitsuya H, Armentano D, Sieberg M, Zwiebel JA, Eglitis MA, McLachlin JR, Wiginton DA, Hutton JJ, et al, Correction of adenosine deaminase deficiency in cultured human T and B cells by retrovirus-mediated gene transfer. Proc Natl Acad Sci U S A83:6563-7 1986

PubMed ID: 3489233

Valerio D, Dekker BM, Duyvesteyn MG, van der Voorn L, Berkvens TM, van Ormondt H, van der Eb AJ, One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity. EMBO J5:113-9 1986

PubMed ID: 3007108

Adrian GS, Wiginton DA, Hutton JJ, Characterization of normal and mutant adenosine deaminase messenger RNAs by translation and hybridization to a cDNA probe. Hum Genet68:169-72 1984

PubMed ID: 6548726

Adrian GS, Wiginton DA, Hutton JJ, Structure of adenosine deaminase mRNAs from normal and adenosine deaminase-deficient human cell lines. Mol Cell Biol4:1712-7 1984

PubMed ID: 6208479

Daddona PE, Shewach DS, Kelley WN, Argos P, Markham AF, Orkin SH, Human adenosine deaminase. cDNA and complete primary amino acid sequence. J Biol Chem259:12101-6 1984

PubMed ID: 6090454

Valerio D, Duyvesteyn MG, van Ormondt H, Meera Khan P, van der Eb AJ, Adenosine deaminase (ADA) deficiency in cells derived from humans with severe combined immunodeficiency is due to an aberration of the ADA protein. Nucleic Acids Res12:1015-24 1984

PubMed ID: 6198631

Hutton JJ, Wiginton DA, Coleman MS, Fuller SA, Limouze S, Lampkin BC, Biochemical and functional abnormalities in lymphocytes from an adenosine deaminase-deficient patient during enzyme replacement therapy. J Clin Invest68:413-21 1981

PubMed ID: 7263861

Dyminski JW, Daoud A, Lampkin BC, Limouze S, Donofrio J, Coleman MS, Hutton JJ, Immunological and biochemical profiles in response to transfusion therapy in an adenosine deaminase-deficient patient with severe combined immunodeficiency disease. Clin Immunol Immunopathol14:307-26 1979

PubMed ID: 498598

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 Chem253:1619-26 1978

PubMed ID: 627559

Donofrio J, Coleman MS, Hutton JJ, Daoud A, Lampkin B, Dyminski J, Overproduction of adenine deoxynucleosides and deoxynucletides in adenosine deaminase deficiency with severe combined immunodeficiency disease. J Clin Invest62:884-7 1978

PubMed ID: 308954