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Background: Oculocutaneous albinism type 4 (OCA4) is a rare autosomal recessive disorder characterized by a reduction of pigmentation in skin, hair, and eyes, and OCA4 is mainly seen in the SLC45A2 gene variants. Objective: To report a Chinese patient suspected of oculocutaneous albinism and identify the causing mutation. Method s : Genomic DNA was extracted from the peripheral blood samples of the patient, his parents, and elder brother. Whole exome sequencing was performed in the family, and Sanger sequencing was then used to verify the mutations. Results: Compound heterozygous variants, c.1304C>A (p.S435Y) and c.301C>G (p.R101G) in SLC45A2 gene, were detected in the proband, which were inherited from his father and mother respectively. Based on the ACMG guidelines, we can interpret the c.1304C>A (p.S435Y) variant as a suspected pathogenic variant and the c.301C>G (p.R101G) variant as a clinically significant unspecified variant. The diagnosis of OCA4 is confirmed. Conclusion: We firstly reported this case of OCA4 with the compound heterozygous variants in the SLC45A2 gene. Our findings further enrich the reservoir of SLC45A2 mutations in OCA4. [ABSTRACT FROM AUTHOR]

Bird plumage coloration is a complex and multifactorial process that involves both genetic and environmental factors. Diverse pigment groups contribute to plumage variation in different birds. In parrots, the predominant green color results from the combination of 2 different primary colors: yellow and blue. Psittacofulvin, a pigment uniquely found in parrots, is responsible for the yellow coloration, while blue is suggested to be the result of light scattering by feather nanostructures and melanin granules. So far, genetic control of melanin-mediated blue coloration has been elusive. In this study, we demonstrated that feather from the yellow mutant rose-ringed parakeet displays loss of melanosome granules in spongy layer of feather barb. Using whole genome sequencing, we found that mutation in SLC45A2, an important solute carrier protein in melanin synthetic pathway, is responsible for the sex-linked yellow phenotype in rose-ringed parakeet. Intriguingly, one of the mutations, P53L found in yellow Psittacula krameri is already reported as P58A/S in the human albinism database, known to be associated with human OCA4. We further showed that mutations in SLC45A2 gene affect melanin production also in other members of Psittaculidae family such as alexandrine and plum-headed parakeets. Additionally, we demonstrate that the mutations associated with the sex-linked yellow phenotype, localized within the transmembrane domains of the SLC45A2 protein, affect the protein localization pattern. This is the first evidence of plumage color variation involving SLC45A2 in parrots and confirmation of associated mutations in the transmembrane domains of the protein that affects its localization. [ABSTRACT FROM AUTHOR]

Iris color is a prominent phenotypic feature of quail. To understand the mechanism of melanin deposition related to quail iris color, iris tissues were selected from Beijing white and Chinese yellow quail for transcriptome analysis. Differentially expressed genes (DEGs) associated with pigmentation were identified using RNA sequencing and validated by quantitative real-time polymerase chain reaction (RT-qPCR). The identified single nucleotide polymorphisms were studied using bioinformatics and iris color correlation analyses. A total of 485 DEGs were obtained, with 223 upregulated and 262 downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Thirty-two genes were annotated using the GO database. Three important pigment synthesis pathways (Notch signaling, melanogenesis, and tyrosine metabolism) were identified in quail iris tissue (P < 0.05). The expression levels of solute carrier family 45 member 2 (SLC45A2), tyrosinase-related protein 1, vitamin D receptor, opsin 5, and docking protein 5 were significantly different between Beijing white and Chinese yellow quail, as verified by RT-qPCR. The c.1061C>T mutation in SLC45A2, which caused a single amino acid change at position 354 (threonine to methionine), was significantly associated with iris color in Beijing white and Chinese yellow quail, and might be the main reason for the different iris colors between these two quail species.

Abstract Background Oculocutaneous albinism type 4 (OCA4) is a rare autosomal recessive disorder characterized by a reduction of pigmentation in skin, hair, and eyes, and OCA4 is mainly seen in the SLC45A2 gene variants. Objective To report a Chinese patient suspected of oculocutaneous albinism and identify the causing mutation. Methods Genomic DNA was extracted from the peripheral blood samples of the patient, his parents, and elder brother. Whole exome sequencing was performed in the family, and Sanger sequencing was then used to verify the mutations. Results Compound heterozygous variants, c.1304C>A (p.S435Y) and c.301C>G (p.R101G) in SLC45A2 gene, were detected in the proband, which were inherited from his father and mother respectively. Based on the ACMG guidelines, we can interpret the c.1304C>A (p.S435Y) variant as a suspected pathogenic variant and the c.301C>G (p.R101G) variant as a clinically significant unspecified variant. The diagnosis of OCA4 is confirmed. Conclusion We firstly reported this case of OCA4 with the compound heterozygous variants in the SLC45A2 gene. Our findings further enrich the reservoir of SLC45A2 mutations in OCA4.

