DNA polymerase alpha defect in the N syndrome

The N syndrome is characterized by mental retardation, malformations, chromosome breakage, and development of T‐cell leukemia (Opitz et al.: Proceedings of the II International Congress IASSMD pp 115–119, 1971; Hess et al.: Clinical Genetics 6:237–246, 1974b, American Journal of Medical Genetics [supplement] 3:383–388, 1987). N syndrome fibroblasts were studied to see if the high chromosome breakage rate associated with this apparently X‐linked syndrome could be related to a deficiency of DNA polymerase alpha, a product of a gene localized to the X chromosome. Bleomycin, which is known to break double‐stranded DNA, produced increased chromosome breakage in normal control, Fanconi anemia, and N syndrome fibroblasts. When aphidicolin was used to inhibit repair mediated by DNA polymerase alpha, both normal control and Fanconi anemia fibroblasts showed significantly more chromosome breakage than was produced by bleomycin alone, but there was no increase in the amount of breakage seen in the N syndrome fibroblasts over that seen with bleomycin alone. This suggests that the N syndrome is due to a mutation affecting the region of the X chromosome on which the gene for DNA polymerase alpha is located, and that the high risk of T‐cell leukemia observed in the hemizygote is due to this DNA repair defect.