Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene

Wijker, Mario; Morgan, Neil V.; Herterich, Sabine; Berkel, Carola G.M. van; Tipping, Alex J.; Groß, H.; Gille, Johan J. P.; Pals, Gerard; Savino, Maria; Altay, Çiğdem; Mohan, Sheila; Dokal, Inderjeet; Cavenagh, J; Marsh, Judith; Weel, M. Van; Ortega, Juan José López; Schüler, D.; Самочатова, Е. В.; Karwacki, Marek W.; Békássy, Albert N.; Abecasis, Manuel; Ebell, Wolfram; Kwee, M. L.; Ravel, Thomy de; Gibson, Rachel A.; Gluckman, Éliane; Arwert, Fré; Joenje, Hans; Savoia, Anna; Hoehn, Holger; Pronk, Jan C.; Mathew, Christopher

doi:10.1038/sj.ejhg.5200248

Cited by 88 publications

(97 citation statements)

References 21 publications

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“…This equates to a detection rate of 97% using the methodology described here, contrasting strongly with the situation in FANCA, where frequent partial deletions make mutation analysis difficult. 18,19 The majority of the mutations described are expected to yield truncated FANCG proteins varying from 7% to 95% of the wild type 68 kD. FANCG is known to form a complex with FANCA, and it has been shown that this binding is due to sequences both in the amino terminal and the carboxy terminal ends of the protein 20 (Kuang et al, 2000 personal communication).…”

Section: Discussionmentioning

confidence: 99%

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9

Demuth

Wlodarski

Tipping³

et al. 2000

Eur J Hum Genet

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FANCG was the third Faconi anaemia gene identified and proved to be identical to the previously cloned XRCC9 gene. We present the pathogenic mutations and sequence variants we have so far identified in a panel of FA-G patients. Mutation screening was performed by PCR, single strand conformational polymorphism analysis and protein truncation tests. Altogether 18 mutations have been determined in 20 families -97% of all expected mutant alleles. All mutation types have been found, with the exception of large deletions, the large majority is predicted to lead to shortened proteins. One stop codon mutation, E105X, has been found in several German patients and this founder mutation accounts for 44% of the mutant FANCG alleles in German FA-G patients. Comparison of clinical phenotypes shows that patients homozygous for this mutation have an earlier onset of the haematological disorder than most other FA-G patients. The mouse Fancg sequence was established in order to evaluate missense mutations. A putative missense mutation, L71P, in a possible leucine zipper motif may affect FANCG binding of FANCA and seems to be associated with a milder clinical phenotype.

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Section: Discussionmentioning

confidence: 99%

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9

Demuth

Wlodarski

Tipping³

et al. 2000

Eur J Hum Genet

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“…22 Five changes were novel missense mutations leading to nonconservative amino-acid substitutions in four cases, none of which was present in 79 normal controls. One additional missense mutation A3982G (causing the aminoacid change T1328A) had previously been reported to be pathogenic, 23 and the other seven nucleotide changes were polymorphisms. A recent analysis of FANCC in 97 cases of sporadic pediatric AML found no evidence of known pathogenic mutations, although one polymorphic variant was present at four-fold greater frequency in the AML cases compared to controls.…”

Section: Introductionmentioning

confidence: 99%

“…We selected the FANCA gene for analysis since mutations in this gene account for 70% of all cases of FA. The mutation profile of FANCA is highly heterogeneous with over 100 different mutations described, 23,[27][28][29] and there is a 40% incidence of large deletions, which remove 1-43 exons from the gene. 28,30 Screening for these mutations thus accounts for nearly 30% of all FA mutations across all complementation groups.…”

Section: Introductionmentioning

confidence: 99%

Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia

et al. 2004

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Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (Po0.0001). Sequencing FANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML.

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“…The SSCP analysis on genomic DNA was identical to that used in a study on FA patients (Wijker et al, 1998). This study shows that the method is able to identify mutations and polymorphisms.…”

Section: Discussionmentioning

confidence: 79%

“…Genomic DNA from eight tumours was also tested in an exonby-exon SSCP analysis described elsewhere (Wijker et al, 1998). The 43 exons of FAA (Lanzano et al, 1997) were amplified from genomic DNA with primers located 40Ð60 bp from the exon boundaries with T7 (sense) and Sp6 (antisense) sequences to facilitate sequencing.…”

Section: Mutation Screeningmentioning

confidence: 99%

Mutation analysis of the Fanconi anaemia A gene in breast tumours with loss of heterozygosity at 16q24.3

et al. 1999

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The recently identified Fanconi anaemia A ( FAA ) gene is located on chromosomal band 16q24.3 within a region that has been frequently reported to show loss of heterozygosity (LOH) in breast cancer. FAA mutation analysis of 19 breast tumours with specific LOH at 16q24.3 was performed. Single-stranded conformational polymorphism (SSCP) analysis on cDNA and genomic DNA, and Southern blotting failed to identify any tumour-specific mutations. Five polymorphisms were identified, but frequencies of occurrence did not deviate from those in a normal control population. Therefore, the FAA gene is not the gene targeted by LOH at 16q24.3 in breast cancer. Another tumour suppressor gene in this chromosomal region remains to be identified. © 1999 Cancer Research Campaign

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Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene

Cited by 88 publications

References 21 publications

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9

Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia

Mutation analysis of the Fanconi anaemia A gene in breast tumours with loss of heterozygosity at 16q24.3

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