Identification of a novel mutation in the KITLG gene in a Chinese family with familial progressive hyper- and hypopigmentation

Abstract

Background: 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. This study aimed to identify the causative mutations of the KITLG gene in two Chinese FPHH cases.Methods: Directly sequencing of the coding regions of KITLG was performed. The pathogenicity prediction was assessed using bioinformatics tools including SIFT, Polyphen2, and SWISS-MODEL, and further evaluated following the American College of Medical Genetics and Genomics (ACMG) guideline 2015.Results: A novel mutation c.104A>T (p.Asn35Ile) and a recurrent mutation c.101C>T (p.Thr34Ile) in KITLG were identified. As SIFT and Polyphen-2 softwares showed, both mutations identified in this study were predicted to be detrimental variations. Three-dimensional protein structures modeling indicated the mutant KITLG proteins might affect KITLG affinity to its receptor c-KIT. According to the ACMG guideline 2015, the novel mutation c.104A>T was ‘Likely Pathogenic’.Conclusions: So far, most of the KITLG mutations are clustered within the conserved VTNNV motif (amino acid 33-37) in exon 2. The known mutations are only involved in 33V, 34T, 36N, 37V but not 35N. We have now identified a novel mutation c.104A>T of KITLG, which was first reported in FPHH located within the conserved 35N of the motif. These results strengthen our understanding of FPHH and expand the mutational spectrum of the KITLG gene.

Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder

“…The initial livedo reticularis-like pattern suggests cutaneous vasculopathy with impaired oxygenation at the periphery of arteriolar supply zones. The subsequent pigmentation may be post-inflammatory, but the final pattern of discrete hyper- and hypopigmented macules is less obviously reticulate and resembles the dyschromatosis seen in familial progressive hyper- and hypopigmentation (OMIM #145250) caused by dominant mutations in KITLG ( 21 ).…”