Autosomal dominant progressive hyperpigmentation and lentigines in a Japanese pedigree due to a missense mutation near the C-terminus of<i>KIT</i>

Takeichi, Takuya; Sugiura, Kazumitsu; Tanahashi, Kana; Noda, Katuhiko; Kono, Michihiro; Akiyama, Masashi

doi:10.1111/bjd.16895

Cited by 2 publications

(3 citation statements)

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“…However, two independent groups have recently revealed a new missense mutation of KIT in patients with hyperpigmentation and lentigines without systemic disorders. T. Takeichi et al reported the c. 2485G > C mutation in exon 17 of KIT in a Japanese pedigree that manifested as progressive hyperpigmentation and lentigines unassociated with any other familiar systemic disease ( 5 ). Almost at the same time, Alain K. et al revealed the same mutation in a 6-year-old girl who presented with atypical lentiginosis and hyperpigmentation without systemic disorders ( 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…In this report, we examined a Chinese pedigree presented with progressive hyperpigmentation and generalized lentigines, carrying the same germline mutation of KIT , suggesting its role in the regulation of the proliferation and melanin production of melanocytes. This missense mutation would lead to an amino acid substitution from alanine to proline at position 829 (A829P) on the kinase activation loop of KIT, generating a unique sequence “Pro-Arg-Leu-Pro,” which was postulated to serve as an Src homology 3 (SH3) domain-binding motif and activate the MAPK signaling cascade ( 2 , 5 ). It has been reported that a secondary somatic A829P mutation of KIT was associated with acquired drug resistance during long-term treatment with imatinib mesylate in GISTs ( 13 , 14 ).…”

Section: Discussionmentioning

confidence: 99%

“…There are two reports of a missense mutation at the kinase activation loop of KIT (c. 2485G > C) that is associated with hyperpigmentation and lentigines without GIST or mastocytosis ( 1 , 5 ). In this study, we reported a Chinese pedigree with progressive hyperpigmentation and generalized lentigines in which the same missense mutation of KIT was confirmed.…”

Section: Introductionmentioning

confidence: 99%

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Case Report: A Missense Mutation of KIT in Hyperpigmentation and Lentigines Unassociated With Systemic Disorders: Report of a Chinese Pedigree and a Literature Review

2022

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BackgroundKIT is a proto-oncogene that is involved in the proliferation, survival, and regulation of melanocytes, mast cells, and the interstitial cells of Cajal. Mutations of KIT have been reported to be associated with hyperpigmentation and lentigines, mastocytosis, and gastrointestinal stromal tumors (GISTs). Some hotspot mutations of KIT have been reported to be associated with mastocytosis and GISTs, while the relationship between KIT mutations and hyperpigmentation and lentigines has not been fully elucidated.MethodsIn this study, we presented a three-generation Chinese pedigree with progressive hyperpigmentation and generalized lentigines inherited in an autosomal dominant pattern. High-throughput sequencing was performed to capture genetic variations in peripheral blood samples of the proband. Also, Sanger sequencing was performed to further verify the result. We also reviewed previous literature on KIT mutations with hyperpigmentation and lentigines.ResultsA missense mutation of the KIT gene was identified: c. 2485G > C, which was co-segregated in the proband and his insulted father. Germline KIT mutations presenting as generalized hyperpigmentation and lentigines without systemic disorders are rare, with only two reports of c. 2485G > C mutation associated with this phenotype in previous literature.ConclusionOur pedigree, together with those two reports, indicates a possible phenotype-genotype correlation of this germline KIT mutation, which might be helpful for genetic counseling, further functional segregation of KIT, and design of targeted therapy in the future.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Case Report: A Missense Mutation of KIT in Hyperpigmentation and Lentigines Unassociated With Systemic Disorders: Report of a Chinese Pedigree and a Literature Review

2022

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Chinese Pedigree with Hereditary Gastrointestinal Stromal Tumors: A Case Report and Literature Review

Liu

Yang

et al. 2023

IJMS

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Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder with only a few affected families reported to date. Here, we report a case of familial GISTs harboring a novel germline mutation within exon 18 of KIT. A 58-year-old male patient presented with gastric subepithelial lesions accompanied by cutaneous hyperpigmentation, which were subsequently diagnosed as multinodular GISTs. Endoscopic surgery was initially conducted to remove the larger lesions, and pathological examinations were then conducted for the diagnosis of GISTs. Family history revealed that some other family members had similar cutaneous pigmentations. Whole-exome sequencing was used to search for potential driver mutations, and Sanger sequencing was used for mutation validation. A novel primary driver mutation of KIT (c.G2485C, p.A829P) was detected in these hereditary GISTs, which has been reported in some targeted chemotherapy-resistant GISTs. Cell models were subsequently established for the rapid screening of candidate drugs and exploring potential mechanisms. This mutation could lead to cell proliferation and imatinib resistance by ligand-independent activation of KIT; however, ripretinib administration was identified as an applicable targeted therapy for this mutation. The mutation activated the JAK/STAT3 and MAPK/ERK pathways, which could be inhibited by ripretinib administration. To the best of our knowledge, this is the first report of the KIT-A829P mutation in familial GISTs, complementing the pathogenesis of familial GISTs and providing valuable information for the precision treatment of this disease.

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Autosomal dominant progressive hyperpigmentation and lentigines in a Japanese pedigree due to a missense mutation near the C-terminus ofKIT

Cited by 2 publications

References 8 publications

Case Report: A Missense Mutation of KIT in Hyperpigmentation and Lentigines Unassociated With Systemic Disorders: Report of a Chinese Pedigree and a Literature Review

Case Report: A Missense Mutation of KIT in Hyperpigmentation and Lentigines Unassociated With Systemic Disorders: Report of a Chinese Pedigree and a Literature Review

Chinese Pedigree with Hereditary Gastrointestinal Stromal Tumors: A Case Report and Literature Review

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