PARENTAL ORIGIN OF GERM-LINE AND SOMATIC - MUTATIONS IN THE RETINOBLASTOMA GENE

Segregation analysis of polymorphic sites within the retinoblastoma (R B) gene and on chromosome 13, as well as the parental origin of the lo st allele in the tumor, were analyzed in 24 families with RB patients. Four mutant alleles transmitted through the germ-line and seven de no vo germ-line mutant alleles were identified in 11 patients with heredi tary RB. Segregation analysis within the RB gene and on chromosome 13 was useful for DNA diagnosis of susceptibility to RB in relatives of h ereditary patients, even if mutations were not identified. All seven d e novo germ-line mutant alleles were paternally derived. The bias towa rd the paternal allele for de novo germ-line mutations of the RB gene was statistically significant. Seven paternal alleles and six maternal alleles were lost in 13 non-hereditary RB tumors with no bias in the parental origin of the somatic allele loss. These results suggest that the physical environment or a deficiency in DNA repair during spermat ogenesis may be associated with significant risk factors for de novo g erm-line mutations.