CDKN2A germline splicing mutation affecting both P16(ink4) and P14(arf) RNA processing in a melanoma/neurofibroma kindred

The CDKN2A locus encodes two tumor suppressor proteins, p16(lnk4) and p14(a rf), through use of alternative first exons. CDKN2A mutations detected in m elanoma families are usually missense or nonsense changes which mainly impa ir p16(lnk4) function. Large genomic deletions spanning the entire locus ha ve been observed in Mo pedigrees with melanomas and nervous tumors. We have detected a novel splice site mutation in a family with melanomas, neurofib romas, and multiple dysplastic nevi. Both alternative mRNAs produced by the mutant allele lacked shared sequences from exon 2, which encodes a substan tial portion (> 50%) of both p16(lnk4) and p14(arf) proteins. The developme nt of neurofibromas can be explained by cooperative effects of combined ina ctivation of p16(ink4) and p14(arf) or, alternatively, of p14(arf) alone. ( C) 2001 Wiley-Liss, Inc.