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.家族性进行性色素沉着与色素减退症（Familial progressive hyper- and hypopigmentation, FPHH, MIM 145250）是一种罕见的遗传性皮肤疾病，其主要临床特征为进行性、弥漫性、部分呈斑片状的色素沉着病变，与散在分布的色素减退斑、雀斑样痣，偶见咖啡牛奶斑（Cafe-au-lait spots, CALs）混杂存在。KIT配体（KIT ligand, KITLG, MIM 184745）基因的杂合突变是导致FPHH的病因。截至目前，仅报道过8种与FPHH相关的KITLG突变，且尚未明确建立清晰的基因型-表型关联。本研究报道了一个中国FPHH家系中发现的新型KITLG c.104A>T（p.Asn35Ile）突变。根据美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics, ACMG）2015版指南，该突变最初被判定为‘可能致病’突变。据我们所知，目前仅有8种不同的错义KITLG突变被报道可导致FPHH。值得注意的是，其中7种已知突变均聚集在一段高度保守的短氨基酸序列VTNNV（第33~37位氨基酸）中。已知KITLG蛋白的VTNNV结构域（第33~37位氨基酸）位于蛋白的第三个β折叠链区域，负责介导配体结合功能。本研究中发现的c.104A>T（p.Asn35Ile）与c.101C>T（p.Thr34Ile）两种突变均位于VTNNV结构域内，且经SIFT与Polyphen-2工具预测为有害变异。通过Swiss-Model服务器预测，突变型KITLG蛋白的三维结构与野生型相比发生了改变。因此该突变可能改变蛋白的结构特性，影响配体与其受体c-Kit的结合亲和力，进而干扰黑素母细胞迁移、黑素体转运及黑素合成过程，最终表现为色素沉着与色素减退并存的表型。