Type I transforming growth factor β receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract

In a search for mutation of the type I transforming growth factor β receptor (TβR-I), we mapped the gene to 9q22 and found a common polymorphism [TβR-I(6A)] and a rare variant [TβR-I(10A)] of TβR-I, causing an in-frame deletion of three alanines and an in-frame insertion of one alanine, respectively, in the receptor's extracellular domain. The biological relevance of the polymorphism TβR-I(6A) was investigated. When TβR-I(6A) was transiently transfected into TβR-I-deficient cells, the growth- inhibitory effects of transforming growth factor β were restored. TβR- I(6A) and TβR-(10A) frequency were assessed in 108 tumor samples and 80 nontumor samples donors of comparable ethnic composition. The frequency of TβR-I(6A) heterozygotes was fairly similar in normal blood donors (8%), in nontumor DNA of patients with a diagnosis of cancer (10%), and in tumor samples (14%). However, the frequency of TβR-I(6A) homozygotes among nontumor (4%) and tumor (8%) samples obtained from patients with a diagnosis of cancer was higher than that predicted by the Hardy-Weinberg law. The clinical and biological significance of TβR-I(6A) homozygosity needs to be further investigated.