GM05292

GM05292 Fibroblast

Description:

XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A; XPA
XPA, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPA

Affected:

Yes

Sex:

Female

Age:

8 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Nucleotide and Nucleic Acid Metabolism

Class

Repair Defective and Chromosomal Instability Syndromes

Cell Type

Fibroblast

Transformant

Untransformed

Race

Japanese

Ethnicity

JAPANESE

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Japanese; XP3KR; dry, pigmented skin; mental retardation; similarly affected identical twin; less than 5% of normal post UV light induced unscheduled DNA synthesis; donor subject is a compound heterozygote for two mutations in the XPA gene:: one allele carries the G-to-C transversion at the 3-prime splice acceptor site of intron 3 of the XPA gene, abolishing the canonical 3-prime splice site and creating two abnormally spliced mRNA forms; the second allele carries a C-to-T substitution at nucleotide 682 (682C>T) which alters the arg-228 codon (CGA) to a nonsense codon (TGA) in exon 6 of the XPA gene [ARG228TER (R228X)].

Characterizations

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase Isoenzyme Electrophoresis

Gene

XPA

Chromosomal Location

9q22.3-q31

Allelic Variant 1

278700.0001; XERODERMA PIGMENTOSUM, TYPE A

Identified Mutation

3-PRIME SPLICE SITE, INTRON 3; Tanaka et al. [Nature 348: 73-76 (1990)] found that most Japanese patients with type A xeroderma pigmentosum had a G-to-C transversion at the 3-prime splice acceptor site of intron 3 of the XPAC gene. Satokata et al. [Proc. Nat. Acad. Sci. 87: 9908-9912, (1990)] found that the single base substitution abolished the canonical 3-prime splice site and created 2 abnormally spliced mRNA forms. The larger form was identical with normal mRNA except for a dinucleotide deletion at the 5-prime end of exon 4. This deletion resulted in a frameshift with premature termination of translation in exon 4. The smaller form had a deletion of the entire exon 3 and the dinucleotide at the 5-prime end of exon 4. A single base substitution creates a new cleavage site for the restriction endonuclease AlwNI. Using the AlwNI RFLP, Satokata et al. [Proc. Nat. Acad. Sci. 87: 9908-9912 (1990)] found that 16 of 21 unrelated Japanese patients with XP were homozygous and 4 were heterozygous for this mutation. However, 11 Caucasians and 2 blacks with group A XP did not have this mutant allele. Kore-eda et al. [Arch. Derm. 128: 971-974 (1992)] demonstrated the usefulness of the polymerase chain reaction (PCR) followed by search for the AlwNI RFLP in the diagnosis of XPA. Cleaver et al. [Hum. Molec. Genet. 4: 1685-1687 (1995)] stated that homozygosity for a G-to-C transversion at the 3-prime acceptor site of intron III/exon IV represents 80 to 90% of Japanese patients with XPA.

Gene

XPA

Chromosomal Location

9q22.3-q31

Allelic Variant 2

278700.0004; XERODERMA PIGMENTOSUM, TYPE A

Identified Mutation

ARG228TER; Satokata et al. [Mutat. Res. 273: 193-202, (1992)] described a nucleotide transition altering the arg-228 codon (CGA) to a nonsense codon (TGA). The mutation created a new cleavage site for the restriction endonuclease HphI.

Phenotypic Data

Remarks

Publications

States JC, McDuffie ER, Myrand SP, McDowell M, Cleaver JE, Distribution of mutations in the human xeroderma pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein. Hum Mutat12:103-13 1998

PubMed ID: 9671271

Satokata I, Tanaka K, Miura N, Narita M, Mimaki T, Satoh Y, Kondo S, Okada Y, Three nonsense mutations responsible for group A xeroderma pigmentosum. Mutat Res273:193-202 1992

PubMed ID: 1372102

Satokata I, Tanaka K, Miura N, Miyamoto I, Satoh Y, Kondo S, Okada Y, Characterization of a splicing mutation in group A xeroderma pigmentosum. Proc Natl Acad Sci U S A87:9908-12 1990

PubMed ID: 1702221