GM04408

GM04408 LCL from B-Lymphocyte

Description:

BLOOM SYNDROME; BLM
RECQ PROTEIN-LIKE 3; RECQL3

Affected:

Yes

Sex:

Male

Age:

4 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Hereditary Cancers
Chromosome Abnormalities
GeT-RM Samples

Class

Repair Defective and Chromosomal Instability Syndromes

Class

Syndromes with Increased Chromosome Breakage

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Ethnicity

JEWISH/ENGLISH

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; B.S. Registry #87; stunted growth; minimal freckling over malar area; normal intelligence; normal sister chromatid exchange in lymphoblast culture; as resistant to killing by ethyl methanesulphonate as control sample; high level of DNA ligase I activity, similar to that of controls; donor subject is a compound heterozygote: one allele has a 6-bp deletion/7-bp insertion [2281_2286delins7] at nucleotide 2,281 of the open reading frame of the RECQL3 gene that results in a frameshift and a stop codon and a second allele has 1-bp deletion at nucleotide 3233 [3233delT] of the RECQL3 gene resulting in a frameshift and premature termination; same donor as GM03498 fibroblast.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

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

CELL CULTURE IDENTIFICATION

GM04408 and GM03498 are lymphoblast and fibroblast cultures derived from the same patient. Willis et al (Carcinogenesis 10:217-219,1989) showed that both cultures were identical for four different isoenzyme markers (PGM1:1; PEGM3:6a; ESD:1; and PGP:1). In addition, these authors showed that HinfI digested DNA from each of the cell types hybridized with two locus specific hypervariable probes (lambda pg3 and PUM) to give distinct patterns of hybridizing DNA fragments which were identical and unique in comparison with several controls. These data identify these cell cultures as having been derived from the same individual.

DNA LIGASE I AND II

Normal levels of DNA ligase I & II activities in lymphoblasts (Willis and Lindahl NATURE 325:355-357,1987). Cell extracts of this culture were assayed for DNA ligase I activity after chromatographic separation of ligases I and II. Willis et al (Carcinogenesis 10:217-219,1989) reported a high level of DNA ligase I activity for this culture which was similar to that observed for controls and clearly different from that observed for Bloom's syndrome cultures. The heat lability of this culture's DNA ligase I was also reported to be the same as observed for the enzyme from normal cells.

SISTER CHROMATID EXCHANGE ANALYSIS

Willis et al (Carcinogenesis 10:217-219,1989) reported that this lymphoblast culture exhibited a low level of spontaneous SCE which was characteristic of normal cell cultures and not Bloom's syndrome cultures.

REPAIR OF UV- OR X RAY-IRRADIATED DNA OR ALKYLATED DNA

Willis et al (Carcinogenesis 10:217-219,1989) reported that this cell culture showed a normal response to the cytotoxic effects of ethyl methane sulphonate. This EMS resistance was similar to that observed for a normal cell culture and unlike the hypersensitive response expected for Bloom's syndrome cultures.

MUTATION VERIFICATION

The 2281del6/ins7 gene mutation in this sample has been verified by 6 laboratories. The 1bp del 3233 deletion has not been verified by multiple labs.

Gene

RECQL3

Chromosomal Location

15q26.1

Allelic Variant 1

604610.0001; BLOOM SYNDROME

Identified Mutation

6-BP DEL/7-BP INS; In 4 ostensibly unrelated persons of Jewish ancestry, Ellis et al. [Cell 83: 655 (1995)] found homozygosity for a 6-bp deletion/7-bp insertion at nucleotide 2281 of the BLM cDNA. Deletion of ATCTGA and insertion of TAGATTC caused the insertion of the novel codons for LDSR after amino acid 736, and after these codons there was a stop codon. Ellis et al. [Cell 83: 655 (1995)] concluded that a person carrying this deletion/insertion mutation was a founder of the Ashkenazi-Jewish population, and that nearly all Ashkenazi Jews with Bloom syndrome inherited the mutation identical by descent from this common ancestor.

Gene

RECQL3

Chromosomal Location

15q26.1

Allelic Variant 2

; BLOOM SYNDROME

Identified Mutation

3233delT

Phenotypic Data

Remarks

Publications

Caballero M, Ge T, Rebelo AR, Seo S, Kim S, Brooks K, Zuccaro M, Kanagaraj R, Vershkov D, Kim D, Smogorzewska A, Smolka M, Benvenisty N, West SC, Egli D, Mace EM, Koren A, Comprehensive analysis of DNA replication timing across 184 cell lines suggests a role for MCM10 in replication timing regulation Human molecular genetics: 2022

PubMed ID: 35394024

Kalman L, Wilson JA, Buller A, Dixon J, Edelmann L, Geller L, Highsmith WE, Holtegaard L, Kornreich R, Rohlfs EM, Payeur TL, Sellers T, Toji L, Muralidharan K, Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent The Journal of molecular diagnostics : JMD11:530-6 2009

PubMed ID: 19815695

German J, Sanz MM, Ciocci S, Ye TZ, Ellis NA, Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry Human mutation28:743-53 2007

PubMed ID: 17407155

Trikka D, Fang Z, Renwick A, Jones SH, Chakraborty R, Kimmel M, Nelson DL, Complex SNP-based haplotypes in three human helicases: implications for cancer association studies. Genome Res12(4):627-39 2002

PubMed ID: 11932247

Foucault F, Vaury C, Barakat A, Thibout D, Planchon P, Jaulin C, Praz F, Amor-Gueret M, Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome. Hum Mol Genet6:1427-34 1997

PubMed ID: 9285778

Nicotera T, Thusu K, Dandona P, Elevated production of active oxygen in Bloom's syndrome cell lines. Cancer Res53:5104-7 1993

PubMed ID: 8221645

Noguiez P, Jaulin C, Praz F, Khelil M, Jeanpierre M, Viegas-Pequignot E, Amor-Gueret M, No relationship between genetic instability in Bloom's syndrome and DNA hypomethylation of some major repetitive sequences. Hum Genet92:57-60 1993

PubMed ID: 8365727

Nicotera TM, Notaro J, Notaro S, Schumer J, Sandberg AA, Elevated superoxide dismutase in Bloom's syndrome: a genetic condition of oxidative stress. Cancer Res49:5239-43 1989

PubMed ID: 2766291

Willis AE, Spurr NK, Lindahl T, Concomitant reversion of the characteristic phenotypic properties of a cell line of Bloom's syndrome origin. Carcinogenesis10:217-9 1989

PubMed ID: 2910526

Willis AE, Lindahl T, DNA ligase I deficiency in Bloom's syndrome. Nature325:355-7 1987

PubMed ID: 3808031

Taylor MW, Long T, Martinez-Valdez H, Downing J, Zeige G, Induction of gamma-interferon activity by elevated temperatures in human B-lymphoblastoid cell lines. Proc Natl Acad Sci U S A81:4033-6 1984

PubMed ID: 6330733

Taylor MW, Kothari RM, Holland GD, Martinez-Valdez H, Zeige G, A comparison of purine and pyrimidine pools in Bloom's syndrome and normal cells. Cancer Biochem Biophys7:19-25 1983

PubMed ID: 6667451