ID00001

ID00001 LCL from B-Lymphocyte

Description:

BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK

Affected:

Yes

Sex:

Male

Age:

12 YR (At Sampling)

Overview

Repository

NIAID - USIDnet

Subcollection

Heritable Diseases

Class

X Chromosome Markers

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Relation to Proband

proband

Confirmation

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; oldest of three affected brothers; diagnosed at age 6 yrs; before initiation of intramuscular gamma globulin therapy, the donor's serum IgG concentration was 590mg/deciliter, his IgM concentration was 18mg/deciliter, and his IgA concentration was below 5mg/deciliter; donor had 0.3-2% B cells in peripheral circulation, whereas patients with typical X-linked agammaglobulinemia have a mean of 0.1% and normal subjects have 5-15%; patient described in Saffran et al, N Engl J Med 330(21):1488-91, 1994; the donor subject has a single point mutation found in the SH2 domain of the coding sequence: an A>G transition at nucleotide 1214 (1214A>G) in exon 12 of the BTK gene, resulting in a change of tyrosine to cysteine at codon 361 [Tyr361Cys (W361C)]

Characterizations

BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK

The mutation in the bruton agammaglobulinemia tyrosine kinase (BTK) gene was detected by sequencing. The protein was found to be decreased by Western blot analysis.

Gene

BTK

Chromosomal Location

Xq22.1

Allelic Variant 1

300300.0003; HYPOAGAMMAGLOBULINEMIA, X-LINKED

Identified Mutation

TYR361CYS; Like most other cytoplasmic tyrosine kinases, the Bruton tyrosine kinase contains a unique amino terminal region, SH3 and SH2 domains (short for SRC homology 3 and 2, respectively), and a carboxy-terminal kinase domain. In a patient with atypical X-linked agammaglobulinemia, Saffran et al. [New Eng. J. Med. 330: 1488-1491 (1994)] found a point mutation in the SH2 domain of BTK in a B-cell line. SH2 domains are critical mediators of binding with phosphotyrosine-containing proteins in the cell. The mutation was located in what crystal-structure studies of the SRC SH2 domain predict is a critical hydrophobic binding pocket. The consequence of this mutation is predicted to be decreased stability of the BTK protein, possibly resulting from the inability of BTK to interact with important substrates. The single point mutation found in the SH2 domain of the coding sequence changed amino acid residue 361 from tyrosine to cysteine as a result of an A-to-G transition at nucleotide 1214 in exon 12.

Phenotypic Data

Remarks

Publications

Saffran DC, Parolini O, Fitch-Hilgenberg ME, Rawlings DJ, Afar DE, Witte ON, Conley ME, Brief report: a point mutation in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked agammaglobulinemia. N Engl J Med330(21):1488-91 1994

PubMed ID: 8164701