Recent evidence indicates the existence of a genetic locus in chromosome region 13q14 that confers susceptibility to
retinoblastoma, a
cancer of the eye in children. A gene encoding a
messenger RNA (
mRNA) of 4.6 kilobases (kb), located in the proximity of
esterase D, was identified as the
retinoblastoma susceptibility (RB) gene on the basis of chromosomal location, homozygous deletion, and
tumor-specific alterations in expression. Transcription of this gene was abnormal in six of six
retinoblastomas examined: in two
tumors, RB
mRNA was not detectable, while four others expressed variable quantities of RB
mRNA with decreased molecular size of about 4.0 kb. In contrast, full-length RB
mRNA was present in human fetal retina and placenta, and in other
tumors such as
neuroblastoma and
medulloblastoma.
DNA from
retinoblastoma cells had a homozygous gene deletion in one case and hemizygous deletion in another case, while the remainder were not grossly different from normal human control
DNA. The gene contains at least 12 exons distributed in a region of over 100 kb. Sequence analysis of
complementary DNA clones yielded a single long open reading frame that could encode a hypothetical
protein of 816
amino acids. A computer-assisted search of a protein sequence database revealed no closely related
proteins. Features of the predicted amino acid sequence include potential
metal-binding domains similar to those found in
nucleic acid-
binding proteins. These results provide a framework for further study of recessive genetic mechanisms in human
cancers.