PMID- 10210316
OWN - NLM
STAT- MEDLINE
DCOM- 19990614
LR  - 20191024
IS  - 0301-472X (Print)
IS  - 0301-472X (Linking)
VI  - 27
IP  - 4
DP  - 1999 Apr
TI  - A patient-derived mutant form of the Fanconi anemia protein, FANCA, is defective 
      in nuclear accumulation.
PG  - 587-93
AB  - Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with 
      at least eight complementation groups (A-H). Three FA genes, corresponding to 
      complementation groups A, C, and G, have been cloned, but the function of the 
      encoded FA proteins remains unknown. We recently demonstrated that the FANCA and 
      FANCC proteins bind and form a nuclear complex. In the current study, we 
      identified a homozygous mutation in the FANCA gene (3329A>C) in an Egyptian FA 
      patient from a consanguineous family. This mutant FANCA allele is predicted to 
      encode a mutant FANCA protein, FANCA(H1110P), in which histidine 1110 is changed 
      to proline. Initially, we characterized the FANCA(H1110P) protein, expressed in 
      an Epstein Barr virus (EBV)-immortalized lymphoblast line derived from the 
      patient. Unlike wild-type FANCA protein expressed in normal lymphoblasts, 
      FANCA(H1110P) was not phosphorylated and failed to bind to FANCC. To test 
      directly the effect of this mutation on FANCA function, we used 
      retroviral-mediated transduction to express either wild-type FANCA or 
      FANCA(H1110P) protein in the FA-A fibroblast line, GM6914. Unlike wild-type 
      FANCA, the mutant protein failed to complement the mitomycin C sensitivity of 
      these cells. In addition, the FANCA(H1110P) protein was defective in nuclear 
      accumulation in the transduced cells. The characteristics of this mutant protein 
      underscore the importance of FANCA phosphorylation, FANCA/FANCC binding, and 
      nuclear accumulation in the function of the FA pathway.
FAU - Kupfer, G
AU  - Kupfer G
AD  - Dana-Farber Cancer Institute, and Department of Pediatrics, Children's Hospital, 
      Harvard Medical School, Boston, MA 02115, USA.
FAU - Naf, D
AU  - Naf D
FAU - Garcia-Higuera, I
AU  - Garcia-Higuera I
FAU - Wasik, J
AU  - Wasik J
FAU - Cheng, A
AU  - Cheng A
FAU - Yamashita, T
AU  - Yamashita T
FAU - Tipping, A
AU  - Tipping A
FAU - Morgan, N
AU  - Morgan N
FAU - Mathew, C G
AU  - Mathew CG
FAU - D'Andrea, A D
AU  - D'Andrea AD
LA  - eng
GR  - K08-H103420/PHS HHS/United States
GR  - P01HL54785/HL/NHLBI NIH HHS/United States
GR  - R01-HL52725/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (FANCC protein, human)
RN  - 0 (Fanconi Anemia Complementation Group C Protein)
RN  - 0 (Fanconi Anemia Complementation Group Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proteins)
SB  - IM
MH  - Amino Acid Substitution/genetics
MH  - *Cell Cycle Proteins
MH  - Cell Line
MH  - Cell Nucleus/*metabolism
MH  - DNA Mutational Analysis
MH  - *DNA-Binding Proteins
MH  - Fanconi Anemia/*genetics/metabolism
MH  - Fanconi Anemia Complementation Group C Protein
MH  - Fanconi Anemia Complementation Group Proteins
MH  - Gene Expression
MH  - Genetic Complementation Test
MH  - Humans
MH  - Immunoblotting
MH  - Lymphocytes/chemistry
MH  - *Nuclear Proteins
MH  - Phosphorylation
MH  - *Point Mutation
MH  - *Protein Biosynthesis
MH  - Proteins/*genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transfection
EDAT- 1999/04/21 02:03
MHDA- 2000/04/01 09:00
CRDT- 1999/04/21 02:03
PHST- 1999/04/21 02:03 [pubmed]
PHST- 2000/04/01 09:00 [medline]
PHST- 1999/04/21 02:03 [entrez]
AID - S0301-472X(99)00022-3 [pii]
AID - 10.1016/s0301-472x(99)00022-3 [doi]
PST - ppublish
SO  - Exp Hematol. 1999 Apr;27(4):587-93. doi: 10.1016/s0301-472x(99)00022-3.