GM16088

GM16088 Fibroblast from Skin, Unspecified

Description:

LIG4 SYNDROME
LIGASE IV, DNA, ATP-DEPENDENT; LIG4

Affected:

Yes

Sex:

Male

Age:

15 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Nucleotide and Nucleic Acid Metabolism

Biopsy Source

Unspecified

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Sample Source

Fibroblast from Skin, Unspecified

Race

White

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Subject with pronounced radiosensitivity but normal viability and without major immune dysfunction; subject died of leukemia; cell lines from normal tissue show pronounced radiosensitivity attributable to defect in DNA ligase IV and are unable to repair DNA double strand breaks; SV40 (pSVneo) transformed cell line is GM16089; donor subject carries an arg278 to his in the LIG4 gene [ARG278HIS (R278H)], resulting from a G-to-A transition at nucleotide 833 (833G>A).

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

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

Gene

LIG4

Chromosomal Location

13q22-q34

Allelic Variant 1

601837.0004; LIG4 SYNDROME

Identified Mutation

ARG278HIS; O'Driscoll et al. [Molec. Cell 8: 1175-1185 (2001)] identified 3 amino acid substitutions in homozygosity in the LIG4 gene of patient 411BR with LIG4 syndrome (606593): ala3 to val, resulting from a C-to-T transition at nucleotide 8, thr9 to ile, resulting from a C-to-T transition at nucleotide 26, and arg278 to his, resulting from a G-to-A transition at nucleotide 833. The arg278-to-his mutation was identical to that identified in patient 180BR, who had leukemia and whose cell line was radiosensitive and defective in double-strand break repair, by Riballo et al. [Curr. Biol. 9: 699-702 (1999)]. The arg278 residue lies within a highly conserved motif encompassing the active site, and the substitution was shown to significantly impair LIG4 function [Riballo et al. J. Biol. Chem. 276: 31124-31132 (2001)].

Phenotypic Data

Remarks

Publications

Liddiard K, Grimstead JW, Cleal K, Evans A, Baird DM, Tracking telomere fusions through crisis reveals conflict between DNA transcription and the DNA damage response NAR cancer3:zcaa044 2020

PubMed ID: 33447828

Wilson PF, Nham PB, Urbin SS, Hinz JM, Jones IM, Thompson LH, Inter-individual variation in DNA double-strand break repair in human fibroblasts before and after exposure to low doses of ionizing radiation Mutation research683:91-7 2009

PubMed ID: 19896956

Al Rashid ST, Dellaire G, Cuddihy A, Jalali F, Vaid M, Coackley C, Folkard M, Xu Y, Chen BP, Chen DJ, Lilge L, Prise KM, Bazett Jones DP, Bristow RG, Evidence for the direct binding of phosphorylated p53 to sites of DNA breaks in vivo Cancer research65:10810-21 2005

PubMed ID: 16322227

Riballo E, Critchlow SE, Teo SH, Doherty AJ, Priestley A, Broughton B, Kysela B, Beamish H, Plowman N, Arlett CF, Lehmann AR, Jackson SP, Jeggo PA, Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr Biol9(13):699-702 1999

PubMed ID: 10395545

Nelms BE, Maser RS, MacKay JF, Lagally MG, Petrini JH, In situ visualization of DNA double-strand break repair in human fibroblasts. Science280(5363):590-2 1998

PubMed ID: 9554850

Badie C, Iliakis G, Foray N, Alsbeih G, Pantellias GE, Okayasu R, Cheong N, Russell NS, Begg AC, Arlett CF, et al, Defective repair of DNA double-strand breaks and chromosome damage in fibroblasts from a radiosensitive leukemia patient. Cancer Res55(6):1232-4 1995

PubMed ID: 7882314

Plowman PN, Bridges BA, Arlett CF, Hinney A, Kingston JE, An instance of clinical radiation morbidity and cellular radiosensitivity, not associated with ataxia-telangiectasia. Br J Radiol63(752):624-8 1990

PubMed ID: 2400879

Jaspers NG, Gatti RA, Baan C, Linssen PC, Bootsma D, Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet Cell Genet49:259-63 1988

PubMed ID: 3248383