Department of Dermatology, Henan Provincial People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, China.
Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu, China.
BMC Med Genomics. 2021 Jan 6;14(1):12. doi: 10.1186/s12920-020-00851-5.
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 the KIT ligand (KITLG, MIM 184745) gene are responsible for FPHH. To date, only eight KITLG mutations have been reported to be associated with FPHH, and no clear genotype-phenotype correlations have been established. This study aimed to identify the causative mutations in the KITLG gene in two Chinese FPHH patients.
Direct sequencing of the coding regions of KITLG was performed. Pathogenicity prediction was performed using bioinformatics tools, including SIFT, Polyphen2, and SWISS-MODEL, and the results were further evaluated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines.
The novel mutation c.104A > T (p.Asn35Ile) and the recurrent mutation c.101C > T (p.Thr34Ile) in KITLG were identified. As shown using SIFT and Polyphen-2 software, both mutations identified in this study were predicted to be detrimental variations. Three-dimensional protein structure modeling indicated that the mutant KITLG proteins might affect the affinity of KITLG for its receptor, c-KIT. According to the 2015 ACMG guidelines, the novel mutation c.104A > T was 'likely pathogenic'.
To date, most of the identified KITLG mutations have been clustered within the conserved VTNNV motif (amino acids 33-37) in exon 2. The known mutations are only involved in 33 V, 34 T, 36 N, and 37 V but not 35 N. We have now identified a novel mutation in KITLG, c.104A > T, that was first reported in FPHH within the conserved 35 N motif. These results strengthen our understanding of FPHH and expand the mutational spectrum of the KITLG gene.
家族性进行性色素沉着过度和减退症（FPHH，MIM 145250）是一种罕见的遗传性皮肤疾病，主要表现为进行性、弥漫性、部分斑驳的色素沉着过度病变，伴有散在的色素减退斑、痣和有时咖啡牛奶斑（CALs）。KIT 配体（KITLG，MIM 184745）基因的杂合突变是 FPHH 的致病原因。迄今为止，已有 8 种 KITLG 突变与 FPHH 相关，但尚未建立明确的基因型-表型相关性。本研究旨在鉴定 2 例中国 FPHH 患者 KITLG 基因的致病突变。
直接测序 KITLG 的编码区。使用生物信息学工具，包括 SIFT、Polyphen2 和 SWISS-MODEL，进行致病性预测，并根据 2015 年美国医学遗传学与基因组学学院（ACMG）指南进一步评估结果。
发现了 KITLG 中的新突变 c.104A > T（p.Asn35Ile）和反复出现的突变 c.101C > T（p.Thr34Ile）。SIFT 和 Polyphen-2 软件显示，本研究中鉴定的两种突变均被预测为有害变异。三维蛋白质结构建模表明，突变的 KITLG 蛋白可能影响 KITLG 与其受体 c-KIT 的亲和力。根据 2015 年 ACMG 指南，新突变 c.104A > T 为“可能致病”。
迄今为止，大多数已鉴定的 KITLG 突变都聚集在exon 2 的保守 VTNNV 基序（氨基酸 33-37）内。已知的突变仅涉及 33V、34T、36N 和 37V，但不涉及 35N。我们现在已经在 KITLG 中鉴定出一个新的突变 c.104A > T，这是首次在 FPHH 中报道的位于保守的 35N 基序内的突变。这些结果加深了我们对 FPHH 的理解，并扩展了 KITLG 基因的突变谱。
