ClinVar

In a 62-year-old woman with multiple endocrine neoplasia type IV (MEN4; 610755), Occhi et al. (2013) identified a heterozygous 4-bp deletion (c.-456_-453delCCTT) in a highly conserved region in the 5-prime untranslated region of the CDKN1B gene. The mutation was not found in the dbSNP or 1000 Genomes Project databases or in 600 control chromosomes. The deletion shifted the upstream open reading frame (ORF) termination codon, thus lengthening the upstream ORF-encoded peptide from 29 to 158 amino acids and shortening the intracistronic space from 429 to 38 bp, with a possible negative influence on translation reinitiation from the main ATG. This change was predicted to prevent proper functioning of the 40S ribosomal subunit during translation. Patient cells showed normal levels of mutant mRNA, but decreased expression of the p27 protein, with weak cytoplasmic staining. Pancreatic tumor cells from the patient showed weak cytoplasmic p27 staining; there was no loss of heterozygosity for the wildtype allele. In vitro functional cellular expression assays showed that the 4-bp deletion impaired translation of a reporter gene by affecting translation reinitiation. The findings elucidated a novel mechanism by which p27 levels can be modulated by changes in the upstream ORF. The patient had acromegaly and a well-differentiated nonfunctioning pancreatic endocrine neoplasm.