Pigmented macules in Waardenburg syndrome type 2 due to <i><scp>KITLG</scp></i> mutation

Ogawa, Yasushi; Kono, Michihiro; Akiyama, Masashi

doi:10.1111/pcmr.12597

Cited by 12 publications

(16 citation statements)

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“…Hearing loss, brilliant blue irides, hypotonia, and motor and language delay. The proband parents both had classical features of piebaldism.KITLG e 12q21.32 Ref 142,143. Unknown Only two publications identified with potential confounders.…”

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confidence: 99%

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome

Saleem

2018

Pediatric Dermatology

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Melanocyte development is orchestrated by a complex interconnecting regulatory network of genes and synergistic interactions. Piebaldism and Waardenburg syndrome are neurocristopathies that arise from mutations in genes involved in this complex network. Our understanding of melanocyte development, Piebaldism, and Waardenburg syndrome has improved dramatically over the past decade. The diagnosis and classification of Waardenburg syndrome, first proposed in 1992 and based on phenotype, have expanded over the past three decades to include genotype. This review focuses on the current understanding of human melanocyte development and the evaluation and management of Piebaldism and Waardenburg syndrome. Management is often challenging and requires a multidisciplinary approach.

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confidence: 99%

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome

Saleem

2018

Pediatric Dermatology

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“…Seco Z et al [12] reported mutations of KITLG, c.286_303delinsT (p.Ser96Ter), c.200_202del (p.His67_Cys68delinsArg), and c.310C>G (p.Leu104Val), cause asymmetric and unilateral hearing loss and Waardenburg Syndrome type 2 (WS2). Ogawa Y et al [13] reported a patient with WS2 who had the unusual complication of large pigmented macules with homozygous KITLG mutation (c.94G>A, p.Arg32Cys). It was speculated that the mechanism of the mutation underlying WS2 leading to membrane incorporation and reducing secretion of KITLG occurs via a gain-of-function or dominantnegative effect.…”

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confidence: 99%

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

Wang

Zhou

et al. 2020

Preprint

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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.

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“…Seco Z et al [12] reported that certain mutations of KITLG, including c.286_303delinsT (p.Ser96Ter), c.200_202del (p.His67_Cys68delinsArg), and c.310C>G (p.Leu104Val), cause asymmetric and unilateral hearing loss and Waardenburg syndrome type 2 (WS2). Ogawa Y et al [13] reported a patient with WS2 who had the unusual complication of large, pigmented macules caused by a homozygous KITLG mutation (c.94G>A, p.Arg32Cys). It was speculated that the mechanism of the mutation underlying WS2 leading to membrane incorporation and reducing secretion of KITLG occurs via a gain-of-function or dominant-negative effect.…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Zhou

et al. 2020

Preprint

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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 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.Methods: 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.Results: 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’.Conclusions: 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 33V, 34T, 36N, and 37V but not 35N. We have now identified a novel mutation in KITLG, c.104A>T, that was first reported in FPHH within the conserved 35N motif. These results strengthen our understanding of FPHH and expand the mutational spectrum of the KITLG gene.

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Pigmented macules in Waardenburg syndrome type 2 due to KITLG mutation

Cited by 12 publications

References 12 publications

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome

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

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

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