CDKN2A point mutations D153spl(c.457G>T) and IVS2+1G>T result in aberrant splice products affecting both p16INK4a and p14ARF

The CDKN2A gene, which encodes the proteins p16INK4a and p14ARF, is located on chromosome 9p21. Germline mutations at this locus increase susceptibility to cutaneous malignant melanoma (CMM). In general, missense and nonsense mutations are primarily responsible for defective p16INK4a and possibly p14ARF protein function and account for ∼20% of inherited CMM cases. We report a G>T transversion mutation in the last nucleotide of exon 2, affecting the aspartic acid residue at position 153 of CDKN2A-p16INK4a in a proband with melanoma. If splicing were unaffected, this mutation would change Asp to Tyr. RT–PCR analysis, however, revealed that this mutation, which we have termed D153spl(c.457G>T), and a previously described mutation at the next nucleotide, IVS2+1G>T, result in identical aberrant splicing affecting both p16INK4a and p14ARF. The two main alternate splice products for each of the two normal transcripts includes a 74 bp deletion in exon 2, revealing a cryptic splice site, and the complete skipping of exon 2. The dual inactivation of p16INK4a and p14ARF may contribute to the CMM in these families.