Simple Summary: Understanding the molecular mechanisms involved in feather color formation is important because coloration is one of the most recognizable characteristics in chickens. In this study, after transcrip-tome sequencing of the wing and neck feather follicle tissues of chickens with different plumage colors, we retrieved differentially expressed genes (DEGs) with the same trends in both the wing and neck and then identified DEGs that may be associated with melanin deposition through GO and KEGG annotation and PPI analysis. Finally, we verified that two genes in chicken melanocytes, SLC45A2 and GPNMB, promote melanocyte melanin deposition in chickens. As an essential genetic and economic trait, chicken feather color has long been an important research topic. To further understand the mechanism of melanin deposition associated with coloration in chicken feathers, we selected feather follicle tissues from the neck and wings of chickens with differently colored feathers (yellow, sub-Columbian, and silver) for transcriptome analysis. We focused on genes that were expressed in both the wings and neck and were expressed with the same trends in breeds with two different plumage colors, specifically, SLC45A2, GPNMB, MLPH, TYR, KIT, WNT11, and FZD1. GO and KEGG enrichment analyses showed the DEGs were enriched in melanin-related pathways, such as tyrosine metabolic pathway and melanogenesis, and PPI analysis highlighted the genes SLC45A2 and GPNMB as associated with melanin deposition. Verification experiments in chicken melanocytes demonstrated that these two genes promote melanocyte melanin deposition. These data enrich our knowledge of the mechanisms that regulate chicken feather color. [ABSTRACT FROM AUTHOR]

Simple Summary: The research aims to investigate familial melanoma, a form of skin cancer that has a genetic predisposition. Melanoma is a dangerous cancer with a high potential for metastasis, and early detection is crucial for reducing its impact on patients. The study focuses on identifying specific genetic mutations associated with familial melanoma and correlating them with distinct dermoscopic patterns. By understanding the relationship between genetic mutations and dermoscopic features, the researchers aim to develop reference models to aid clinicians in identifying high-risk patients and their families. Establishing these correlations could lead to improved screening and a timely detection of new tumors in individuals with a family history of melanoma. Cutaneous melanoma is a highly aggressive skin cancer. It is estimated that 5% to 10% of the underlying mutations are hereditary and responsible for familial (or hereditary) melanoma. These patients are prone to the early development and higher risk of multiple melanomas. In recent years, an increasing number of genes have been identified thanks to genetic testing, allowing the subsequent surveillance of individuals at risk, yet it is still difficult to predict the presence of these mutations on a clinical basis. In this scenario, specific phenotypic and dermoscopic features could help clinicians in their identification. The aim of this work has been to correlate mutations to prevalent dermoscopic patterns, paving the way for reference models useful in clinical practice. In our cohort, out of 115 patients referred to genetic counseling for melanoma, 25 tested positive (21.7%) for critical mutations: CDKN2A (n = 12), MITF (n = 3), BAP1 (n = 1), MC1R (n = 3), PTEN (n = 1), TYR (n = 2), OCA2 (n = 1), and SLC45A2 (n = 2). The phenotype profiles obtained through the digital acquisition, analysis, and description of both benign and malignant pigmented lesions showed a predominance of the type II skin phenotype, with an elevated mean total nevus number (182 moles, range 75–390). As for dermoscopic features, specific mutation-related patterns were described in terms of pigmentation, areas of regression, and vascular structures. Although further studies with larger cohorts are needed, our work represents the beginning of a new approach to the study and diagnosis of familial melanoma, underlining the importance of clinical and dermoscopic patterns, which may constitute a reference model for each gene, enabling comparison. [ABSTRACT FROM AUTHOR]

Albinism is the most common color variation described in fish and is a fascinating trait of some ornamental fish species. Albino mutants can be generated by knocking out core genes affecting melanin synthesis like slc45a2 in several fish species. However, genetic mutation remains challenging for species with unknown genome information. In this study, we generated albino mutants in two selected ornamental fish species, royal farlowella (Sturisoma panamense), and redhead cichlid (Vieja melanura). For this purpose, we carried out phylogenetic analyses of fish slc45a2 sequences and identified a highly conserved region among different fish species. A pair of degenerate primers spanning this region was designed and used to amplify a conserved slc45a2 fragment of 340 bp from the two fish species. Based on the amplified sequences, a target site in the 6th exon was used for designing guide RNA and this targeted site was first verified by the CRISPR/Cas9 system in the zebrafish (Danio rerio) model for the effectiveness. Then, specific guide RNAs were designed for the two ornamental fish species and tested. Most of the injected larvae completely lost black pigment over the whole body and eyes. DNA sequencing confirmed a high degree of mutation at the targeted site. Overall, we described a fast and efficient method to generate albino phenotype in fish species by targeting the conserved 6th exon of slc45a2 gene for genome editing via CRISPR/Cas9 and this approach could be a new genetic tool to generate desirable albino ornamental fish. [ABSTRACT FROM AUTHOR]

ABSTRACT: Columbian coloration patterns in plumage are widespread phenomena in several standard breeds of poultry, such as the Columbian Plymouth Rock chicken. H line chicken plumage is generally a pure white except in the hackle, wing, and tail plumage, which coloration is very similar to the Columbian plumage pattern, but with the barring substituting for the black vertical striping. Thus, we refer to this plumage coloration as “sub-Columbian” pattern. However, the genetic basis of this phenotype remains unknown. Here, a F3 cross population between yellow plumage roosters and sub-Columbian plumage hens was constructed, for verifying sub-Columbian plumage was sex-linked dominant inheritance. To identify the candidate regions, F2 generation sub-Columbian plumage hens and yellow plumage hens with their parental lines were used for BSA-seq, and sub-Columbian plumage genes were mapped to a 10.46 Mb interval on chromosome Z. Remarkably, by transcriptome analysis of the neck and wing tip follicle tissues of the 2 plumage colors, we demonstrated that within the interval, only 1 gene, SLC45A2 expressed significant differently (P < 0.05). Through KASP, we identified L347M and A10331272T in solute carrier family 45 member 2 (SLC45A2), and B2 haplotype of cyclin-dependent kinase inhibitor 2A (CDKN2A), showed near complete association with the phenotype. Eventually, we designed a hybridization experiment for verifying the locus of sub-Columbian plumage, which is inherited through Z-linked dominant inheritance and is controlled by SLC45A2 and CDKN2A.

Albinism is a genetic disorder, present worldwide, caused by mutations in genes affecting melanin production or transport in the skin, hair and eyes. To date, mutations in at least 20 different genes have been identified. Oculo-cutaneous Albinism type IV (OCA4) is the most frequent form in Asia but has been reported in all populations, including Europeans. Little is known about the genotype-phenotype correlation. We identified two main phenotypes via the analysis of 30 OCA4 patients with a molecularly proven diagnosis. The first, found in 20 patients, is clinically indistinguishable from the classical OCA1 phenotype. The genotype-to-phenotype correlation suggests that this phenotype is associated with homozygous or compound heterozygous nonsense or deletion variants with frameshift leading to translation interruption in the SLC45A2 gene. The second phenotype, found in 10 patients, is characterized by very mild hypopigmentation of the hair (light brown or even dark hair) and skin that is similar to the general population. In this group, visual acuity is variable, but it can be subnormal, foveal hypoplasia can be low grade or even normal, and nystagmus may be lacking. These mild to moderate phenotypes are associated with at least one missense mutation in SLC45A2. [ABSTRACT FROM AUTHOR]

Body colour is an important economic trait for commercial fishes. Recently, a new colour morph displaying market-favoured yellow skin (termed as yellow-mutant, YM) of northern snakehead (Channa argus) was discovered in China. We confirmed that YM snakehead is an albino with complete loss of melanin in the skin and eyes by histological and ultrastructural observations, and inherited as a recessive Mendelian trait. By applying genomic analysis approaches, in combination with gene knockdown and rescue experiments, we suggested a non-sense mutation in slc45a2 (c.383G > A) is the causation for the YM snakehead. Notably, significantly higher levels of key melanogenesis genes (tyr, tyrp1, dct and pmel) and phospho-MITF protein were detected in YM snakehead than those in wild-type individuals, and the underlying mechanism was further investigated by comparative transcriptomic analysis. Results revealed that differential expressed genes involved in pathways like MAPK, WNT and calcium signalling were significantly induced in YM snakehead, which might account for the increased amount of melanogenesis elements, and presumably be stimulated by fibroblast-derived melanogenic factors in a paracrine manner. Our study clarified the genetic basis of colour variation in C. argus and provided the preliminary clue indicating the potential involvement of fibroblasts in pigmentation in fish.

As an essential genetic and economic trait, chicken feather color has long been an important research topic. To further understand the mechanism of melanin deposition associated with coloration in chicken feathers, we selected feather follicle tissues from the neck and wings of chickens with differently colored feathers (yellow, sub-Columbian, and silver) for transcriptome analysis. We focused on genes that were expressed in both the wings and neck and were expressed with the same trends in breeds with two different plumage colors, specifically, SLC45A2, GPNMB, MLPH, TYR, KIT, WNT11, and FZD1. GO and KEGG enrichment analyses showed the DEGs were enriched in melanin-related pathways, such as tyrosine metabolic pathway and melanogenesis, and PPI analysis highlighted the genes SLC45A2 and GPNMB as associated with melanin deposition. Verification experiments in chicken melanocytes demonstrated that these two genes promote melanocyte melanin deposition. These data enrich our knowledge of the mechanisms that regulate chicken feather color.

Summary: The Mangalitza lard‐type pig breed is well known for its fat appearance and curly hair, and it is mainly distributed in Eastern Europe. Four main lines were created in the nineteenth century by artificial selection: Blond Mangalitza, Black Mangalitza, Swallow‐Belly Mangalitza and Red Mangalitza. The Swallow‐Belly line has a black coat combined with yellow‐blond throat and underbelly. In the current work, we aimed to investigate if the colourations of Mangalitza pigs are genetically determined by one or a few loci whose frequencies have been modified by artificial selection. The results of selection scans, with HapFLK and BayeScan, and of a GWAS for coat colour highlighted the existence of one region on SSC16 (18–20 Mb) with potential effects on hair pigmentation (Red vs. Blond contrast). The analysis of the gene content of this region allowed us to detect the solute carrier family 45 member 2 (SLC45A2) locus as a candidate gene for this trait. The polymorphism of the SLC45A2 locus has been associated with reduced levels or the absence of melanin in several mammalian species. The genotyping of four missense polymorphisms evidenced that rs341599992:G > A and rs693695020:G > A SNPs are strongly but not fully associated with the red and blond coat colours of Mangalitza pigs, a result that was confirmed by performing a haplotype association test. The near fixation of alternative SLC45A2 genotypes in Red and Blond Mangalitza pigs provides a compelling example of the consequences of a divergent directional selection for coat colour in a domestic species. [ABSTRACT FROM AUTHOR]

To identify the mutational spectrum of 63 northwest Chinese probands with Oculocutaneous albinism (OCA), and identify correlations between phenotype and genotype. We recruited 63 clinically diagnosed with OCA patients in Gansu Provincial Maternal and Child Health Care Hospital. Mutation screening analysis was performed by direct sequencing and NGS-target sequencing to screen the variants on genes related to OCA. PolyPhen2 and PROVEN tools were used to predict the possible functional role of the novel variants. We assessed the pathogenicity of the novel mutations according to the clinical interpretation of genetic variants by ACMG/AMP 2015 guideline. By molecular testing, 56 of the OCA probands were diagnosed as OCA 1, three were OCA 2 and one was OCA 4. The most common variants of TYR were c.929insC(33.7%), c.896 G > A(12.5%), c.832 C > T(9.6%).We found five novel variants of TYR that have not previously been reported. We make an accurate diagnosis and classification for the OCA probands. Our result enlarged the mutational spectrum of TYR and SLC45A2. These findings could be useful for genetic counseling and gene diagnosis of OCA in Northwest of China. [ABSTRACT FROM AUTHOR]

Iris color is a prominent phenotypic feature of quail. To understand the mechanism of melanin deposition related to quail iris color, iris tissues were selected from Beijing white and Chinese yellow quail for transcriptome analysis. Differentially expressed genes (DEGs) associated with pigmentation were identified using RNA sequencing and validated by quantitative real-time polymerase chain reaction (RT-qPCR). The identified single nucleotide polymorphisms were studied using bioinformatics and iris color correlation analyses. A total of 485 DEGs were obtained, with 223 upregulated and 262 downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Thirty-two genes were annotated using the GO database. Three important pigment synthesis pathways (Notch signaling, melanogenesis, and tyrosine metabolism) were identified in quail iris tissue ( P < 0.05 ). The expression levels of solute carrier family 45 member 2 ( SLC45A2 ), tyrosinase-related protein 1, vitamin D receptor, opsin 5, and docking protein 5 were significantly different between Beijing white and Chinese yellow quail, as verified by RT-qPCR. The c.1061C>T mutation in SLC45A2 , which caused a single amino acid change at position 354 (threonine to methionine), was significantly associated with iris color in Beijing white and Chinese yellow quail, and might be the main reason for the different iris colors between these two quail species., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest., (2024 Japan Poultry Science Association.)

Non-syndromic oculocutaneous albinism (nsOCA) is an inherited disorder of melanin biosynthesis with autosomal recessive mode of inheritance, presenting either hypopigmented or depigmented skin, hair, and eyes. It is genetically heterogeneous with seven loci (OCA1–OCA7) reported to date. In the present study, we have reported three consanguineous families (A, B, C) presenting identical nsOCA phenotypes. Sanger sequencing revealed a novel [NM_000372.5: c.826 T > C, p.(Cys276Arg)] and a recurrent variant [NM_000372.5: c.832C > T, p.(Arg278∗)] in tyrosinase (TYR) in families A and B, respectively. Microsatellite marker-based homozygosity mapping linked family C to OCA4. Sequence analysis identified a novel insertion variant (NM_016180.5: c.1331_1332insA) in the SLC45A2. Further, in silico mutagenesis and dynamic simulation approaches revealed that a novel Cys276Arg variant abolished the cysteine bridge and might contribute toward decreased stability of the TYR protein. Our study expands the mutation spectrum of the TYR and SLC45A2 genes and emphasizes that molecular investigations are essential for accurate disease diagnosis.

Oculocutaneous albinism (OCA) is a genetic disorder characterized by skin, hair, and eye hypopigmentation due to a reduction or absence of melanin. Clinical manifestations include vision problems and a high susceptibility to skin cancer. In its non-syndromic form, OCA is associated with six genes and one chromosomal region. Because OCA subtypes are not always clinically distinguishable, molecular analysis has become an important tool for classifying types of OCA, which facilitates genetic counseling and can guide the development of new therapies. We studied eight Brazilian individuals aged 1.5–18 years old with clinical diagnosis of OCA. Assessment of ophthalmologic characteristics showed results consistent with albinism, including reduced visual acuity, nystagmus, and loss of stereoscopic vision. We also observed the appearance of the strabismus and changes in static refraction over a 2-year period. Dermatologic evaluation showed that no participants had preneoplastic skin lesions, despite half of the participants reporting insufficient knowledge about skin care in albinism. Whole-exome and Sanger sequencing revealed eight different mutations: six in the TYR gene and two in the SLC45A2 gene, of which one was novel and two were described in a population study but were not previously associated with the OCA phenotype. We performed two ophthalmological evaluations, 2 years apart; and one dermatological evaluation. To the best of our knowledge, this is the first study to perform clinical follow-up and genetic analysis of a Brazilian cohort with albinism. Here, we report three new OCA causing mutations.

Non-syndromic oculocutaneous albinism (nsOCA) is an inherited disorder of melanin biosynthesis with autosomal recessive mode of inheritance, presenting either hypopigmented or depigmented skin, hair, and eyes. It is genetically heterogeneous with seven loci (OCA1–OCA7) reported to date. In the present study, we have reported three consanguineous families (A, B, C) presenting identical nsOCA phenotypes. Sanger sequencing revealed a novel [NM_000372.5: c.826 T > C, p.(Cys276Arg)] and a recurrent variant [NM_000372.5: c.832C > T, p.(Arg278∗)] in tyrosinase (TYR) in families A and B, respectively. Microsatellite marker-based homozygosity mapping linked family C to OCA4. Sequence analysis identified a novel insertion variant (NM_016180.5: c.1331_1332insA) in the SLC45A2. Further, in silico mutagenesis and dynamic simulation approaches revealed that a novel Cys276Arg variant abolished the cysteine bridge and might contribute toward decreased stability of the TYR protein. Our study expands the mutation spectrum of the TYR and SLC45A2 genes and emphasizes that molecular investigations are essential for accurate disease diagnosis. [ABSTRACT FROM AUTHOR]

Summary: Eye colour genetics have been extensively studied in humans since the rediscovery of Mendel's laws. This trait was first interpreted using simplistic genetic models but soon it was realised that it is more complex. In this study, we analysed eye colour variability in a Large White pig population (n = 897) and report the results of GWASs based on several comparisons including pigs having four main eye colour categories (three with both pigmented eyes of different brown grades: pale, 17.9%; medium, 14.8%; and dark, 54.3%; another one with both eyes completely depigmented, 3.8%) and heterochromia patterns (heterochromia iridis – depigmented iris sectors in pigmented irises, 3.2%; heterochromia iridum – one whole eye iris of depigmented phenotype and the other eye with the iris completely pigmented, 5.9%). Pigs were genotyped with the Illumina PorcineSNP60 BeadChip and GEMMA was used for the association analyses. The results indicated that SLC45A2 (on chromosome 16, SSC16), EDNRB (SSC11) and KITLG (SSC5) affect the different grades of brown pigmentation of the eyes, the bilateral eye depigmentation defect and the heterochromia iridis defect recorded in this white pig population respectively. These genes are involved in several mechanisms affecting pigmentation. Significant associations for the eye depigmented patterns were also identified for SNPs on two SSC4 regions (including two candidate genes: NOTCH2 and PREX2) and on SSC6, SSC8 and SSC14 (including COL17A1 as candidate gene). This study provided useful information to understand eye pigmentation mechanisms, further valuing the pig as animal model to study complex phenotypes in humans. [ABSTRACT FROM AUTHOR]

Oculocutaneous albinism (OCA) is a genetic disorder characterized by skin, hair, and eye hypopigmentation due to a reduction or absence of melanin. Clinical manifestations include vision problems and a high susceptibility to skin cancer. In its non-syndromic form, OCA is associated with six genes and one chromosomal region. Because OCA subtypes are not always clinically distinguishable, molecular analysis has become an important tool for classifying types of OCA, which facilitates genetic counseling and can guide the development of new therapies. We studied eight Brazilian individuals aged 1.5–18 years old with clinical diagnosis of OCA. Assessment of ophthalmologic characteristics showed results consistent with albinism, including reduced visual acuity, nystagmus, and loss of stereoscopic vision. We also observed the appearance of the strabismus and changes in static refraction over a 2-year period. Dermatologic evaluation showed that no participants had preneoplastic skin lesions, despite half of the participants reporting insufficient knowledge about skin care in albinism. Whole-exome and Sanger sequencing revealed eight different mutations: six in the TYR gene and two in the SLC45A2 gene, of which one was novel and two were described in a population study but were not previously associated with the OCA phenotype. We performed two ophthalmological evaluations, 2 years apart; and one dermatological evaluation. To the best of our knowledge, this is the first study to perform clinical follow-up and genetic analysis of a Brazilian cohort with albinism. Here, we report three new OCA causing mutations. [ABSTRACT FROM AUTHOR]

Abstract Background Oculocutaneous albinism (OCA) is a group of heterogeneous autosomal recessive genetic disorder of melanin synthesis results in hypopigmented hair, skin, and eyes. OCA type 1, OCA type 2, and OCA type 4, which are respectively caused by mutations in TYR, OCA2, and SLC45A2 have high morbidity rates in Asia. Methods TYR, OCA2, and SLC45A2 mutation analysis was carried out on 18 nonconsanguineous OCA patients and four fetuses were included for prenatal diagnose. Three genes of all individuals were amplified by polymerase chain reaction and examined by Sanger sequencing. The pathogenicity of the detected mutations were analyzed by Mutation Taster, PolyPhen 2, and SIFT software, and the conservation of the substituted amino acids were analyzed by MEGA software. Results Eleven TYR mutations, three OCA2 mutations, and two SLC45A2 mutations were identified in 14 OCA type 1 patients, two OCA type 2 patients, and two OCA type 4 patients. c.1021A>G, p.R341G in TYR, c.1096_1104del, p.V366*, and c.1079C>T, p.S360F in OCA2 were novel. One of the four fetuses carried compound heterozygous mutation of TYR and became spontaneous abortion, the other three carried no mutations and appeared normal at birth. Conclusion In this study, specific clinical characteristics of OCA patients were described. Three novel pathogenic mutations were identified which will enrich the mutation spectrum of OCA, and the prenatal genetic screening in fetus at risk of OCA can provide vital information for genetic counseling.

Bird plumage coloration is a complex and multifactorial process that involves both genetic and environmental factors. Diverse pigment groups contribute to plumage variation in different birds. In parrots, the predominant green color results from the combination of 2 different primary colors: yellow and blue. Psittacofulvin, a pigment uniquely found in parrots, is responsible for the yellow coloration, while blue is suggested to be the result of light scattering by feather nanostructures and melanin granules. So far, genetic control of melanin-mediated blue coloration has been elusive. In this study, we demonstrated that feather from the yellow mutant rose-ringed parakeet displays loss of melanosome granules in spongy layer of feather barb. Using whole genome sequencing, we found that mutation in SLC45A2, an important solute carrier protein in melanin synthetic pathway, is responsible for the sex-linked yellow phenotype in rose-ringed parakeet. Intriguingly, one of the mutations, P53L found in yellow Psittacula krameri is already reported as P58A/S in the human albinism database, known to be associated with human OCA4. We further showed that mutations in SLC45A2 gene affect melanin production also in other members of Psittaculidae family such as alexandrine and plum-headed parakeets. Additionally, we demonstrate that the mutations associated with the sex-linked yellow phenotype, localized within the transmembrane domains of the SLC45A2 protein, affect the protein localization pattern. This is the first evidence of plumage color variation involving SLC45A2 in parrots and confirmation of associated mutations in the transmembrane domains of the protein that affects its localization., Competing Interests: Conflicts of interest The author(s) declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Approximately 1%–2% of cutaneous melanoma (CM) is classified as strongly familial. We sought to investigate unexplained CM predisposition in families negative for the known susceptibility genes using next‐generation sequencing of affected individuals. Segregation of germline variants of interest within families was assessed by Sanger sequencing. Several heterozygous variants in oculocutaneous albinism (OCA) genes: TYR, OCA2, TYRP1 and SLC45A2, were present in our CM cohort. OCA is a group of autosomal recessive genetic disorders, resulting in pigmentation defects of the eyes, hair and skin. Missense variants classified as pathogenic for OCA were present in multiple families and some fully segregated with CM. The functionally compromised TYR p.T373K variant was present in three unrelated families. In OCA2, known pathogenic variants: p.V443I and p.N489D, were present in three families and one family, respectively. We identified a likely pathogenic SLC45A2 frameshift variant that fully segregated with CM in a family of four cases. Another four‐case family harboured cosegregating variants (p.A24T and p.R153C) of uncertain functional significance in TYRP1. We conclude that rare, heterozygous variants in OCA genes confer moderate risk for CM. [ABSTRACT FROM AUTHOR]

Oculocutaneous albinism (OCA) type 4 is one of the most common types of albinism among Japanese population. In some patients who were clinically diagnosed with OCA, we have found a heterozygous pathological mutation in the coding region of SLC45A2, the gene responsible for OCA4, not leading to a DNA‐based diagnosis. In this study, we evaluated pathological variants in the promoter region of SLC45A2 in these patients. The results indicated that the majority of the patients had a 4‐bp deletion in the said region (c.‐492_489delAATG; GenBank accession number: NM_016180; rs984225803) in the contralateral allele. These patients displayed a mild phenotype, especially regarding eye manifestations. The results of the luciferase reporter assay and electrophoretic mobility shift assay supported the pathological role of the variant. In addition, four of 220 alleles in Japanese normal control subjects also showed the deletion variant, indicating that this variant could possibly be a skin color‐associated variant. [ABSTRACT FROM AUTHOR]

Columbian coloration patterns in plumage are widespread phenomena in several standard breeds of poultry, such as the Columbian Plymouth Rock chicken. H line chicken plumage is generally a pure white except in the hackle, wing, and tail plumage, which coloration is very similar to the Columbian plumage pattern, but with the barring substituting for the black vertical striping. Thus, we refer to this plumage coloration as "sub-Columbian" pattern. However, the genetic basis of this phenotype remains unknown. Here, a F3 cross population between yellow plumage roosters and sub-Columbian plumage hens was constructed, for verifying sub-Columbian plumage was sex-linked dominant inheritance. To identify the candidate regions, F2 generation sub-Columbian plumage hens and yellow plumage hens with their parental lines were used for BSA-seq, and sub-Columbian plumage genes were mapped to a 10.46 Mb interval on chromosome Z. Remarkably, by transcriptome analysis of the neck and wing tip follicle tissues of the 2 plumage colors, we demonstrated that within the interval, only 1 gene, SLC45A2 expressed significant differently (P < 0.05). Through KASP, we identified L347M and A10331272T in solute carrier family 45 member 2 ( SLC45A2 ), and B2 haplotype of cyclin-dependent kinase inhibitor 2A ( CDKN2A ), showed near complete association with the phenotype. Eventually, we designed a hybridization experiment for verifying the locus of sub-Columbian plumage, which is inherited through Z-linked dominant inheritance and is controlled by SLC45A2 and CDKN2A. [ABSTRACT FROM AUTHOR]

The Solute Carrier Family 45, Member 2 ( SLC45A2 ) gene encodes the Membrane-Associated Transporter Protein (MATP), which mediates melanin synthesis by tyrosinase trafficking and proton transportation to melanosomes. At least two SLC45A2 coding SNPs [E272K (rs26722) and L374F (rs16891982)] were reported influencing normal variation of human pigmentation. Here we aimed at evaluating the influence of haplotypes of 12 SNPs within SLC45A2 in the determination of eye, hair and skin pigmentation in a highly admixed population sample and comparing their frequencies with the ones found in data retrieved from the 1000 Genomes Project. To achieve this goal, 12 SLC45A2 SNPs were evaluated in 288 unrelated individuals from the Ribeirão Preto city area, Southeastern Brazil. SNPs were genotyped by PCR-RFLP or Allele-specific PCR, followed by polyacrylamide gel electrophoresis. Haplotypes of each individual were inferred by two independent computational methods, PHASE and Partition-Ligation–Expectation-Maximization (PL-EM) algorithms, and 34 different haplotypes were identified. The hp9 haplotype was the most frequent (58.3%) and was associated with the presence of blond/red hair, pale skin, blue eyes and freckles. All haplotypes significantly associated with dark or light pigmentation features harbor the 374L and 374F alleles, respectively. These results emphasize the role played by haplotypes at SLC45A2 in the determination of pigmentation aspects of human populations and reinforce the relevance of SNP L374F in human pigmentation. [ABSTRACT FROM AUTHOR]

Twenty-two variants (single nucleotide polymorphisms – SNPs) of the genes involved in hair pigmentation (OCA2, HERC2, MC1R, SLC24A5, SLC45A2, TPCN2, TYR, TYRP1) were genotyped in a group of 186 Polish participants, representing a range of hair colours (45 red, 64 blond, 77 dark). A genotype-phenotype association analysis was performed. Using z -statistics we identified three variants highly associated with different hair colour categories (rs12913832:A>G in HERC2, rs1805007:T>C and rs1805008:C>T in MC1R). Two variants: rs1800401:C>T in OCA2 and rs16891982:C>G in SLC45A2 showed a high probability of a relation with hair colour, although that probability did not exceed the threshold of statistical significance after applying the Bonferroni correction. We created and validated mathematical logistic regression models in order to test the usefulness of the sets of polymorphisms for hair colour prediction in the Polish population. We subjected four models to stratified cross-validation. The first model consisted of three polymorphisms that proved to be important in the associative analysis. The second model included, apart from the mentioned polymorphisms, additionally rs16891982:C>G in SLC45A. The third model included, apart from the variants relevant in the associating analysis, rs1800401:C>T in OCA. The fourth model consisted of the set of polymorphisms from the first model supplemented with rs16891982:C>G in SLC45A and rs1800401:C>T in OCA. The validation of our models has shown that the inclusion of rs16891982:C>G in SLC45A and rs1800401:C>T in OCA increases the prediction of red hair in comparison with the algorithm including only rs12913832:A>G in HERC2, rs1805007:T>C and rs1805008:C>T in MC1R. The model consisting of all the five above-mentioned genetic variants has shown good prediction accuracies, expressed by the area under the curve (AUC) of the receiver operating characteristics: 0.84 for the red-haired, 0.82 for the dark-haired and 0.71 for the blond-haired. A genotype-phenotype association analysis brought results similar to those in other studies and confirmed the role of rs16891982:C>G, rs12913832:A>G, rs1805007:T>C and rs1805008:C>T in hair colour determination in the Polish population. Our study demonstrated for the first time the possibility of a share of the rs1800401:C>T SNP in the OCA2 gene in hair colour determination. Including this single nucleotide polymorphism in the actual hair colour predicting models would improve their predictive accuracy. [ABSTRACT FROM AUTHOR]

Considering the hidden mode of inheritance of some coat-color-associated alleles, we investigated the presence/absence of coat-color-associated alleles in 1093 domestic horses of 55 breeds and 20 specimens of Przewalski's horse. For coat-color genotyping, allele specific PCR, pyrosequencing and Li-Cor analyses were conducted on 12 coat-color-associated alleles of five genes. Our data provide deep insight into the distribution of coat-color-associated alleles within breeds. We found that the alleles for the basic colorations (bay, black, and chestnut) are widely distributed and occur in nearly all breeds. Alleles leading to dilutions or patterns are rare in domestic breeds and were not found in Przewalski's horse. Higher frequencies of these alleles are only found in breeds that are selected for their expressed phenotypes (e.g., Kinsky horse, Lewitzer, Tinker). Nevertheless, our study produced strong evidence that molecular testing of the coat color is necessary for well-defined phenotyping to avoid unexpected colorations of offspring that can result in legal action. [ABSTRACT FROM AUTHOR]

Introduction. To investigate whether the membrane-associated transporter protein SLC45A2 is differentially expressed in the skin of sheep with different coat colors and to determine its correlation with coat color establishment in sheep. Material and methods. The expression of SLC45A2 in sheep skin samples with different coat colors was qualitatively and quantitatively analyzed by PCR amplification, RT-PCR, immunohistochemical staining and Western blotting. Results. A 193-bp SLC45A2 CDS sequence was successfully amplified from sheep skin samples with diverse coat colors. RT-PCR analysis revealed that SLC45A2 mRNA was expressed in all sheep skin samples tested, with relative expression levels of 512.74 ± 121.51 in black skin, 143.38 ± 119.31 and 1.36 ± 0.09 in black dots and white dots of piebald skin, respectively, and 1.02 ± 0.23 in white skin (p < 0.01**). Positive SLC45A2 protein bands were also detected in all skin samples by Western blot analysis, with relative expression levels of 0.85 ± ± 0.17** in black skin, 0.60 ± 0.05** and 0.34 ± 0.07 in black dots and white dots of piebald skin, respectively, and 0.20 ± 0.05 in white skin (p < 0.01**). Immunohistochemical assays revealed that SLC45A2 was expressed in the hair follicle matrix, the inner and outer root sheath, and the dermal papilla in the skin tissues with different coat colors. These patterns were quantified by optical density (OD) analysis, which yielded relative expression levels of 0.23 ± 0.11 in black skin, 0.19 ± 0.09 and 0.10 ± 0.03 in black dots and white dots of piebald skin, respectively, and 0.08 ± 0.01 in white skin (p < 0.05*). Conclusion. SLC45A2 is detectably expressed in sheep skin of all coat colors, though at significantly different levels. SLC45A2 may participate in the establishment of coat color by regulating the synthesis and trafficking of melanin.   [ABSTRACT FROM AUTHOR]

