GM03403

GM03403 LCL from B-Lymphocyte

Description:

BLOOM SYNDROME; BLM
RECQ PROTEIN-LIKE 3; RECQL3

Affected:

Yes

Sex:

Male

Age:

33 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

Alternate IDs

GM17361 [BLOOM SYNDROME; BLM]

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Ethnicity

ASHKENAZI

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; B.S. Registry #9; birth weight = 2,000 grams; failure to thrive in infancy with vomiting and diarrhea; weight at 18 months = 3.5 kg; at age 10 years: weight = 17.3 kg (mean weight of 4 1/2 year old), height = 118 cm (mean height of 6 1/2 year old); microcephaly; congenital dwarfism; facial telangiectasias: telangiectatic erythematous spots covered the nose, the adjacent parts of the cheeks, and lower part of the forehead; bullous crusted lesions covering the vermilion of underlip; cafe-au-lait spots on right shoulder and back; normal bone age at age 10 years; photosensitivity; high-pitched voice; rectal carcinoma and basal cell carcinoma of eyelid diagnosed at age 38 years; increased sister chromatid exchange; chromosome breakage; reduced level of DNA ligase I activity; donor subject is homozygous for a 6-bp deletion/7-bp insertion [2281_2286delins7] at nucleotide 2,281 of the open reading frame of the RECQL3 gene, which results in a frameshift and a stop codon; same donor as GM03402 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

DNASE ACTIVITY

Mezzina et al (Nucleic Acids Res 17:3091-3106,1989) studied DNase activity in this Bloom's syndrome culture. The results presented indicated that the DNase specific activity in crude extracts of this culture was higher than in appropriate control cell cultures.

DNA LIGASE I AND II

25% of normal DNA ligase I & normal DNA ligase II activity in lymphoblasts. DNA ligase I activity is more heat labile than normal (Willis and Lindahl NATURE 325:355-357,1987). Mezzina et al (Nucleic Acids Res 17:3091-3106,1989) studied DNA ligase activity in this Bloom's syndrome culture. The results presented indicated that the DNA ligase specific activity in crude extracts of this culture was higher than in control cells and that the ligase activity correlated to a major 130 kDa polypeptide. In 1989, Willis et al (Carcinogenesis 10:217-219) confirmed the observation that this Bloom's syndrome culture had an anomalously low level of DNA ligase I activity which showed abnormal heat lability.

MEX PHENOTYPES

Willis et al. (Proc Natl Acad Sci USA 84:8016,1987) reported a Mexphenotype based upon DNA (guanine-O6)-methyltransferase assay.

SISTER CHROMATID EXCHANGE ANALYSIS

High number of SCEs (60-80 per cell) in lymphoblast culture (Willis et al Proc Natl Acad Sci USA 84:8016-8020,1987).

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 hypersensitive response to the cytotoxic effects of ethyl methane sulphonate compared to a normal cell culture.

MUTATION VERIFICATION

The gene mutation(s) in this sample have been verified by 6 laboratories.

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

604610.0001; BLOOM SYNDROME

Identified Mutation

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: 2021

PubMed ID: 35394024

Mendez-Bermudez A, Hidalgo-Bravo A, Cotton VE, Gravani A, Jeyapalan JN, Royle NJ, The roles of WRN and BLM RecQ helicases in the Alternative Lengthening of Telomeres Nucleic acids research40:10809-20 2012

PubMed ID: 22989712

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

Ho CC, Siu WY, Lau A, Chan WM, Arooz T, Poon RY, Stalled replication induces p53 accumulation through distinct mechanisms from DNA damage checkpoint pathways Cancer research66:2233-41 2006

PubMed ID: 16489026

Jack R. Edelman and Yue J. Lin, Accretion of unstable heterochromatin as the origin of double minute chromosomes: evidence from Bloom Syndrome Cytologia (Tokyo)68:75-82 2003

PubMed ID: 16489026

Franchitto A, Pichierri P, Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest. J Cell Biol157(1):19-30 2002

PubMed ID: 11916980

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

Pedrazzi G, Perrera C, Blaser H, Kuster P, Marra G, Davies SL, Ryu GH, Freire R, Hickson ID, Jiricny J, Stagljar I., Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1. Nucleic Acids Res29(21):4378-86 2001

PubMed ID: 11691925

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

Mezzina M, Nardelli J, Nocentini S, Remault G, Sarasin A, DNA ligase activity in human cell lines from normal donors and Bloom's syndrome patients. Nucleic Acids Res17:3091-106 1989

PubMed ID: 2726453

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

Weksberg R, Smith C, Anson-Cartwright L, Maloney K, Bloom syndrome: a single complementation group defines patients of diverse ethnic origin. Am J Hum Genet42:816-24 1988

PubMed ID: 3163468

Willis, Structural alterations of DNA ligase I in Bloom syndrome. Proc Natl Acad Sci USA84:8016 (1987):816-24 1987

PubMed ID: 3163468

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

PubMed ID: 3808031

Katzenellenbogen, A contribution to Bloom's syndrome. Arch Dermatol82:609 (1960):355-7 1960

PubMed ID: 3808031