GM02445

GM02445 Fibroblast

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:

3 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Nucleotide and Nucleic Acid Metabolism

Cell Type

Fibroblast

Transformant

Untransformed

Race

Black/African American

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

ISCN

46,XY

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; failure to thrive; multiple pneumonias and oral/skin moniliasis; long-term hospitalization starting at age 26 months: immunologic studies showed variable but persistent lymphopenia, low numbers of T lymphocytes, relatively increased percentage of B lymphocytes, bone marrow aspirate with few lymphocytes or plasma cells, lymph node biopsy revealed a "hypoplastic node with follicles but largely absent T-dependent areas and sinus histiocytosis", quantitative immunoglobins remained normal; height and weight increased to 25th-50th percentile by age 6 years but subject remained lymphopenic; between ages 11-14 years the absolute lymphocyte count was normal with a normal percentage of T cells; no medical problems at age 20 years (no theapy from age 13-20 years); HLA type A2,30,B7,39; enzyme phenotypes: 6PGD=A, G6PD=A, Peptidases A,C,&D=1, Acid A-glucosidase=1, Neutral A-glucosidase C=3, & GLO-1=2; 46,XY; ADA activity shortly after diagnosis was 1% of normal in erythrocytes and 18% of normal in mixed mononuclear cells; ADA in both cultured lymphoid and fibroblast cell lines established at diagnosis showed deficiency of ADA with <1% of normal ADA activity; a lymphoid cell line established at age 16 years exhibited >50% of normal ADA activity; studies performed on the lymphoid and fibroblast cell lines established at the time of diagnosis found the donor subject to be a compound heterozygote: one allele has a G>A transition at nucleotide 302 in exon 4 of the ADA gene [302G>A] resulting in a substitution of glutamine for arginine at codon 101 [Arg101Gln(R101Q)] and a second allele has a splice-donor-site mutation in IVS1(+1GT>CT) resulting in an unstable mRNA; the B cell line expressing ADA activity (established at age 16 years) contained the missense Arg101Gln mutation but lacked the splice-site mutation; donor subject determined to have somatic mosaicism; same donor as GM01715 lymphocyte.

Characterizations

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Chromosome Analysis

adenosine deaminase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.5.4.4; 1% activity.

adenosine deaminase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.5.4.4; 18% activity.

Gene

ADA

Chromosomal Location

20q13.11

Allelic Variant 1

608958.0003; SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY

Identified Mutation

ARG101GLN; In cell line GM01715 from an immunodeficient patient, Bonthron et al. [J Clin Invest 76: 894(1985)] found a point mutation in codon 101 (CGG to CAG) of ADA; this change predicts an amino acid change from arginine to glutamine. The mutation was apparently responsible for loss of function in the gene because the predicted primary structure of the enzyme was otherwise entirely normal. The demonstration of 2 different mutations in codon 101 leading to ADA deficiency indicates that this amino acid position is critical for stability and/or activity of the enzyme protein.

Gene

ADA

Chromosomal Location

20q13.11

Allelic Variant 2

608958.0024; SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY

Identified Mutation

IVS1DS, G>C, +1; Hirschhorn et al. [Ann Hum Genet 58: 1 (1994)] found that fibroblast and B-cell lines established at the time of diagnosis of ADA deficiency (GM02445 and GM01715) were heteroallelic for a newly identified splice site mutation (+1 GT-to-CT transversion) at the donor splice site in IVS1 and for a previously described arg101-to-gln missense mutation in exon 4 (102700.0003). As described earlier, by the time the patient was 16 years of age, the mutation had disappeared from the B cells but not from the fibroblasts and the patient had undergone spontaneous recovery from ADA deficiency.

Phenotypic Data

Remarks

Publications

Hirschhorn R, Yang DR, Israni A, Huie ML, Ownby DR, Somatic mosaicism for a newly identified splice-site mutation in a patient with adenosine deaminase-deficient immunodeficiency and spontaneous clinical recovery. Am J Hum Genet55(1):59-68 1994

PubMed ID: 8023852

Bonthron DT, Markham AF, Ginsburg D, Orkin SH, Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency. J Clin Invest76:894-7 1985

PubMed ID: 3839802

Daddona PE, Mitchell BS, Meuwissen HJ, Davidson BL, Wilson JM, Koller CA, Adenosine deaminase deficiency with normal immune function. An acidic enzyme mutation. J Clin Invest72:483-92 1983

PubMed ID: 6603477

Uberti J, Peterson WD Jr, Lightbody JJ, Johnson RM, A phenotypically normal revertant of an adenosine deaminase-deficient lymphoblast cell line. J Immunol130:2866-70 1983

PubMed ID: 6854019

Daddona PE, Kelley WN, Characteristics of an aminohydrolase distinct from adenosine deaminase in cultured human lymphoblasts. Biochim Biophys Acta658:280-90 1981

PubMed ID: 6972784

Daddona PE, Frohman MA, Kelley WN, Human adenosine deaminase and its binding protein in normal and adenosine deaminase-deficient fibroblast cell strains. J Biol Chem255:5681-7 1980

PubMed ID: 7380831