Pigment Cell & Melanoma Research最新文献

Oculocutaneous albinism type 1 (OCA1) caused by pathogenic variants of the TYR gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in skin, hair, and eyes. We had the opportunity to examine five East Cameroon Baka rainforest hunter-gatherers (historically called “Pygmies”) with albinism and belonging to three different families. Screening of known albinism genes revealed a homozygous missense variant in the TYR gene, NM_000372.5: c.1109T>C; p.Met370Thr. In addition, one patient was also hemizygous for a variant in GPR143, the gene involved in ocular albinism (OA1). Another patient was also heterozygous for the common African and Afro-American 2.7-kb deletion in the OCA2 gene indicating admixture of one parent with neighboring Nzimé Bantu-speaking farmers. This is the first report of the occurrence of OCA1 in African rainforest hunter-gatherers.

Shank color in chickens is a classic quantitative trait governed by four genetic loci. Among these, the Inhibition of dermal melanin (ID) locus, which suppresses dermal melanogenesis in the shank, is the sole sex-linked mutation and its molecular mechanisms remain elusive. To identify the causal mutation, we established a resource population segregating for shank colors. A genome-wide association study utilizing FarmCPU software identified a top-associated SNP on the Z chromosome. Linkage mapping subsequently narrowed the candidate region, within which we discovered a candidate structural variant associated with the yellow shank phenotype. This variant is characterized by a 143 bp deletion coupled with a 2 bp insertion. CDKN2A was the only gene within the same topologically associating domain to exhibit differential expression. Functional validation via CRISPR/Cas9-edited cells demonstrated that this mutation regulates CDKN2A transcription and is responsible for the ID shank color in chickens. We propose that the resulting absence of melanocytes is likely due to apoptosis. This work resolves the molecular basis of the ID locus, thereby completing the genetic puzzle of chicken shank color. This discovery enables the development of molecular markers for auto-sexing of day-old chicks, a tool with significant potential for the poultry industry.

Giant congenital melanocytic nevi (GCMN) are benign mosaic disorders that may give rise to various tumor types through incompletely understood mechanisms. We characterized a series of two melanomas and four mesenchymal tumors (two embryonal rhabdomyosarcomas, one small round cell sarcoma, one low-grade mesenchymal tumor) arising in GCMN. Median onset age was 3.5 years and 3 months for melanoma and mesenchymal tumor patients, respectively. Both melanoma patients succumbed within 27 months from diagnosis, whereas no patients progressed in the mesenchymal group (median follow-up 46 months). NRAS Q61, BRAF V600E mutation, and a novel in frame BIN1::BRAF fusion were detected in four, one, and one cases, respectively, with a higher variant allele frequency in the tumors compared with the matched GCMN. Copy number alterations and/or copy-neutral loss of heterozygosity were exclusively found in the tumors in all cases. An inactivating ASXL1 variant and an in-frame KDM5B::LPGAT1 fusion were identified in one melanoma; paternal disomy of 11p15.5 in both embryonal rhabdomyosarcomas. Mesenchymal tumors and melanomas showed distinct transcriptional profiles enriched in muscle and synapse organization and epidermal differentiation genes, respectively.

We present a comprehensive molecular and epidemiological analysis of albinism in a Russian cohort, comprising 177 probands with isolated (OCA1, OCA2, OCA3, OCA4, and OA) and syndromic (HPS-associated) forms of the disease. The comparative analysis of population frequencies between the National Genetic Initiative “100,000 + Me” (NGI) project and GnomAD (v3.1.2) revealed variants in the TYR gene (NM_000372.5):c.650G>A and c.1037-7 T>A, which are specifically prevalent in the Russian population. The functional analysis was provided for variants in the TYR gene, which can probably affect splicing. Based on the population frequency in the NGI project, we calculated the minimal estimated disease frequencies for isolated forms of albinism. Using molecular genetic results, functional analysis, and ACMG classification, the diagnosis was confirmed in 71.8% (127/177) of the cases in the Russian cohort.

We present an updated analysis of albinism in Japan, encompassing both oculocutaneous albinism (OCA) and ocular albinism (OA), based on 290 families, which expands our previous study by 100 additional families. The overall frequency distribution of major subtypes remained consistent with our previous findings: OCA4 remains the most prevalent subtype (67 patients, 23.1%), followed by OCA1 (57 patients, 19.7%), Hermansky–Pudlak syndrome (HPS) 1 (35 patients, 12.1%), and OCA2 (30 patients, 10.3%). Notably, our expanded analysis identified patients with rare subtypes, including OCA3, OCA6, HPS2, HPS3, HPS5, and HPS6, as well as OA, further demonstrating the genetic diversity of albinism in the Japanese population. Through comprehensive genetic screening of the additional 100 families, we identified 17 patients harboring previously unreported pathological variants across multiple albinism subtypes. These findings expand the variant spectrum of albinism in Japan, provide valuable insights for genetic counseling, and underscore the critical importance of comprehensive clinical evaluation and long-term multidisciplinary follow-up for patients with albinism, particularly those with HPS subtypes.

Dyschromatosis universalis hereditaria (DUH) is characterized by autosomal dominant inheritance and widespread involvement of hyperpigmentation and depigmentation. In our previous study, we identified mutations in the SH3 domain-containing protein 1 (SASH1) associated with the DUH phenotype in Chinese families and predicted that the SASH1/THBS1/TGF-β1 signaling pathway mediates melanin production and melanocyte transport. However, the molecular regulatory mechanisms remain unclear. By modulating the expression of SASH1 and THBS1, we assessed the expression of genes within the SASH1/THBS1/TGF-β1 pathway and evaluated cell phenotypes and melanin synthesis in the A375 and PIG1 cell lines. Through in vivo subcutaneous injection of SASH1 knockdown A375 cells into nude mice, we tested whether SASH1-TGF-β1 signaling may regulate cancer growth. Our findings demonstrated that SASH1 inhibits proliferation, migration, invasion, epithelial–mesenchymal transition, and promotes melanin synthesis through TGF-β1 signaling, while THBS1 counteracts the increase in TGF-β1 levels induced by SASH1 knockdown. We further showed that SASH1 suppresses TGF-β1 through its regulatory effect on THBS1, thereby inhibiting melanin metastasis and promoting melanin synthesis, which offers potential therapeutic insights into the modulation of TGF-β1.

Cellular senescence is associated with altered lipid metabolism, including increased cellular lipid uptake, upregulated lipid biosynthesis, and deregulated lipid breakdown. Previous studies have reported that carnitine palmitoyltransferase (CPT), the rate-limiting enzyme in fatty acid oxidation that catalyzes the conversion of acyl-CoA to acylcarnitine, is involved in various senescence-related diseases. Although solar lentigo (SL) is an age-related pigmentary disorder characterized by the accumulation of senescent cells, its role in metabolic dysregulation has rarely been investigated. Integrated transcriptomic profiling of SL skin samples, combining mRNA sequencing, differential gene expression, pathway enrichment analyses, metabolic flux simulations, and protein–protein interaction analysis, was conducted to demonstrate the molecular alterations in SL compared to perilesional normal skin. We found transcriptomic alterations in mitochondrial energy metabolism-associated genes. Metabolic flux simulations revealed that carnitine-associated reactions involved in fatty acid oxidation were upregulated. Using a multi-omics approach, CPT1B was selected as a potential marker for SL. Using a zebrafish model, CPT1B was implicated in melanogenesis. CPT1B-mediated metabolic alteration is a key driver of SL pathogenesis. Targeting CPT1B and the associated lipid metabolism pathways is a novel therapeutic approach for managing SL and age-related pigmentation disorders.