GM02434

GM02434 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:

7 MO (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

White

Family Member

Relation to Proband

proband

Confirmation

Biochemical characterization after cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; physical exam at birth was normal; subject was placed in protective isolation after birth and had good weight gain and no infections during the first 6 weeks; no thymic shadow seen on chest x-ray; perianal abscesses were intermittently present between one and ten months of age; normal development; normal kidneys but possible obstruction of left ureter; T cells were 44% and 46% at 3 and 9 days of age, respectively and B cells were 43% and 19%, respectively; leukopenia; immunoglobulin levels at 20 days of age were normal; deficient RBC & fibroblast ADA activity; residual ADA activity could be detected in mononuclear-cell/platelet preparations; less than 1.5% of ADA activity was seen in amniotic fluid cells; enzyme phenotypes: G6PD=B; 6PGD=A; peptidases A, C, & D=1; & PGM 1 & 3=1; donor subject is a compound heterozygote: one allele has a T>G transversion at nucleotide 911 in exon 10 of the ADA gene [911T>G] resulting in a substitution of arginine for leucine at codon 304 [Leu304Arg (L304R)] and a second allele has a C>T transition at nucleotide 466 of the ADA gene [466C>T] resulting in a substitution of cysteine for arginine at codon 156 [Arg156Cys (R156C)]; affected sister died at 9 months of age; mother is GM02433; same donor as GM02471 lymphocyte.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis

adenosine deaminase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.5.4.4; <1.5% activity.

Gene

ADA

Chromosomal Location

20q13.11

Allelic Variant 1

608958.0005; SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY

Identified Mutation

LEU304ARG; In a patient with SCID due to ADA deficiency (102700) originally reported by Hirschhorn et al. (1975), Valerio et al. (1986) identified compound heterozygosity for 2 mutations in the ADA gene: one was a T-to-G transversion in exon 10, resulting in a leu304-to-arg (L304R) substitution. Functional expression studies showed that the L304R substitution resulted in ADA enzyme inactivation.

Gene

ADA

Chromosomal Location

20q13.11

Allelic Variant 2

608958.0018; SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY

Identified Mutation

ARG156CYS; In 2 patients with SCID who were unusual for reportedly responding to the limited form of enzyme therapy provided by repeated partial exchange transfusions {Polmar et al. [N Engl J Med 295: 1337 (1976); Dyminski et al. [Clin Immunol Immunopathol 14: 307 (1979)]}, Hirschhorn [Hum Mutat 1: 166 (1992)] found two new missense mutations, arg156-to-cys and ser291-to-leu (102700.0019). The first of these was found in cell line GM02471 and represented a CGC-to-TGC transition at codon 156.

Phenotypic Data

Remarks

Publications

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

Polmar SH, Stern RC, Schwartz AL, Wetzler EM, Chase PA, Hirschhorn R, Enzyme replacement therapy for adenosine deaminase deficiency and severe combined immunodeficiency. N Engl J Med295:1337-43 1976

PubMed ID: 980079

Hirschhorn R, Beratis N, Rosen FS, Parkman R, Stern R, Polmar S, Adenosine-deaminase deficiency in a child diagnosed prenatally. Lancet1:73-75 1975

PubMed ID: 46025

Polmar SH, Wetzler EM, Stern RC, Hirschhorn R, Restoration of in-vitro lymphocyte responses with exogenous adenosine deaminase in a patient with severe combined immunodeficiency. Lancet2:743-6 1975

PubMed ID: 52774