Predominance of null mutations in ataxia-telangiectasia.
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.
Gilad
S
S
Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
Khosravi
R
R
Shkedy
D
D
Uziel
T
T
Ziv
Y
Y
Savitsky
K
K
Rotman
G
G
Smith
S
S
Chessa
L
L
Jorgensen
T J
TJ
Harnik
R
R
Frydman
M
M
Sanal
O
O
Portnoi
S
S
Goldwicz
Z
Z
Jaspers
N G
NG
Gatti
R A
RA
Lenoir
G
G
Lavin
M F
MF
Tatsumi
K
K
Wegner
R D
RD
Shiloh
Y
Y
Bar-Shira
A
A
D000595:Amino Acid Sequence; D001260:Ataxia Telangiectasia / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004247:DNA; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases