Pigment Cell & Melanoma Research最新文献

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.

The transcription factor SOX10 plays an important role in promoting determination and differentiation of melanocytes, and mutations affecting SOX10 expression or function often result in dramatic pigment phenotypes. In domestic rock pigeon, homozygosity for either of two regulatory mutations upstream of Sox10 known as recessive red causes birds to display bright red pheomelanic plumage instead of wild-type blue/black eumelanic plumage. In this study, we identify a common set of differentially expressed melanogenic genes in feathers from recessive red birds homozygous for either mutant allele, most notably a downregulation of Tyrp1, Slc24a5, Pmel, Mlana, and Hpgds and upregulation of Slc7a11. Collectively, these changes may promote pheomelanin synthesis and inhibit eumelanin synthesis. We also identify other altered pathways including genes involved in galactolipid synthesis and stem cell biology. We further examined the chromatin occupancy of SOX10 in pigeon melanocytes by ChIPseq to identify the subset of differentially expressed genes that are most likely to be direct targets of SOX10 function, and uncover evidence that SOX10 promotes its own expression by binding to the mcs7 melanocyte enhancer. Together, these data provide a more comprehensive picture of the role that SOX10 plays in melanocyte biology.

This article highlights the most recent updates in vitiligo that were presented in the sixth Vitiligo International Symposium, which was held in Cairo, Egypt from 13 to 15 December 2024. During this conference, worldwide vitiligo experts shared their experience in the different aspects of vitiligo, starting with vitiligo pathogenesis and all the basic science behind vitiligo, going forward to the different assessment tools, including artificial intelligence, and the different therapeutic modalities including new therapeutic targets. Epidemiology and quality of life, along with a dedicated session for people with vitiligo, were included as well. A session for clinical cases was also held this year in which different challenging cases with vitiligo and vitiligo mimickers were presented.

Advanced melanoma is typically treated with immune checkpoint inhibitors (ICIs) and targeted therapies. However, their efficacy is limited in acral and mucosal melanomas, which are more prevalent in non-White populations and often exhibit low tumor mutational burden and lack BRAF mutations. Fusion genes, widely used as therapeutic targets in other cancers, may represent alternative targets in these melanoma subtypes. This study aimed to detect fusion genes in Japanese melanomas lacking major driver mutations (BRAF, RAS, NF1, or KIT) using a custom RNA-based anchored multiplex polymerase chain reaction (AMP) panel. RNA extracted from 14 tumors, primarily formalin-fixed paraffin-embedded specimens, was analyzed using a custom Archer FUSIONPlex panel. Libraries were successfully generated in 80% of cases, and two in-frame fusions—MAD1L1::BRAF and CIC::MEGF8—were identified (17%). MAD1L1::BRAF retained the BRAF kinase domain and may be targetable by MEK inhibitors. CIC::MEGF8, a novel fusion in melanoma, may result in transcriptional dysregulation through CIC loss of function. This Method paper outlines the AMP workflow, including troubleshooting strategies and quality control criteria, and demonstrates its applicability to clinical samples. Our findings support the utility of RNA-based fusion detection in driver-negative melanomas and the potential of fusion genes as actionable targets.