title: Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype.
abstract: FANCD2 is an evolutionarily conserved Fanconi anemia (FA) gene that plays a key role in DNA double-strand-type damage responses. Using complementation assays and immunoblotting, a consortium of American and European groups assigned 29 patients with FA from 23 families and 4 additional unrelated patients to complementation group FA-D2. This amounts to 3%-6% of FA-affected patients registered in various data sets. Malformations are frequent in FA-D2 patients, and hematological manifestations appear earlier and progress more rapidly when compared with all other patients combined (FA-non-D2) in the International Fanconi Anemia Registry. FANCD2 is flanked by two pseudogenes. Mutation analysis revealed the expected total of 66 mutated alleles, 34 of which result in aberrant splicing patterns. Many mutations are recurrent and have ethnic associations and shared allelic haplotypes. There were no biallelic null mutations; residual FANCD2 protein of both isotypes was observed in all available patient cell lines. These analyses suggest that, unlike the knockout mouse model, total absence of FANCD2 does not exist in FA-D2 patients, because of constraints on viable combinations of FANCD2 mutations. Although hypomorphic mutations arie involved, clinically, these patients have a relatively severe form of FA.
authors: Department of Human Genetics, University of Wurzburg, Wurzburg, Germany.
authors: Reinhard
authors: R
authors: Kalb
authors: Kornelia
authors: K
authors: Neveling
authors: Holger
authors: H
authors: Hoehn
authors: Hildegard
authors: H
authors: Schneider
authors: Yvonne
authors: Y
authors: Linka
authors: Sat Dev
authors: SD
authors: Batish
authors: Curtis
authors: C
authors: Hunt
authors: Marianne
authors: M
authors: Berwick
authors: Elsa
authors: E
authors: Callen
authors: Jordi
authors: J
authors: Surralles
authors: Jose A
authors: JA
authors: Casado
authors: Juan
authors: J
authors: Bueren
authors: Angeles
authors: A
authors: Dasi
authors: Jean
authors: J
authors: Soulier
authors: Eliane
authors: E
authors: Gluckman
authors: C Michel
authors: CM
authors: Zwaan
authors: Rosalina
authors: R
authors: van Spaendonk
authors: Gerard
authors: G
authors: Pals
authors: Johan P
authors: JP
authors: de Winter
authors: Hans
authors: H
authors: Joenje
authors: Markus
authors: M
authors: Grompe
authors: Arleen D
authors: AD
authors: Auerbach
authors: Helmut
authors: H
authors: Hanenberg
authors: Detlev
authors: D
authors: Schindler
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005091:Exons; D005199:Fanconi Anemia / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D005260:Female; D005816:Genetic Complementation Test; D006801:Humans; D007438:Introns; D008297:Male; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D011544:Pseudogenes; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics
chemical_list: D017931:DNA Primers; D052236:Fanconi Anemia Complementation Group D2 Protein; D012322:RNA Precursors