GENES FROM HUMAN CHROMOSOME 11P15.5

摘要

We previously reported the isolation of a 2.5 Mb tumor-suppressing subchromosomal transferable fragment (STF) from 11p15.5, and the identification of 9 known genes and 4 novel genes within this STF. We now report the isolation of a 4th, 5th, and 6th novel cDNA, designated here as TSSC5 (tumor-suppressing Stf cDNA 4, 5, and 6), located within the STF. TSSC4 encodes a predicted protein of 329 amino acids. TSSC5 encodes a predicted protein of 424 amino acids. TSSC6 encodes a predicted protein of 290 amino acids. Sequence analysis suggests that TSSC5 is a membrane protein with 10 transmembrane segments, and it is located between two imprinted genes, p57KIP2 and TSSC3. Northern blot hybridization revealed a 1.6 kb transcript for TSSC4 and TSSC5 in multiple adult tissues and in fetal tissues. Expression in fetal liver and kidney is consistent with a potential role in embryonal tumors. We also found that TSSC5 is imprinted with preferential expression from the maternal chromosome. Mutational analysis of TSSC5 by direct DNA sequencing of exons revealed a base substitution of G1120A in a Wilms tumor and modified normal kidney, changing Arg at codon 309 to Gln. No other mutation was detected in 48 Wilms tumors (WT) and 24 Beckwith-Wiedemann syndrome (BWS) patients. The G1120A substitution thus likely represents a tumor predisposing mutation, as the mutant allele was of maternal origin and preferentially expressed in the patient. A second base substitution, C892T, was found in a lung cancer, changing Ser at codon 233 to Phe. This substitution was absent from the matched normal tissue and thus represented a somatic mutation. We also found loss of heterozygosity in the lung cancer, suggesting that TSSC5 may be a conventional tumor suppressor gene.