Albinism and Melanosomal Abnormalities

Facts about Albino Dobermans

Albinism and Melanosomal Abnormalities

Ahmed, F., & Shire, J. G. M. (1985). Lysosomal mutations inhibit lipofuscinosis of the spleen in C57BL mice. Journal of Heredity, 76(4), 311-312. Beige (bg) and reduced pigmentation (rp) are recessive mutations affecting lysosomal function. Homozygosity for beige prevented lipofuscinosis of the spleen in C57BL mice, and its incidence was greatly reduced by homozygosity for rp. Dilute (d) homozygotes, with normal lysosomes, were susceptible to lipofuscinosis even though their melanosomes were more severely affected than those of beige mice.

Anderson, L. L., Paller, A. S., Malpass, D., Schmidt, M. L., & Berger, T. G. (1992). Chediak-Higashi syndrome in a black child. Pediatr Dermatol, 9(1), 31-6. Chediak-Higashi syndrome (CHS) is an uncommon genetic disorder with a constellation of clinical, pathologic, and immunologic manifestations.....Pathognomonic intracellular inclusions in white blood cells are well recognized; however, characteristic abnormal melanin aggregation into giant melanosomes also occurs, as can be readily seen by histologic evaluation of hair.....

Bertram, T., Coignoul, F., & Cheville, N. (1984). Ocular dysgenesis in Australian Shepherd dogs. Journal of the American Animal Hospital Association, 20(1), 177-182. Clinical, haematological, and microscopic studies were carried out on three littermate Australian Shepherds with abnormal coat colour and ocular dysgenesis; control dogs were one unaffected littermate and an unrelated mongrel. Affected dogs had abnormal vision but no other clinical or haematological defects. The severity of ocular lesions was correlated with the amount of white in the haircoat. Ocular lesions included retinal dysplasia, cataracts, scleral ectasia, staphyloma, and defects in pigment epithelium and choroid. Dysplastic retinae were thick, and the inner and outer nuclear and plexiform layers were folded into rosettes. Retinal changes in the unaffected littermate consisted of thinning of the inner plexiform and nerve fibre layer. Cysts were observed in the adrenal and pituitary glands of one affected dog. This study suggests that in the Australian Shepherd, occult manifestations of the ocular dystrophy syndrome may exist in dogs with normal coat colour and eye size, and the primary lesions of the retinal pigment epithelium consist of hypopigmentation and altered melanosome structure.

Boissy, R. E., & Nordlund, J. J. (1997). Molecular basis of congenital hypopigmentary disorders in humans: a review. Pigment Cell Res, 10(1-2), 12-24. Many specific gene products are sequentially made and utilized by the melanocyte as it emigrates from its embryonic origin, migrates into specific target sites, synthesizes melanin(s) within a specialized organelle, transfers pigment granules to neighboring cells, and responds to various exogenous cues. A mutation in many of the respective encoding genes can disrupt this process of melanogenesis and can result in hypopigmentary disorders. Following are examples highlighting this scenario. A subset of neural crest derived cells emigrate from the dorsal surface of the neural tube, become committed to the melanoblast lineage, and are targeted along the dorsal lateral pathway. The specific transcription factors PAX3 and MITF (microphthalmia transcription factor) appear to play a regulatory role in early embryonic development of the pigment system and in associated diseases (the Waardenburg syndromes). During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts. Lack or dysfunction of these receptors result in Apert syndrome, Hirschsprung syndrome and piebaldism, respectively. Once the melanocyte resides in its target tissue, a plethora of melanocyte specific enzymes and structural proteins are coordinately expressed to form the melanosome and to convert tyrosine to melanin within it. Mutations in the genes encoding these proteins results in a family of congenital hypopigmentary diseases called oculocutaneous albinism (OCA). The tyrosinase gene family of proteins (tyrosinase, TRP1, and TRP2) regulate the type of eumelanin synthesized and mutations affecting them result in OCA1, OCA3, and slaty (in the murine system), respectively. The P protein, with 12 transmembrane domains localized to the melanosome, has no assigned function as of yet but is responsible for OCA2 when dysfunctional. There are other genetically based syndromes, phenotypically resembling albinism, in which the synthesis of pigmented melanosomes, as well as specialized organelles of other cell types, is compromised. The Hermansky-Pudlak syndrome (HPS) and the Chediak-Higashi syndrome (CHS) are two such disorders. Eventually, the functional melanocyte must be maintained in the tissue throughout life. In some cases it is lost either normally or prematurely. White hair results in the absence of melanocytes repopulating the germinative hair follicle during subsequent anagen stages. Vitiligo, in contrast, results from the destruction and removal of the melanocyte in the epidermis and mucous membranes.

