GM16756

GM16756 LCL from B-Lymphocyte

Description:

FANCONI ANEMIA, COMPLEMENTATION GROUP D2; FANCD2
FANCD2 GENE; FANCD2

Affected:

Yes

Sex:

Male

Age:

7 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

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

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; line PD20.L; complementation group D2; café au lait spots; thrombocytopenia, anemia, and leukopenia at age 5; bleeding at age 7; MMC and DEB sensitivity; chromosome instability; donor subject is a compound heterozygote: one allele has an A>G transition at nucleotide 376 of the FANCD2 gene [376A>G] resulting in a substitution of glycine for serine at codon 126 as well as abnormal splicing and the insertion of 13 bp from intron 5 into the mRNA via the utilization of a cryptic splice site [Ser126Gly (S126G) and 13-bp INS], and a second allele has a G>A transition at nucleotide 3707 of the FANCD2 gene [3707G>A] resulting in a substitution of histidine for arginine at codon 1236 [Arg1236His (R1236H)]; affected sibling; corrected version of this line is GM16634; immortalized fibroblast line is GM16633.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

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

Gene

FANCD2

Chromosomal Location

3p25.3

Allelic Variant 1

227646.0002; FANCONI ANEMIA, COMPLEMENTATION GROUP D2

Identified Mutation

SER126GLY AND 13-BP INS; In the PD20 cell line from a family with Fanconi anemia complementation group D2, Timmers et al. (Molec Cell 7:241-248, 2001) identified an A-to-G transition at nucleotide 376 of the FANCD2 gene, resulting in a ser126-to-gly substitution. The mutation also resulted in abnormal splicing and the insertion of 13 bp from intron 5 into the mRNA via the utilization of a cryptic splice site. Forty-three of 43 (100%) independently cloned RT-PCR products with this mutation contained this insertion, whereas only 1 of 31 (3%) control cDNA clones displayed misspliced mRNA. The 13-bp insertion generated a frameshift and predicts a severely truncated protein of 180 amino acids. The mutation was not a common polymorphism and was inherited from the mother. The paternal mutation identified in this family was an arg1236-to-his substitution (227646.0001).

Gene

FANCD2

Chromosomal Location

3p25.3

Allelic Variant 2

227646.0001; FANCONI ANEMIA, COMPLEMENTATION GROUP D2

Identified Mutation

ARG1236HIS; In the PD20 cell line from a family with Fanconi anemia complementation group D2, Timmers et al. (Molec Cell 7:241-248, 2001) identified a G-to-A transition at nucleotide 3707 of the FANCD2 gene, resulting in an arg1236-to-his substitution. The mutation was not a common polymorphism and was inherited from the father. The maternal mutation identified in this family was an A-to-G transition at nucleotide 376 (227646.0002).

Phenotypic Data

Remarks

Publications

Olazabal-Herrero A, He B, Kwon Y, Gupta AK, Dutta A, Huang Y, Boddu P, Liang Z, Liang F, Teng Y, Lan L, Chen X, Pei H, Pillai MM, Sung P, Kupfer GM, The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export Cell reports43:113610 2024

PubMed ID: 38165804

Hammarsten O, Muslimovic A, Thunström S, Ek T, Johansson P, Use of the cell division assay to diagnose Fanconi anemia patients' hypersensitivity to mitomycin C Cytometry Part B, Clinical cytometry43:113610 2021

PubMed ID: 32857894

Oppezzo A, Bourseguin J, Renaud E, Pawlikowska P, Rosselli F, Microphthalmia transcription factor expression contributes to bone marrow failure in Fanconi anemia The Journal of clinical investigation43:113610 2019

PubMed ID: 31877112

Liang Z, Liang F, Teng Y, Chen X, Liu J, Longerich S, Rao T, Green AM, Collins NB, Xiong Y, Lan L, Sung P, Kupfer GM, Binding of FANCI-FANCD2 Complex to RNA and R-Loops Stimulates Robust FANCD2 Monoubiquitination Cell reports26:564-572.e5 2018

PubMed ID: 30650351

Whitney M, Thayer M, Reifsteck C, Olson S, Smith L, Jakobs PM, Leach R, Naylor S, Joenje H, Grompe M, Microcell mediated chromosome transfer maps the Fanconi anaemia group D gene to chromosome 3p. Nat Genet11:341-3 1995

PubMed ID: 7581463