A novel mutation in the KITLG gene

Familial progressive hyper- and hypopigmentation (FPHH, MIM 145250) is a rare hereditary skin disorder that is predominantly characterized by progressive, diffuse, partly blotchy hyperpigmented lesions intermingled with scattered hypopigmented spots, lentigines and sometimes Cafe-au-lait spots (CALs).Heterozygous mutations of KIT ligand (KITLG, MIM 184745) gene is responsible for FPHH. To date, only eight KITLG mutations were reported to be associated with FPHH and no clear genotype-phenotype correlations had been well established. Here we reported a novel c.104A>T (p.Asn35Ile) mutation of KITLG in a Chinese FPHH family. According to the ACMG guideline 2015, the mutation was initially identified as a ‘Likely Pathogenic’ mutation. As far as we know, only eight different missense KITLG mutations have been reported to cause FPHH. Notably, seven known mutations were clustered in a highly conserved short amino acid sequence VTNNV (amino acids 33-37) . It was known VTNNV domain of KITLG protein (amino acids 33–37), lies within the third b-strand of the protein and is responsible for the binding functions. Both mutations c.104A>T (p.Asn35Ile) and c.101C>T (p.Thr34Ile) found in this study were located located in the VTNNV domain and predicted to be detrimental variations by SIFT and Polyphen-2 tools. Using the Swiss-Model servers, three-dimensional structures of mutant KITLG proteins were found changed as compared with the wild type. Therefore it might change the features of the protein and affect the ligand affinity to its receptor c-Kit, thus may affect migration of melanoblasts, melanosome transfer and melanin synthesis, conferring a phenotype with hyper- and hypopigmentation.