Boissy, R. E., Smyth, J. R., Jr., & Fite, K. V. (1983). Progressive cytologic changes during the development of delayed feather amelanosis and associated choroidal defects in the DAM chicken line. A vitiligo model. Am J Pathol, 111(2), 197-212. Newly hatched Gallus domesticus chicks of the delayed amelanotic (DAM) line have phenotypically normal down pigmentation. Functioning pigment cells are present in the down plumage, choroid, and retinal pigment epithelium. However, histologic and ultrastructural studies reveal that after hatching regenerating feather melanocytes synthesize melanosomes with abnormal, irregularly shaped surfaces and pigmented extensions. Eventually retraction of melanocytic dendrites and clumping of pigment occurs concomitantly with intracellular compartmentalization of the abnormal melanosomes. ....

Cellini, A., Morroni, M., Simonetti, O., & Offidani, A. (1998). Hypomelanosis of Ito: a case report with clinical and ultrastructural data. J Eur Acad Dermatol Venereol, 10(1), 73-6. Hypomelanosis of Ito (HI) is an uncommon skin disorder characterized by the presence of hypochromic areas associated with visceral abnormalities, the most common being neurological, muscular, skeletal and ocular. ....An electron microscopic study of a hypomelanotic area showed decreased functional activity in the melanocytes, which contained only a few rudimentary cytoplasmatic projections and poorly developed organelles. In addition, there was a reduction in the number of mature melanosomes.

Cole, D. E. (1985). Occulocutaneous hypopigmentation of Angus cattle. Dissertation Abstracts International, B, 45(10), 3128. 23 Angus cattle with oculocutaneous hypopigmentation had a chocolate-brown haircoat and slate-grey muzzle and teats. Irises were tan-coloured with a pale blue central area around the pupils, which severely constricted during daylight. The cattle were photophobic and reluctant to graze in sunlight, transmission electron microscopy of iris and ciliary body revealed a disorganized melanosomal matrix, immature melanosomes and flocculant melanin, thought to be the cause of the hypopigmentation. It was concluded from breeding trials that this condition was inherited as a simple autosomal recessive trait.

Collier, L. L., King, E. J., & Prieur, D. J. (1985). Aberrant melanosome development in the retinal pigmented epithelium of cats with Chediak-Higashi syndrome. Exp Eye Res, 41(3), 305-11. The Chediak-Higashi syndrome is a genetic disorder characterized by greatly enlarged cytoplasmic granules, including lysosomes and melanosomes. Eyes of humans and animals with Chediak-Higashi syndrome are hypopigmented to various degrees. Intraocular melanin granules vary in size, with some being massively enlarged. Electron microscopic examination of retinal pigmented epithelium of kittens with Chediak-Higashi syndrome disclosed a number of abnormalities of premelanosomes and melanosomes. Few premelanosomes were present. Most of the melanin granules were giant sized, but their structures varied. Some of the giant granules were composed of several premelanosomes and melanosomes in different stages of maturation. Others contained randomly oriented melanofilaments between melanosomes. There were also complex giant granules consisting of both melanosomal and lysosomal components.....

Collier, L. L., Prieur, D. J., & King, E. J. (1984). Ocular melanin pigmentation anomalies in cats, cattle, mink, and mice with Chediak-Higashi syndrome: histologic observations. Curr Eye Res, 3(10), 1241-51. The Chediak-Higashi syndrome (CHS) is a hereditary disorder of man, with the homologous condition reported in five animal species. Multiple defects, including oculocutaneous hypopigmentation, are present in individuals with this syndrome. Giant cytoplasmic granules, including melanosomes and lysosomes, are characteristic.....Melanin granules of abnormal sizes and shapes were present in neuroepithelial and uveal tissues of CHS animals of all four species. ....

Duran McKinster, C., Rodriguez Jurado, R., Ridaura, C., de la Luz Orozco Covarrubias, M., Tamayo, L., & Ruiz Maldonando, R. (1999). Elejalde syndrome--a melanolysosomal neurocutaneous syndrome: clinical and morphological findings in 7 patients. Arch Dermatol, 135(2), 182-6. BACKGROUND: Silvery hair and severe dysfunction of the central nervous system (neuroectodermal melanolysosomal disease or Elejalde syndrome) characterize this rare autosomal recessive disease. Main clinical features include silver-leaden hair, bronze skin after sun exposure, and neurologic involvement (seizures, severe hypotonia, and mental retardation). Large granules of melanin unevenly distributed in the hair shaft are observed. Abnormal melanocytes and melanosomes and abnormal inclusion bodies in fibroblasts may be present. Differential diagnosis with Chediak-Higashi syndrome and Griscelli syndrome must be done. ....

Frenk, E., & Calame, A. (1977). [Familial oculo-cutaneous hypopigmentation of dominant transmission due to a disorder in melanocyte formation. Association of Prader-Willi syndrome with a chromosome abnormality in one of the subjects involved]. Schweiz Med Wochenschr, 107(52), 1964-8. Four members of a Swiss family were affected with oculo-cutaneous hypopigmentation of dominant transmission which differed from the previously described cases of dominant oculo-cutaneous albinism by its ultrastructure. The hypopigmentation described here is characterized by the formation of numerous, but very small, melanosomes. Melanocytic tyrosinase activity was normal in light microscopy. However, on electron microscopy, tyrosinase activity was strong in premelanosomes of stage I only, and decreased rapidly in the later stages....

