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Concept: Albinism


Albino and hooded (or piebald) rats are one of the most frequently used laboratory animals for the past 150 years. Despite this fact, the origin of the albino mutation as well as the genetic basis of the hooded phenotype remained unclear. Recently, the albino mutation has been identified as the Arg299His missense mutation in the Tyrosinase gene and the hooded (H) locus has been mapped to the ∼460-kb region in which only the Kit gene exists. Here, we surveyed 172 laboratory rat strains for the albino mutation and the hooded (h) mutation that we identified by positional cloning approach to investigate possible genetic roots and relationships of albino and hooded rats. All of 117 existing laboratory albino rats shared the same albino missense mutation, indicating they had only one single ancestor. Genetic fine mapping followed by de novo sequencing of BAC inserts covering the H locus revealed that an endogenous retrovirus (ERV) element was inserted into the first intron of the Kit gene where the hooded allele maps. A solitary long terminal repeat (LTR) was found at the same position to the ERV insertion in another allele of the H locus, which causes the so called Irish (h(i)) phenotype. The ERV and the solitary LTR insertions were completely associated with the hooded and Irish coat patterns, respectively, across all colored rat strains examined. Interestingly, all 117 albino rat strains shared the ERV insertion without any exception, which strongly suggests that the albino mutation had originally occurred in hooded rats.

Concepts: DNA, Gene, Genetics, Mutation, Allele, Evolution, Point mutation, Albinism


The purpose of this study was to elucidate the molecular basis of ocular albinism type I in a Chinese pedigree.

Concepts: DNA, Mutation, Allele, Point mutation, Missense mutation, Nonsense mutation, Albinism, Ocular albinism


BACKGROUND: Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2. METHODS: We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. RESULTS: The siblings' phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood. CONCLUSIONS: This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

Concepts: Genetic disorder, Mutation, Allele, Evolution, Phenylketonuria, Zygosity, Albinism, Dominance


Albinism represents a group of genetic disorders with a broad spectrum of hypopigmentary phenotypes dependent on the genetic background of the patients. Oculocutaneous albinism (OCA) patients have little or no pigment in their eyes, skin and hair, whereas ocular albinism (OA) primarily presents the ocular symptoms, and the skin and hair color may vary from near normal to very fair. Mutations in genes directly or indirectly regulating melanin production are responsible for different forms of albinism with overlapping clinical features. In this study, 27 albinistic individuals from 24 families were screened for causal variants by a PCR-sequencing based approach. TYR, OCA2, TYRP1, SLC45A2, SLC24A5, TYRP2 and SILV were selected as candidate genes. We identified 5 TYR and 3 OCA2 mutations, majority in homozygous state, in 8 unrelated patients including a case of autosomal recessive ocular albinism (AROA). A homozygous 4-nucleotide novel insertion in SLC24A5 was detected in a person showing with extreme cutaneous hypopigmentation. A potential causal variant was identified in the TYRP2 gene in a single patient. Haplotype analyses in the patients carrying homozygous mutations in the classical OCA genes suggested founder effect. This is the first report of an Indian AROA patient harboring a mutation in OCA2. Our results also reveal for the first time that mutations in SLC24A5 could contribute to extreme hypopigmentation in humans.

Concepts: Genetics, Mutation, Allele, Evolution, Melanin, Human skin color, Albinism, Oculocutaneous albinism


To evaluate the benefits of phacoemulsification and intraocular lens implantation in patients with oculocutaneous albinism (OCA).

Concepts: Lens, Intraocular lens, Albinism, Oculocutaneous albinism


Colour patterns of adult fish are produced by several types of pigment cells that distribute in the dermis during juvenile development. The zebrafish, Danio rerio, displays a striking pattern of dark stripes of melanophores interspersed by light stripes of xanthophores. Mutants lacking either cell type do not form proper stripes, indicating that interactions between these two chromatophore types are required for stripe formation. A third cell type, silvery iridophores, participates to render a shiny appearance to the pattern, but its role in stripe formation has been unclear. Mutations in rose (rse) or shady (shd) cause a lack or strong reduction of iridophores in adult fish; in addition, the melanophore number is drastically reduced and stripes are broken up into spots. We show that rse and shd are autonomously required in iridophores, as mutant melanophores form normal sized stripes when confronted with wild-type iridophores in chimeric animals. We describe stripe formation in mutants missing one or two of the three chromatophore types. None of the chromatophore types alone is able to create a pattern but residual stripe formation occurs with two cell types. Our analysis shows that iridophores promote and sustain melanophores. Furthermore, iridophores attract xanthophores, whereas xanthophores repel melanophores. We present a model for the interactions between the three chromatophore types underlying stripe formation. Stripe formation is initiated by iridophores appearing at the horizontal myoseptum, which serves as a morphological landmark for stripe orientation, but is subsequently a self-organising process.

Concepts: Albinism, Melanocyte, Cuttlefish, Camouflage, Melanocortin 1 receptor, Chromatophore, Biological pigment, Cells


The skin pigment pattern of zebrafish is a good model system in which to study the mechanism of biological pattern formation. Although it is known that interactions between melanophores and xanthophores play a key role in the formation of adult pigment stripes, molecular mechanisms for these interactions remain largely unknown. Here, we show that Delta/Notch signaling contributes to these interactions. Ablation of xanthophores in yellow stripes induced the death of melanophores in black stripes, suggesting that melanophores require a survival signal from distant xanthophores. We found that deltaC and notch1a were expressed by xanthophores and melanophores, respectively. Moreover, inhibition of Delta/Notch signaling killed melanophores, whereas activation of Delta/Notch signaling ectopically in melanophores rescued the survival of these cells, both in the context of pharmacological inhibition of Delta/Notch signaling and after ablation of xanthophores. Finally, we showed by in vivo imaging of cell membranes that melanophores extend long projections towards xanthophores in the yellow stripes. These data suggest that Delta/Notch signaling is responsible for a survival signal provided by xanthophores to melanophores. As cellular projections can enable long-range interaction between membrane-bound ligands and their receptors, we propose that such projections, combined with direct cell-cell contacts, can substitute for the effect of a diffusible factor that would be expected by the conventional reaction-diffusion (Turing) model.

Concepts: Cell membrane, Model organism, Interaction, Pattern, Albinism, Eye color, Chromatophore, Biological pigment


Skin pigment patterns of vertebrates are a classic system for understanding fundamental mechanisms of morphogenesis, differentiation, and pattern formation, and recent studies of zebrafish have started to elucidate the cellular interactions and molecular mechanisms underlying these processes. In this species, horizontal dark stripes of melanophores alternate with light interstripes of yellow or orange xanthophores and iridescent iridophores. We showed previously that the highly conserved zinc finger protein Basonuclin-2 (Bnc2) is required in the environment in which pigment cells reside to promote the development and maintenance of all three classes of pigment cells; bnc2 mutants lack body stripes and interstripes. Previous studies also revealed that interactions between melanophores and xanthophores are necessary for organizing stripes and interstripes. Here we show that bnc2 promotes melanophore and xanthophore development by regulating expression of the growth factors Kit ligand a (Kitlga) and Colony stimulating factor-1 (Csf1), respectively. Yet, we found that rescue of melanophores and xanthophores was insufficient for the recovery of stripes in the bnc2 mutant. We therefore asked whether bnc2-dependent iridophores might contribute to stripe and interstripe patterning as well. We found that iridophores themselves express Csf1, and by ablating iridophores in wild-type and mutant backgrounds, we showed that iridophores contribute to organizing both melanophores and xanthophores during the development of stripes and interstripes. Our results reveal an important role for the cellular environment in promoting adult pigment pattern formation and identify new components of a pigment-cell autonomous pattern-generating system likely to have broad implications for understanding how pigment patterns develop and evolve.

Concepts: Pattern, Albinism, Melanocyte, Eye color, Camouflage, Melanocortin 1 receptor, Chromatophore, Biological pigment


Although classically associated with urban environments in invertebrates, melanism in terrestrial snakes is more often linked to occupancy of cool climates [1-3]. Thermal advantages to melanism do not apply in aquatic snakes [4], but although turtle-headed seasnakes (Emydocephalus annulatus) are banded or blotched across a wide geographic range [5], most individuals are melanic in polluted inshore bays of the Pacific island of New Caledonia [4]. Why has melanism evolved in these urban sites? Because trace elements bind to melanin, darker feathers enhance a bird’s ability to shed pollutants [6]. Reptiles in polluted habitats also accumulate trace elements, which are expelled when the skin is sloughed [7-11]. Might melanism enable snakes to rid themselves of harmful pollutants? We measured trace elements in sloughed skins of seasnakes from urban-industrial versus other areas and in dark versus light skin. For the latter comparison, we used data from laticaudine seasnakes (sea kraits Laticauda spp.), in which each individual is dark and light banded, facilitating comparisons between dark and light skin. As predicted, concentrations of trace elements were higher in snakes from urban-industrial areas and higher in darker than paler skin (even within the same slough). The rate of excretion of trace elements is further enhanced by higher frequencies of sloughing in melanic than banded individuals, even within the same population, because of higher rates of algal settlement on darker skin. Thus, melanism of seasnakes in polluted sites may facilitate excretion of trace elements via sloughing. VIDEO ABSTRACT.

Concepts: Skin, Melanin, Peppered moth evolution, Melanism, Albinism, Snake, Elapidae, Leucism


The corn snake (Pantherophis guttatus) is a new model species particularly appropriate for investigating the processes generating colours in reptiles because numerous colour and pattern mutants have been isolated in the last five decades. Using our captive-bred colony of corn snakes, transcriptomic and genomic next-generation sequencing, exome assembly, and genotyping of SNPs in multiple families, we delimit the genomic interval bearing the causal mutation of amelanism, the oldest colour variant observed in that species. Proceeding with sequencing the candidate gene OCA2 in the uncovered genomic interval, we identify that the insertion of an LTR-retrotransposon in its 11(th) intron results in a considerable truncation of the p protein and likely constitutes the causal mutation of amelanism in corn snakes. As amelanistic snakes exhibit white, instead of black, borders around an otherwise normal pattern of dorsal orange saddles and lateral blotches, our results indicate that melanocytes lacking melanin are able to participate to the normal patterning of other colours in the skin. In combination with research in the zebrafish, this work opens the perspective of using corn snake colour and pattern variants to investigate the generative processes of skin colour patterning shared among major vertebrate lineages.

Concepts: DNA, Gene, Genetics, Model organism, Melanin, Human skin color, Hybrid, Albinism