Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype.
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.
Kalb
Reinhard
R
Department of Human Genetics, University of Wurzburg, Wurzburg, Germany.
Neveling
Kornelia
K
Hoehn
Holger
H
Schneider
Hildegard
H
Linka
Yvonne
Y
Batish
Sat Dev
SD
Hunt
Curtis
C
Berwick
Marianne
M
Callen
Elsa
E
Surralles
Jordi
J
Casado
Jose A
JA
Bueren
Juan
J
Dasi
Angeles
A
Soulier
Jean
J
Gluckman
Eliane
E
Zwaan
C Michel
CM
van Spaendonk
Rosalina
R
Pals
Gerard
G
de Winter
Johan P
JP
Joenje
Hans
H
Grompe
Markus
M
Auerbach
Arleen D
AD
Hanenberg
Helmut
H
Schindler
Detlev
D
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
D017931:DNA Primers; D052236:Fanconi Anemia Complementation Group D2 Protein; D012322:RNA Precursors