Frenk, E., & Lattion, F. (1982). The melanin pigmentary disorder in a family with Hermansky-Pudlak syndrome. J Invest Dermatol, 78(2), 141-3. The albinotic skin and hair of 2 patients with Hermansky-Pudlak syndrome were investigated by light and electron microscopy. Incubation of hairbulbs and epidermis in 1-dopa revealed a weak tyrosinase activity. The epidermal melanocyte population was of normal density. The most striking feature was the presence of numerous giant melanosomes resembling those mainly reported in various hyperpigmented skin lesions. The association of this melanosomal disorder with the platelet dysfunction and ceroid storage typical of the autosomal recessive Hermansky-Pudlak syndrome might provide new insights into the mechanism leading to formation of giant melanosomes.

Gahl, W. A., Potterf, B., Durham Pierre, D., Brilliant, M. H., & Hearing, V. J. (1995). Melanosomal tyrosine transport in normal and pink-eyed dilution murine melanocytes. Pigment Cell Res, 8(5), 229-33. Tyrosine is the endogenous substrate for melanin production within melanosomes, but the method of tyrosine transport into the melanosome has not been investigated. In the mouse, melanogenesis is disrupted by mutations in the p gene resulting in the pink-eyed dilution phenotype...We determined that normal (melan-a) melanosome-rich granular fractions take up 10 microns [3H]tyrosine at 21.1 +/- 6.1 (SEM, standard error of the mean) pmol/min/mg protein (N = 7) compared with 21.3 +/- 5.8 SEM pmol/min/mg protein (N = 5) for pink-eyed dilution, whose plasma membrane tyrosine transport was also normal (Km 89 microM; Vmax 302 pmol/min/mg cell protein). We also demonstrated that pink-eyed dilution melanosomes are immature by virtue of their low density, high hexosaminidase activity, and lack of pigment.....

Garner, A., & Jay, B. S. (1980). Macromelanosomes in X-linked ocular albinism. Histopathology, 4(3), 243-54. Examination of clinically normal skin from four patients with X-linked ocular albinism of the Nettleship-Falls type by light and electron microscopy revealed the presence of macromelanosomes in some melanocytes and keratinocytes. Measuring up to 5 micron many of the abnormal melanosomes showed a concentrically laminated structure suggestive of a phasic growth pattern. Epidermis from three female carriers contained similar but fewer macromelanosomes.....

Griscelli, C., Durandy, A., Guy Grand, D., Daguillard, F., Herzog, C., & Prunieras, M. (1978). A syndrome associating partial albinism and immunodeficiency. Am J Med, 65(4), 691-702. Two unrelated patients with partial albinism, frequent pyogenic infections and acute episodes of fever, neutropenia and thrombocytopenia are described. Their pigmentary dilution was characterized by large clumps of pigments in the hair shafts and an accumulation of melanosomes in melanocytes.....This pigmentary dilution, different from all other human albinisms, resembles the unique defect of the mutant dilute (d-d) mouse. Despite the presence of an adequate number of T and B lymphocytes, the patients were hypogammaglobulinemic, deficient in antibody production and incapable of manifesting delayed skin hypersensitivity or of rejecting skin grafts. Their leukocytes did not stimulate normal lymphocytes and could not generate cytotoxic cells during mixed leukocyte reaction. T lymphocytes of one patient were unable to exert a helper effect on the maturation of B lymphocytes into immunoglobulin-containing cells following in vitro stimulation with pokeweed mitogen. This suggests that the humoral deficiency might be secondary to a defect of helper T lymphocytes. ....

Beermann, F., Orlow, S. J., Boissy, R. E., Schmidt, A., Boissy, Y. L., & Lamoreux, M. L. (1995). Misrouting of tyrosinase with a truncated cytoplasmic tail as a result of the murine platinum (cp) mutation. Exp Eye Res, 61(5), 599-607. Mice homozygous for the platinum (cp) allele at the albino locus manifest severe oculocutaneous albinism despite the presence in vitro of tyrosinase activity at 25% wild-type levels. We demonstrate that the cp allele results from an A-->T substitution, changing a lysine residue at position 489 to a termination codon, with truncation of tyrosinase's cytoplasmic tail. In choroidal melanocytes of neonatal mutant mice, tyrosinase activity could be detected in the trans Golgi network, but was absent from melanosomes. Instead, it was detected in vesicles in the cell periphery and dendrites, and on the extracellular surface. In the retinal pigment epithelium, activity was present on the extracellular apical and basolateral surfaces. Our results demonstrate misrouting of a mutant tyrosinase lacking its cytoplasmic tail, providing an explanation for the severe effect of this mutation on ocular and cutaneous pigmentation. MIME: Albinism,-Oculocutaneous-enzymology; Choroid-ultrasonography; DNA-analysis; Melanocytes-ultrasonography; Membrane-Proteins-genetics; Mice-; Mice,-Inbred-C57BL; Microscopy,-Electron; Monophenol-Monooxygenase-chemistry; Monophenol-Monooxygenase-physiology; Polymerase-Chain-Reaction MJME: *Albinism,-Oculocutaneous-genetics; *Monophenol-Monooxygenase-genetics; *Pigment-Epithelium-of-Eye-enzymology; *Point-Mutation

Boissy, R. E., Zhao, Y., & Gahl, W. A. (1998). Altered protein localization in melanocytes from Hermansky-Pudlak syndrome: support for the role of the HPS gene product in intracellular trafficking. Lab Invest, 78(9), 1037-48 Issn: 0023-6837. Patients with Hermansky-Pudlak syndrome (HPS) exhibit moderate to mild hypopigmentation of the skin, hair, and eyes. To understand the inherent basis for this reduced pigmentation, pure cultures of melanocytes were derived using skin biopsies obtained from four patients with HPS. A nucleotide lesion in the HPS gene was identified in these individuals. Expression of HPS mRNA, parameters of melanin synthesis, characteristics in ultrastructural morphology, and expression of melanocyte-specific proteins were assessed in HPS melanocytes. The patients' cells appeared microscopically hypopigmented, and melanin content ranged from 0% to 50% of that for normal melanocytes. In cell lysates of HPS melanocytes, tyrosine hydroxylase activity was within the normal range, but in intact HPS melanocytes, it was almost half that of normal melanocytes. HPS melanocytes also appeared refractory to stimulators of melanization, eg, a combination of isobutyl methylxanthine and cholera toxin (IBMX/CT). HPS melanocytes contained many morphologically normal melanosomes, mostly Stage II with a few Stage I or III. After dihydroxyphenylalanine (DOPA) incubation, there appeared to be an equal number of Stage II and III melanosomes with the addition of a moderate number of Stage IV melanosomes. A characteristic ultrastructural feature of most HPS melanocytes was a variety of unusual cellular structures. These aberrancies include the following: (a) large membrane-bound complexes containing membranous chambers, unpigmented, and pigmented melanosomes, irregular deposits of DOPA reaction products, and granular/amorphous material sometimes resembling the cytoplasm; and (b) DOPA-positive rings delineated on either side by limiting membranes. The expression of tyrosinase-related protein-1 and granulophysin, a 40-kd membrane protein originally identified as a component of platelet-dense bodies that are undetectable in HPS, was assessed by light microscopy immunofluorescence. For both proteins, HPS melanocytes exhibited a large granular pattern of expression throughout the cell, which seems to correlate with the large membrane complexes observed ultrastructurally. These observations support the hypothesis that the HPS gene product is involved in organellogenesis. We propose that in the melanocyte, the HPS gene product regulates in part the trafficking of melanocyte-specific proteins from the trans-Golgi network to preformed premelanosomes. MIME: Albinism,-Oculocutaneous-pathology; Antigens,-CD-metabolism; Cells,-Cultured; Gene-Expression-physiology; Melanins-biosynthesis; Melanocytes-ultrastructure; Membrane-Proteins-genetics; Microscopy,-Electron; Mutation-genetics; Platelet-Membrane-Glycoproteins-metabolism; Tissue-Distribution MJME: *Albinism,-Oculocutaneous-metabolism; *Intracellular-Membranes-metabolism; *Melanocytes-metabolism; *Membrane-Proteins-physiology; *Proteins-metabolism

Boissy, R. E., & Nordlund, J. J. (1997). Molecular basis of congenital hypopigmentary disorders in humans: a review. Pigment Cell Res, 10(1-2), 12-24 Issn: 0893-5785. Many specific gene products are sequentially made and utilized by the melanocyte as it emigrates from its embryonic origin, migrates into specific target sites, synthesizes melanin(s) within a specialized organelle, transfers pigment granules to neighboring cells, and responds to various exogenous cues. A mutation in many of the respective encoding genes can disrupt this process of melanogenesis and can result in hypopigmentary disorders. Following are examples highlighting this scenario. A subset of neural crest derived cells emigrate from the dorsal surface of the neural tube, become committed to the melanoblast lineage, and are targeted along the dorsal lateral pathway. The specific transcription factors PAX3 and MITF (microphthalmia transcription factor) appear to play a regulatory role in early embryonic development of the pigment system and in associated diseases (the Waardenburg syndromes). During the subsequent development and commitment of the melanoblast, concomitant expression of the receptors for fibroblasts growth factor (FGFR2), endothelin-B (EDNRB), and steel factor (cKIT) also appears essential for the continued survival of migrating melanoblasts. Lack or dysfunction of these receptors result in Apert syndrome, Hirschsprung syndrome and piebaldism, respectively. Once the melanocyte resides in its target tissue, a plethora of melanocyte specific enzymes and structural proteins are coordinately expressed to form the melanosome and to convert tyrosine to melanin within it. Mutations in the genes encoding these proteins results in a family of congenital hypopigmentary diseases called oculocutaneous albinism (OCA). The tyrosinase gene family of proteins (tyrosinase, TRP1, and TRP2) regulate the type of eumelanin synthesized and mutations affecting them result in OCA1, OCA3, and slaty (in the murine system), respectively. The P protein, with 12 transmembrane domains localized to the melanosome, has no assigned function as of yet but is responsible for OCA2 when dysfunctional. There are other genetically based syndromes, phenotypically resembling albinism, in which the synthesis of pigmented melanosomes, as well as specialized organelles of other cell types, is compromised. The Hermansky-Pudlak syndrome (HPS) and the Chediak-Higashi syndrome (CHS) are two such disorders. Eventually, the functional melanocyte must be maintained in the tissue throughout life. In some cases it is lost either normally or prematurely. White hair results in the absence of melanocytes repopulating the germinative hair follicle during subsequent anagen stages. Vitiligo, in contrast, results from the destruction and removal of the melanocyte in the epidermis and mucous membranes. MIME: Acrocephalosyndactylia-etiology;

Courtens, W., Broeckx, W., Ledoux, M., & Vamosa, E. (1989). Oculocerebral hypopigmentation syndrome (Cross syndrome) in a Gipsy child. Acta Paediatr Scand, 78(5), 806-10 Issn: 0001-656x. A boy aged 2 years, born prematurely to Gipsy parents, presented with hypopigmentation severe encephalopathy with athetoid movements, bilateral ocular anomalies including cloudy corneas, iris atrophy and cataracts, as well as dental defects. Ultrastructural examination of the skin disclosed scare melanosomes. Although the neurologic and ocular anomalies might have been accounted for by his extreme prematurity, their association with hypomelanogenesis and dental defects support, in this patient the diagnosis of the oculocerebral hypopigmentation syndrome (Cross syndrome). MIME: Child,-Preschool; Skin-pathology; Syndrome- MJME: *Albinism-diagnosis; *Cataract-diagnosis; *Dental-Enamel-Hypoplasia-diagnosis; *Mental-Retardation-diagnosis

Dell'Angelica, E. C., Shotelersuk, V., Aguilar, R. C., Gahl, W. A., & Bonifacino, J. S. (1999). Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell, 3(1), 11-21 Issn: 1097-2765. Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defective lysosome-related organelles. Here, we report the identification of two HPS patients with mutations in the beta 3A subunit of the heterotetrameric AP-3 complex. The patients' fibroblasts exhibit drastically reduced levels of AP-3 due to enhanced degradation of mutant beta 3A. The AP-3 deficiency results in increased surface expression of the lysosomal membrane proteins CD63, lamp-1, and lamp-2, but not of nonlysosomal proteins. These differential effects are consistent with the preferential interaction of the AP-3 mu 3A subunit with tyrosine-based signals involved in lysosomal targeting. Our results suggest that AP-3 functions in protein sorting to lysosomes and provide an example of a human disease in which altered trafficking of integral membrane proteins is due to mutations in a component of the sorting machinery. MIME: Antigens,-CD-metabolism; DNA-Mutational-Analysis; Fibroblasts-; Flow-Cytometry; Melanosomes-metabolism; Membrane-Glycoproteins-metabolism; Membrane-Proteins-genetics; Membrane-Proteins-metabolism; Microscopy,-Fluorescence; Molecular-Sequence-Data; Platelet-Membrane-Glycoproteins-metabolism; Protein-Processing,-Post-Translational-genetics; RNA,-Messenger-metabolism MJME: *Albinism,-Oculocutaneous-genetics; *Nerve-Tissue-Proteins-genetics; *Phosphoproteins-genetics; *Proteins-metabolism

Eady, R. A., Gunner, D. B., Garner, A., & Rodeck, C. H. (1983). Prenatal diagnosis of oculocutaneous albinism by electron microscopy of fetal skin. J Invest Dermatol, 80(3), 210-2 Issn: 0022-202x. Oculocutaneous albinism was diagnosed prenatally by electron microscopic examination of fetal skin samples taken during fetoscopy at 20 weeks of gestation. Melanosome development in hair bulb melanocytes progressed no further than stage II, indicating a lack of melanin synthesis. In 4 age-matched control fetuses, numerous stage IV melanosomes, signifying active melanin synthesis, were identified. The diagnosis was confirmed after the pregnancy was terminated at 22 weeks. Examination of the fetal eye showed absence of pigment in the retinal epithelium and uvea at a stage when ocular melanogenesis would normally be active. This study shows that oculocutaneous albinism can be detected in the second trimester using similar techniques to those employed in the prenatal diagnosis of epidermolysis bullosa and ichthyosis. MIME: Adult-; Albinism-pathology; Melanins-deficiency; Pregnancy- MJME: *Albinism-diagnosis; *Fetoscopy-; *Melanocytes-ultrastructure; *Prenatal-Diagnosis; *Skin-ultrastructure

Fukuzawa, T., & Ide, H. (1986). Further studies on the melanophores of periodic albino mutant of Xenopus laevis. J Embryol Exp Morphol, 91, 65-78 Issn: 0022-0752. It is still unknown why dermal melanophores disappear during larval development, and why no or very few epidermal melanophores appear during and after metamorphosis, in Xenopus laevis showing periodic albinism (ap). To elucidate these points, we investigated the occurrence of depigmentation in mutant (ap/ap) melanophores during in vitro proliferation and the incidence of melanophore differentiation from mutant melanoblasts in the skin in vitro. During in vitro proliferation of mutant melanophores, ap-type melanosomes decreased in number gradually and instead the number of premelanosomes increased in the cells, which caused depigmentation at the light microscopic level in the culture. Depigmentation was observed only in mutant melanophores, and not in wild-type (+/+) melanophores. These results suggest that autonomous depigmentation of mutant dermal melanophores is the cause of the disappearance of these cells in vivo. Dopa-positive melanoblasts were demonstrated in both wild-type and mutant skins. However, the melanoblasts of metamorphosed mutant froglets did not differentiate in vitro, while those of wild-type froglets did. These results suggest that mutant melanoblasts in the skin of froglets lose the potency to differentiate into melanophores, and that this causes the lack of mutant melanophores in the froglets. The site of action of the ap gene is also discussed. MIME: Cell-Differentiation; Cells,-Cultured; Melanophores-cytology; Melanophores-ultrastructure; Metamorphosis,-Biological; Microscopy,-Electron; Mutation-; Periodicity-; Xenopus-laevis MJME: *Albinism-physiopathology; *Melanophores-physiology

Granholm, N. H., Japs, R. A., & Kappenman, K. E. (1990). Differentiation of hairbulb pigment cell melanosomes in compound agouti and albino locus mouse mutants (Ay, a, c2J; C57BL/6J). Pigment Cell Res, 3(1), 16-27 Issn: 0893-5785. Our objective was to determine using electron microscopy how nonagouti (a), lethal yellow (Ay), and albino (c2J) genes affect the program of mouse hairbulb melanosome differentiation; 1,921 hairbulb melanosomes from four genotypes (a/a C/C = B,Ay/a C/C = Y, a/a c2J/c2J = BA, and Ay/a c2J/c2J = YA) were scored for developmental stage, length, and width. Qualitative and quantitative electron microscopy revealed the following. An albino locus-induced diminution of melanosome size suggests that the albino locus is involved in structural features of melanosomes not directly related to the synthesis and deployment of tyrosinase. Ratio data on melanosome length-to-width confirm that the agouti locus determines melanosome shape, either spherical or elliptical; melanization is not required for melanosomes to achieve their agouti-locus-determined shapes. YA (Ay/a c2J/c2J) melanosomes, characterized by poorly organized matrices, absence of active tyrosinase, unusually large membrane invaginations, and significantly smaller dimensions than those of BA (a/a c2J/c2J), showed additive effects of both Ay and c2J alleles. These data suggest that the albino locus plays a structural as well as functional (tyrosinase) role in the differentiation of mouse hairbulb melanosomes. The agouti locus, even in the absence of melanization, directs melanosome shape either via synthesis and deployment of agouti-locus-encoded matrix proteins or by other structural factors. The additive effects of Ay and c2J alleles in compound YA mutants document the importance of specific interactions both functional and structural between agouti and albino loci. MIME: Albinism-genetics; Analysis-of-Variance; Cell-Differentiation; Genes,-Lethal; Genotype-; Hair-Color-genetics; Melanocytes-ultrastructure; Mice-; Mice,-Inbred-C57BL; Mice,-Mutant-Strains MJME: *Hair-cytology; *Melanocytes-cytology; *Pigmentation-genetics

Hull, M. T., & Epinette, W. W. (1984). Giant melanosomes in the dysplastic nevus syndrome. Electron microscopic observations. Dermatologica, 168(3), 112-6 Issn: 0011-9075. Multiple pigmented lesions including benign lentigines, typical nevi, and dysplastic nevi from 3 patients with the dysplastic nevus syndrome contained giant melanosomes (GM). Ultrastructurally the GM were composed of microvesicles, but lacked limiting membrane and filamentous internal structure. As such, they resembled the GM found in 4 other patients with dysplastic nevus syndrome, leopard syndrome and ocular albinism, but differed from those found in the cafe-au-lait spots of neurofibromatosis, nevus spilus, vitiliginous achromia, and certain animals. MIME: Lentigo-pathology; Microscopy,-Electron; Nevus,-Pigmented-genetics; Skin-pathology; Skin-Neoplasms-genetics; Syndrome- MJME: *Melanocytes-ultrastructure; *Nevus,-Pigmented-pathology; *Skin-Neoplasms-pathology

Jimbow, K., & Horikoshi, T. (1982). The nature and significance of macromelanosomes in pigmented skin lesions: their morphological characteristics, specificity for their occurrence, and possible mechanisms for their formation. Am J Dermatopathol, 4(5), 413-20 Issn: 0193-1091. The nature and significance of macromelanosomes, or giant melanosomes, in various pigmented skin lesions are characterized in this paper in terms of a) their morphological features, b) the specificity for their occurrence, and c) the possible mechanisms responsible for their formation. These granules occur most frequently in the skin and eyes of persons with x-linked ocular albinism of the Nettleship-Fall type, in the cafe-au-lait macules of neurofibromatosis, and in the pigmented macules of xeroderma pigmentosa. In these genetic disorders, skin biopsy for detection of the macromelanosomes could be valuable for confirming the diagnosis and for establishing who in asymptomatic families are carriers of the disorders. The macromelanosomes seem not to be formed solely by autophagic degradation of melanosomes, as has been proposed recently in studies of melanocytic nevi and lentigo simplex where aggregation of the macromelanosomes and melanosomes often do occur through autophagocytosis. The macromelanosomes in these genetic disorders may be formed by a more complex process in which the melanocytes are coded for aberrant melanogenesis with formation of precursor vacuoles similar to those of pheomelanosomes and with continuous accumulation of vesiculoglobular bodies. We suggest that vesiculoglobular bodies are crucial to the formation of macromelanosomes. MIME: Autophagocytosis-; Lentigo-pathology; Neurofibromatosis-1-pathology; Nevus,-Pigmented-pathology; Vacuoles-pathology MJME: *Melanocytes-ultrastructure

Jimbow, K., Fitzpatrick, T. B., Szabo, G., & Hori, Y. (1975). Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. J Invest Dermatol, 64(1), 50-62 Issn: 0022-202x. Subcellular defects of hypomelanosis in tuberous sclerosis (TS) (28 subjects) were compared by light and electron microscopy with oThere forms of congenital circumscribed hypomelanosis that occur in nevus depigmentosus (ND) (8 subjects) and in piebaldism (PB) (4 subjects), respectively. On the light microscopic level in both TS and ND, the population density of functioning melanocytes was normal but each perikaryon was small, and dopa activity was decreased. On the ultrastructural level, the hypomelanotic skin and hair of TS were associated with a decrease in the synthesis, melanization, and size of melanosomes; the decrease in the size of melanosomes resulted in the aggregation of melanosomes (i.e., a melanosome complex) in the keratinocytes in all the specimens examined. In ND, ther were no obvious changes in the size and melanocytes. the hypomelanosis of ND is related to the decreased synthesis and also, perhaps, abnormal transfer of melanosomes. In PB the hypomelanosis of the skin and hair results from the absence of functional melanocytes. The hypermelanotic areas of PB, however, characteristically contain melanocytes that synthesize abnormal (sperical and granular) as well as normal (ellipsoidal and lamellar) melanosomes. MIME: Adolescence-; Adult-; Caucasoid-Race; Child-; Child,-Preschool; Dopa-metabolism; Hair-ultrastructure; Infant-; Keratin-biosynthesis; Melanins-; Melanocytes-metabolism; Melanocytes-pathology; Melanocytes-ultrastructure; Microscopy,-Electron; Negroid-Race; Organoids-metabolism; Organoids-ultrastructure; Pigmentation-Disorders-pathology; Skin-ultrastructure MJME: *Albinism-pathology; *Nevus-pathology; *Pigmentation-Disorders-congenital; *Skin-Neoplasms-pathology; *Tuberous-Sclerosis-pathology

Kidson, S. H., Richards, P. D., Rawoot, F., & Kromberg, J. G. (1993). An ultrastructural study of melanocytes and melanosomes in the skin and hair bulbs of rufous albinos. Pigment Cell Res, 6(4 Pt 1), 209-14. We have examined hair bulb and skin melanocytes of rufous albinos from Southern Africa to further characterize this form of albinism. In the skin melanocytes we find both eumelanosomes and pheomelanosomes at various stages of melanization and, in addition, there appeared to be many aberrant incompletely melanized melanosomes. On average, rufous melanosomes are 30% smaller than normal black skin melanosomes. In the keratinocytes, the melanosomes are packaged into distinct aggregations, whereas in normal black skin, they occur singly. We suggest that the reddish skin color of these albinos is a consequence of an increase in the pheomelanin synthesis resulting in a raised pheomelanin/eumelanin ratio and that the aggregation of melanosomes results in a skin color slightly lighter than normal. In hair bulb melanocytes, only eumelanosomes were seen and these were mostly incompletely melanized. These findings correlate with our visual observations that the hair color of Southern African albinos is very pale (light brown or ginger). ....

