Fragility and spiralization anomalies of the chromosomes in three cases, including fraternal twins, with Fanconi’s anemia, type Estren-Dameshek

Schmid, Werner; Fanconi, G

doi:10.1159/000130845

Cited by 14 publications

(7 citation statements)

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“…21,22 However, this patient has mutations in the FANCG gene as do other patients with a more classical phenotype. There is, therefore, no genetic basis for the Estren Dameschek subtype.…”

Section: Discussionmentioning

confidence: 84%

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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“…21,22 However, this patient has mutations in the FANCG gene as do other patients with a more classical phenotype. There is, therefore, no genetic basis for the Estren Dameschek subtype.…”

Section: Discussionmentioning

confidence: 84%

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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“…A repair pathway known as the Fanconi anemia (FA) pathway has evolved to specifically deal with these types of lesions. FA is a recessive developmental and cancer predisposition syndrome whose patients display multi-organ defects, bone marrow failure in childhood (Fanconi, 1967; Schmid and Fanconi, 1978) and a high incidence of malignancies (Alter et al, 2003). Cells from FA patients are hypersensitive to DNA interstrand crosslinking agents such as mitomycin C (MMC) (Auerbach and Wolman, 1976).…”

Section: Introductionmentioning

confidence: 99%

A Genetic Screen Identifies FAN1, a Fanconi Anemia-Associated Nuclease Necessary for DNA Interstrand Crosslink Repair

et al. 2010

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Summary The Fanconi Anemia (FA) pathway is responsible for interstrand crosslink repair. At the heart of this pathway is the FANCI-FAND2 (ID) complex, which, upon ubiquitination by the FA core complex, travels to sites of damage to coordinate repair that includes nucleolytic modification of the DNA surrounding the lesion and translesion synthesis. How the ID complex regulates these events is unknown. Here we describe a shRNA screen that led to the identification of two nucleases necessary for crosslink repair, FAN1 and EXDL2. FAN1 co-localizes at sites of DNA damage with the ID complex in a manner dependent on FAN1’s ubiquitin binding domain (UBZ), the ID complex, and monoubiquitination of FANCD2. FAN1 possesses intrinsic 5′-3′ exonuclease activity and endonuclease activity that cleaves nicked and branched structures. We propose that FAN1 is a repair nuclease that is recruited to sites of crosslink damage in part through binding the ubiquitinated ID complex through its UBZ domain.

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“…The FA pathway has evolved in higher eukaryotes specifically to respond to this type of lesion by coordinating S phase arrest and DNA repair [22,23]. FA is a recessive developmental and cancer predisposition syndrome that displays multiorgan defects, bone marrow failure in childhood [24,25] and a high incidence of malignancies [26]. FA is caused by mutations in 13 FANC genes which render cells hypersensitive to DNA interstrand crosslinking agents such as mitomycin C [27].…”

Section: Discussionmentioning

confidence: 99%

FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer

Park

Odefrey

Hammet

et al. 2011

Breast Cancer Res Treat

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We are interested in the characterisation of previously undescribed contributions to the heritable component of human cancers. To this end, we applied whole-exome capture, followed by massively parallel sequence analysis to the germline DNA of two greater than third-degree affected relatives from four multiple-case, early-onset breast cancer families. Prior testing for variants in known breast cancer susceptibility, genes in these families did not identify causal mutations. We detected and confirmed two different variants in the DNA damage repair gene FAN1 (R377W, chr15:31197995 C>T and R507H, chr15:31202961 G>A [hg19]) which were not present in dbSNP131. In one family, FAN1 R377W, predicted to be damaging by SIFT and PolyPhen2, was present in all six tested members with cancer (five with breast cancer, one with malignant melanoma). In another family, FAN1 R507H, predicted to be damaging by SIFT but benign by PolyPhen2, was observed in one of two tested members with breast cancer. We genotyped FAN1 R377W and R507H variants across 1417 population-based cases and 1490 unaffected population-based controls (frequency-matched for age). These variants were rare in the Australian population (minor allele frequencies of 0.0064 and 0.010, respectively) and were not associated with breast cancer risk (OR = 0.80, 95% CI[0.39-1.61], P = 0.50 and OR = 0.74, 95% CI[0.41-1.29], P = 0.26, respectively). Analysis of breast cancer risks for relatives of case and control carriers did not find evidence of an increased risk. Despite the biological role of FAN1, the plausibility of its role as a breast cancer predisposition gene, and the possible deleterious nature of the identified variants, these two variants do not appear to be causal for breast cancer. Future studies to extend the genetic analysis of FAN1 will further explore its possible role as a breast cancer susceptibility gene.

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Fragility and spiralization anomalies of the chromosomes in three cases, including fraternal twins, with Fanconi’s anemia, type Estren-Dameshek

Cited by 14 publications

References 0 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

A Genetic Screen Identifies FAN1, a Fanconi Anemia-Associated Nuclease Necessary for DNA Interstrand Crosslink Repair

FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer

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