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(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.