Body colour is an important economic trait for commercial fishes. Recently, a new colour morph displaying market-favoured yellow skin (termed as yellow-mutant, YM) of northern snakehead ( Channa argus ) was discovered in China. We confirmed that YM snakehead is an albino with complete loss of melanin in the skin and eyes by histological and ultrastructural observations, and inherited as a recessive Mendelian trait. By applying genomic analysis approaches, in combination with gene knockdown and rescue experiments, we suggested a non-sense mutation in slc45a2 (c.383G > A) is the causation for the YM snakehead. Notably, significantly higher levels of key melanogenesis genes ( tyr , tyrp1 , dct and pmel ) and phospho-MITF protein were detected in YM snakehead than those in wild-type individuals, and the underlying mechanism was further investigated by comparative transcriptomic analysis. Results revealed that differential expressed genes involved in pathways like MAPK, WNT and calcium signalling were significantly induced in YM snakehead, which might account for the increased amount of melanogenesis elements, and presumably be stimulated by fibroblast-derived melanogenic factors in a paracrine manner. Our study clarified the genetic basis of colour variation in C. argus and provided the preliminary clue indicating the potential involvement of fibroblasts in pigmentation in fish.

Albinism is a rare genetic disease associated with reduced melanin pigment biosynthesis in eyes, skin or hair. Clinically it is categorized, based on the affected tissue, into two types i.e ocular albinism (OA); when hypopigmentation influence the retinal pigment epithelium leaving skin and hair unaffected, and oculocutaneous albinism (OCA); when hypopigmentation occur in hair, skin and eye. Various genetic studies to date identified six genes (TYR, TYRP1, OCA2, SLC45A2, SLC24A5, C10orf11) and a locus (OCA5) for whom the candidate gene is yet to be known. All these reported genes, at the molecular level, are involved in melanin pigment biosynthesis. Among these reported genes, TYR and OCA2 are the most prevalent genetic factors of OCA in Pakistani population. The study will assist in understanding the molecular factors of OCA and melanin synthesis pathway to reduce its prevalence rate. The review aims to systematically reread and analyze the oculocutaneous albinism and its various types in the context of developed world as well as Pakistani community. [ABSTRACT FROM AUTHOR]

The introduction of engineered site-specific DNA endonucleases has brought precise genome editing in many model organisms and human cells into the realm of possibility. In zebrafish, loss-of-function alleles have been successfully produced; however, germ line transmission of functional targeted knock-ins of protein tags or of SNP exchanges have not been reported. Here we show by phenotypic rescue that the CRISPR/Cas system can be used to target and repair a premature stop codon at the albino (alb) locus in zebrafish with high efficiency and precision. Using circular donor DNA containing CRISPR target sites we obtain close to 50% of larvae with precise homology-directed repair of the albb4 mutation, a small fraction of which transmitted the repaired allele in the germ line to the next generation (3/28 adult fish). The in vivo demonstration of germ line transmission of a precise SNP exchange in zebrafish underscores its suitability as a model for genetic research. [ABSTRACT FROM AUTHOR]

The members of the solute carrier 45 (SLC45) family have been implicated in the regulation of glucose homoeostasis in the brain (SLC45A1), with skin and hair pigmentation (SLC45A2), and with prostate cancer and myelination (SLC45A3). However, apart from SLC45A1, a proton-associated glucose transporter, the function of these proteins is still largely unknown, although sequence similarities to plant sucrose transporters mark them as a putative sucrose transporter family. Heterologous expression of the three members SLC45A2, SLC45A3 and SLC45A4 in Saccharomyces cerevisiae confirmed that they are indeed sucrose transporters. [14C]Sucrose-uptake measurements revealed intermediate transport affinities with Km values of approximately 5 mM. Transport activities were best under slightly acidic conditions and were inhibited by the protonophore carbonyl cyanide m-chlorophenylhydrazone, demonstrating an H+ -coupled transport mechanism. Na+, on the other hand, had no effect on sucrose transport. Competitive inhibition assays indicated a possible transport also of glucose and fructose. Real-time PCR of mouse tissues confirmed mRNA expression of SLC45A2 in eyes and skin and of SLC45A3 primarily in the prostate, but also in other tissues, whereas SLC45A4 showed a predominantly ubiquitous expression. Altogether the results provide new insights into the physiological significance of SLC45 family members and challenge existing concepts of mammalian sugar transport, as they (i) transport a disaccharide, and (ii) perform secondary active transport in a proton-dependent manner. [ABSTRACT FROM AUTHOR]