title: Somatic mutation of TSSC5, a novel imprinted gene from human chromosome 11p15.5.
abstract: We previously reported the isolation of a 2.5 Mb tumor-suppressing subchromosomal transferable fragment (STF) from 11p15.5 and the identification of nine known genes and four novel genes within this STF. We now report the isolation of a fifth novel cDNA, tumor-suppressing STF cDNA 5, designated TSSC5, located within the STF. TSSC5 encodes a predicted protein of 424 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 in multiple adult tissues and in fetal liver and kidney, consistent with a potential role in embryonal tumors. We also found that TSSC5 is imprinted with preferential expression from the maternal chromosome. Reverse transcription-PCR analysis of TSSC5 revealed frequent occurrence of aberrant RNA splicing, which deleted exons 4, 5, and 6 in Wilms' tumors. Mutational analysis of TSSC5 by direct DNA sequencing of exons revealed a base substitution of G1120A in a Wilms' tumor, matched normal kidney, and the patient's mother, changed Arg at codon 309 to Gln. The G1120A substitution thus represents either a rare polymorphism or a tumor-predisposing mutation, because the mutant allele was of maternal origin and preferentially expressed in the patient's tissue. 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 in the adult human lung and an imprinted tumor suppressor gene in the fetal kidney.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Lee
authors.forename: C
authors.initials: C
authors.lastname: Reeves
authors.forename: A
authors.initials: A
authors.lastname: Schmitt
authors.forename: K
authors.initials: K
authors.lastname: Su
authors.forename: T D
authors.initials: TD
authors.lastname: Connors
authors.forename: R J
authors.initials: RJ
authors.lastname: Hu
authors.forename: S
authors.initials: S
authors.lastname: Brandenburg
authors.forename: M J
authors.initials: MJ
authors.lastname: Lee
authors.forename: G
authors.initials: G
authors.lastname: Miller
authors.forename: A P
authors.initials: AP
authors.lastname: Feinberg
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D009396:Wilms Tumor / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins