CDKN2A germline splicing mutation affecting both p16ink4 and p14arf RNA processing in a melanoma/neurofibroma kindred

Abstract

The CDKN2A locus encodes two tumor suppressor proteins, p16^ink4 and p14^arf, through use of alternative first exons. CDKN2A mutations detected in melanoma families are usually missense or nonsense changes which mainly impair p16^ink4 function. Large genomic deletions spanning the entire locus have been observed in two pedigrees with melanomas and nervous tumors. We have detected a novel splice site mutation in a family with melanomas, neurofibromas, and multiple dysplastic nevi. Both alternative mRNAs produced by the mutant allele lacked shared sequences from exon 2, which encodes a substantial portion (>50%) of both p16^ink4 and p14^arf proteins. The development of neurofibromas can be explained by cooperative effects of combined inactivation of p16^ink4 and p14^arf or, alternatively, of p14^arf alone.