Fine Exon–Intron Structure of the Fanconi Anemia Group A (FAA) Gene and Characterization of Two Genomic Deletions

Centra, Michele; Memeo, Elena; D’Apolito, Maria; Savino, Maria; Ianzano, Leonarda; Notarangelo, Angelo; Liu, Jingmei; Doggett, Norman A.; Zelante, Leopoldo; Savoia, Anna

doi:10.1006/geno.1998.5353

Cited by 39 publications

(39 citation statements)

References 16 publications

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“…2B) showed that the breakpoint occurred at two homologous sequences in introns 11 and 31 of the FANCA gene, and that these sequences were themselves highly homologous with several subfamilies of Alu repeats. A similar mechanism has been detected in deletions of exons 16-17 and exons 18-21 of FANCA (27,28). Indeed, Alu and other repeat-mediated recombinations appear to be a relatively common cause of pathological mutation in humans (29,30).…”

Section: Discussionmentioning

confidence: 77%

Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa

Tipping

Pearson

Morgan

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

105

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Fanconi anemia (FA) is a rare, genetically heterogeneous autosomal recessive disorder associated with progressive aplastic anemia, congenital abnormalities, and cancer. FA has a very high incidence in the Afrikaner population of South Africa, possibly due to a founder effect. Previously we observed allelic association between polymorphic markers flanking the FA group A gene (FANCA) and disease chromosomes in Afrikaners. We genotyped 26 FA families with microsatellite and single nucleotide polymorphic markers and detected five FANCA haplotypes. Mutation scanning of the FANCA gene revealed association of these haplotypes with four different mutations. The most common was an intragenic deletion of exons 12-31, accounting for 60% of FA chromosomes in 46 unrelated Afrikaner FA patients, while two other mutations accounted for an additional 20%. Screening for these mutations in the European populations ancestral to the Afrikaners detected one patient from the Western Ruhr region of Germany who was heterozygous for the major deletion. The mutation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogical investigation of 12 Afrikaner families with FA revealed that all were descended from a French Huguenot couple who arrived at the Cape on June 5, 1688, whereas mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular and genealogical evidence is consistent with transmission of the major mutation to Western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa.

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Section: Discussionmentioning

confidence: 77%

Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa

Tipping

Pearson

Morgan

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

105

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“…In addition to deletions of the entire gene, 13 we found deletions ranging from a single exon loss, such as exon 4 or 15, to removal of up to 26 exons. Although their breakpoints have not been characterized, the deletions are likely to have occurred at the numerous Alu repeats that are present in the FANCA intronic sequences.…”

Section: Fanca Mutationsmentioning

confidence: 89%

Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o napproximately 80% of FA patients worldwide, will not be successful in at least 20%. Secondly, there is a wide spectrum of mutations, mainly private, spanning the entire genes, including intragenic deletions, as frequently observed in FANCA (http://www.rockefeller.edu/fanconi/). Since mutational screening would largely benefit from a preliminary knowledge of the candidate gene, complementation by cell fusion or by viral transduction, as well as protein analyses, have been established as screening strategies to identify the putative gene that is defective. 6,7 Thirdly, a false negative or inconclusive chromosomal breakage test might occur in patients who develop hematopoietic mosaicism due to reversion of the cellular FA phenotype. 8,9 This phenomenon arises if a spontaneous genetic event reconstitutes normal protein activity of one allele. Since it is unlikely that the same somatic event will also occur in primary skin fibroblasts, these cells are often used for mutational screening.In this paper, we report the molecular data of 100 FA families enrolled into the National Network of the Marrow Failure Study Group of the Italian Association of Pediatric Hematology and Oncology. This cohort consists of 76 new families, as well as 24 families that have been described in previous reports. 10,11 Methods Patients, cell lines, and DNA samplesPatients with a positive chromosomal breakage test were included in this study for molecular screening of FA genes by the National Network of the Marrow Failure Study Group of the Italian Association of Pediatric Hematology and Oncology. All the subjects or their legal guardians gave written informed consent to the investigation, according to the Declaration of Helsinki. Protocols were approved by the ethics review boards of the institutions that enrolled the patients. DNA was extracted from peripheral blood, lymphoblastoid cell lines and/or primary fibroblasts. Complementation and Western blot analysesLymphoblast cell lines, peripheral blood T lymphocytes or primary fibroblasts were transduced with retroviral expressing the cDNAs for FANCA, FANCC or FANCG as previously reported. 6 Complementation was considered to occur when the viability of the transduced cells increased by more than 20% that of controls at at least three different mitomycin C concentrations. Western blot analysis of FANCD2 using a monoclonal antibody (Santa Cruz, CA, USA; diluted 1:500) was performed as previously described. 10 Sequencing analysis and multiplex ligation-dependent probe amplificationThe coding exons of the FA genes and their flanking regions were sequenced using a set of oligonucleotides (the primer sequences are available upon request) according to standard procedures. 10 Six samples were first analyzed using the Ion PGM TM system for next generation sequencing of the 16 FA genes according to the manufacturer's protocols (Life Technologies). Variants with minor allele frequency less than 1% were then confirmed by Sanger sequencing as above. N...

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“…25,34,35 However, when one of the breakpoints is telomeric versus exon 1, it is possible that the deletion does not result from intrachromosomal recombination, but from a terminal deletion (with a single breakpoint) as FANCA is very close to 16q telomere. In addition, it is not known whether long distance recombination can also cause FANCA deletions.…”

Section: Breakpoint Characterization Of Ex1-20delmentioning

confidence: 99%

Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations

Castellà

Pujol

Callén

et al. 2011

Blood

115

126

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Fine Exon–Intron Structure of the Fanconi Anemia Group A (FAA) Gene and Characterization of Two Genomic Deletions

Cited by 39 publications

References 16 publications

Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa

Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa

Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology

Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations

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