LETTER TO THE EDITOR
A novel germline mutation in CDK4 codon 24 associated to
Arg24Leu, c.71G>T, CDK4, melanoma
To the Editor:
Germline mutations of the CDK4 gene have been reported in
18 familial cutaneous melanoma (CM) cases worldwide, with only
2 substitutions, the c.70C>T,p.Arg24Cys and c.71G>A,p.Arg24His,
described to date.
Moreover, the acquired CDK4 p.Asn41Ser variant
has been related to sporadic metastatic malignant melanoma.
A, Family pedigree: segregation of CDK4 p.Arg24Leu mutation (*). B, CDK4 c.71G>T,p.Arg24Leu mutation. C, Homology model of
the wild-type CDK4 (orange) in complex with p16(INK4)a (green). The CDK4 Arg24 residue (spheres) engages intermolecular interactions with
the binding surface of the inhibitors. (D) to (G) Arg24 (orange) establishes salt bridges with 2 conserved aspartate residues of (D) p16(INK4)a,
(E) p15(INK4)b, (F) p18(INK4)c and (G) p19(INK4)d (green). These interactions are lost in the mutant complexes (white). H, Predicted Gibbs free
energy of binding variations (ΔΔG, in kcal/mol) between CDK4 and its partners upon mutations. ΔΔG values indicate decrease affinity
Received: 29 June 2017 Revised: 21 August 2017 Accepted: 23 August 2017
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
934 wileyonlinelibrary.com/journal/cge Clinical Genetics. 2018;93:934–935.