GM16096

GM16096 Fibroblast from Skin, Unspecified

Description:

IMMUNODEFICIENCY 96; IMD96
LIGASE I, DNA, ATP-DEPENDENT; LIG1

Affected:

Yes

Sex:

Female

Age:

18 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

Hypogammaglobulinemia; syndrome of immunodeficiency, increased sensitivity to DNA-damaging agents, and delayed development attributed to loss of DNA ligase I function; died at the age of 19 years with lymphoma; SV40 (PSVneo) transformed cell line is GM16097; donor subject was a compound heterozygote, carrying two different missense mutations in the LIG1 gene: the paternal allele showed a substitution of lysine for glutamic acid-566 [GLU566LYS (E566K)] resulting from G-to-A transition and the maternal allele carried an arg771-to-trp mutation [ARG771TRP (R771W)], the result of a C-to-T transition.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

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

Gene

LIG1

Chromosomal Location

19q13.2-q13.3

Allelic Variant 1

126391.0001; DNA LIGASE I DEFICIENCY

Identified Mutation

GLU566LYS; Webster et al. [In: Bridges, B. A.; Harnden, D. G. : Ataxia-telangiectasia: A Cellular and Molecular Link between Cancer, Neuropathology, and Immune Deficiency. New York: John Wiley Pp. 379-386 (1982)] described a syndrome of immunodeficiency and increased cellular sensitivity to DNA-damaging agents. The patient had sun sensitivity and stunted growth and died at the age of 19 years with lymphoma [Webster et al. Lancet 339: 1508-1509 (1992)]. Developmental milestones had been delayed; the proband was less than 130 cm tall at age 14 years [Webster et al. Lancet 339: 1508-1509 (1992)].. The cell line derived from the patient, called 46BR, was shown by Barnes et al. [Cell 69: 495-503 (1992)] to contain 2 missense mutations in different alleles of the DNA ligase I gene, i.e., the patient was a compound heterozygote. One allele showed a substitution of lysine for glutamic acid-566 and was presumably derived from the deceased father because the other allele carried an arg771-to-trp mutation (126391.0002) which was present also in the mother of the proband. The cultured fibroblasts exhibited retarded joining of Okazaki fragments during DNA replication and hypersensitivity to a variety of DNA-damaging agents.

Gene

LIG1

Chromosomal Location

19q13.2-q13.3

Allelic Variant 2

126391.0002; DNA LIGASE I DEFICIENCY

Identified Mutation

ARG771TRP; Webster et al. [In: Bridges, B. A.; Harnden, D. G. : Ataxia-telangiectasia: A Cellular and Molecular Link between Cancer, Neuropathology, and Immune Deficiency. New York: John Wiley Pp. 379-386 (1982)] described a syndrome of immunodeficiency and increased cellular sensitivity to DNA-damaging agents. The patient had sun sensitivity and stunted growth and died at the age of 19 years with lymphoma [Webster et al. Lancet 339: 1508-1509 (1992)]. Developmental milestones had been delayed; the proband was less than 130 cm tall at age 14 years [Webster et al. Lancet 339: 1508-1509 (1992)].. The cell line derived from the patient, called 46BR, was shown by Barnes et al. [Cell 69: 495-503 (1992)] to contain 2 missense mutations in different alleles of the DNA ligase I gene, i.e., the patient was a compound heterozygote. One allele showed a substitution of lysine for glutamic acid-566 and was presumably derived from the deceased father because the other allele carried an arg771-to-trp mutation (126391.0002) which was present also in the mother of the proband. The cultured fibroblasts exhibited retarded joining of Okazaki fragments during DNA replication and hypersensitivity to a variety of DNA-damaging agents.

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

Barnes DE, Tomkinson AE, Lehmann AR, Webster AD, Lindahl T, Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents. Cell69(3):495-503 1992

PubMed ID: 1581963

Webster AD, Barnes DE, Arlett CF, Lehmann AR, Lindahl T, Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene. Lancet339(8808):1508-9 1992

PubMed ID: 1351188

Henderson LM, Arlett CF, Harcourt SA, Lehmann AR, Broughton BC, Cells from an immunodeficient patient (46BR) with a defect in DNA ligation are hypomutable but hypersensitive to the induction of sister chromatid exchanges. Proc Natl Acad Sci U S A82:2044-8 1985

PubMed ID: 3856882

Squires S, Johnson RT, U.v. induces long-lived DNA breaks in Cockayne's syndrome and cells from an immunodeficient individual (46BR): defects and disturbance in post incision steps of excision repair. Carcinogenesis4(5):565-72 1983

PubMed ID: 6850988

Teo IA, Arlett CF, Harcourt SA, Priestley A, Broughton BC, Multiple hypersensitivity to mutagens in a cell strain (46BR) derived from a patient with immuno-deficiencies. Mutat Res107:371-86 1983

PubMed ID: 6408472