Kikuchi, A., Shimizu, H., & Nishikawa, T. (1995). Epidermal melanocytes in normal and tyrosinase-negative oculocutaneous albinism fetuses. Arch Dermatol Res, 287(6), 529-33 Issn: 0340-3696. In tyrosinase-negative (type IA) oculocutaneous albinism (tyr(-) OCA) fetuses the development of melanocytes has not been fully elucidated. We analysed the distribution of melanocytes in skin samples from a fetus with tyr(-) OCA and from four normal fetuses. Skin samples obtained from 12 different body sites of each fetus were examined by transmission electron microscopy, an electron microscopic DOPA reaction test and immunohistochemistry. No S100 protein-positive cells were detected in any sample. There were fewer HMB-45-positive melanocytes in the skin of the tyr(-) OCA fetus than in the skin of normal fetuses from all body sites sampled. The greatest number of HMB-45-positive melanocytes was present in samples from the scalp of the normal fetuses and in those from the lower limbs of the tyr(-) OCA fetus. Very few melanocytes were detected immunohistochemically in samples from the soles and palms, though their presence was confirmed by transmission electron microscopy. The electron microscopic DOPA reaction test enhanced the melanization of melanocytes in samples from the normal fetuses but not in those from the tyr(-) OCA fetus. Postembedding immunogold electron microscopy using the HMB-45 antibody revealed that the HMB-45 antigen was localized mainly on stages I and II melanosomes. The presence of epidermal melanocytes in samples from all fetal body areas obtained at 17-21 weeks of gestation justifies the use of the electron microscopic DOPA reaction test in the prenatal diagnosis of tyr(-) OCA. MIME: Albinism,-Oculocutaneous-immunology; Albinism,-Oculocutaneous-metabolism; Epidermis-cytology; Fetus-immunology; Immunohistochemistry-; Langerhans-Cells-metabolism; Microscopy,-Electron; Neoplasm-Proteins-analysis MJME: *Albinism,-Oculocutaneous-pathology; *Fetus-cytology; *Melanocytes-metabolism; *Monophenol-Monooxygenase-metabolism

McCartney, A. C., Spalton, D. J., & Bull, T. B. (1985). Type IV melanosomes of the human albino iris. Br J Ophthalmol, 69(7), 537-41 Issn: 0007-1161. Electron microscopy of an iris biopsy specimen from a clinically tyrosinase-negative human albino demonstrated type IV mature melanosomes. Possible mechanisms for the formation in this condition of these organelles, which have not previously been described at this site, are discussed. MIME: Cell-Count; Microscopy,-Electron; Middle-Age MJME: *Albinism-pathology; *Iris-ultrastructure; *Melanocytes-ultrastructure; *Organoids-ultrastructure

Nakagawa, H., Hori, Y., Sato, S., Fitzpatrick, T. B., & Martuza, R. L. (1984). The nature and origin of the melanin macroglobule. J Invest Dermatol, 83(2), 134-9 Issn: 0022-202x. The melanin macroglobule (MMG), formerly called "macromelanosome," is a cytoplasmic spherical granule formed in the melanocyte, varying in size from one to several microns, much larger than normal ellipsoidal melanosomes. Although ultrastructural features of MMG have been adequately described in the past, there has been a disagreement about the formation process of MMG. In order to further elucidate the nature and origin of MMG, electron microscopic studies were conducted in several pigmentary disorders. Our findings included: (1) The most remarkable characteristics of MMG are (a) the pleomorphism of their internal structure and (b) the variation of their size. (2) MMG do not represent true melanosomes but unique forms of autolysosomes resulting from the fusion of autophagosomes (containing various numbers of melanosomes) with primary and/or secondary lysosomes. (3) MMG are retained within melanocytes or transferred to keratinocytes and to Langerhans cells in the epidermis, and to macrophages in the dermis in any of their developmental stages. After transfer, MMG can fuse with other heterolysosomes and probably increase in size in these cells. We regard melanosome complexes as but one step in an autophagic process within melanocytes which can, on occasion, produce MMG as residual bodies. MIME: Acid-Phosphatase-metabolism; Albinism-pathology; Autophagocytosis-; Biopsy-; Eye-Diseases-pathology; Histocytochemistry-; Melanocytes-enzymology; Microscopy,-Electron; Microscopy,-Electron,-Scanning; Monophenol-Monooxygenase-metabolism; Neurofibromatosis-1-ultrastructure; Nevus,-Pigmented-ultrastructure; Skin-Neoplasms-ultrastructure; Terminology- MJME: *Melanocytes-ultrastructure

O'Donnell, F. E., Jr., Hambrick, G. W., Jr., Green, W. R., Iliff, W. J., & Stone, D. L. (1976). X-linked ocular albinism. An oculocutaneous macromelanosomal disorder. Arch Ophthalmol, 94(11), 1883-92 Issn: 0003-9950. Three unrelated kindreds with the Nettleship-Falls type of X-linked ocular albinism were studied. Postmortem examination of the eyes of an affected man revealed the presence of macromelanosomes in the pigment epithelia. Skin biopsy specimens of this patient, seven other affected male, and nine carrier female kindred members revealed the presence of Fontana-positive and dopa oxidase-positive macromelanosomes within the epidermis and dermis. Although clinically this disorder has been considered to be a form of albinism confined to the eyes, these findings indicate that an unusual disturbance in melanosome production characterized by macromelanosome formation affects the skin and the eyes. Histopathologic study of the skin is a useful adjunct in the diagnosis of X-linked ocular albinism, both in the affected and the carrier states. Linkage studies confirmed the close association of the Xg blood group with this disorder. MIME: Adult-; Child-; Eye-Diseases-pathology; Infant,-Newborn; Melanins-; Melanocytes-pathology; Melanocytes-ultrastructure; Pedigree-; Skin-Diseases-pathology MJME: *Albinism-genetics; *Eye-Diseases-genetics; *Sex-Chromosomes; *Skin-Diseases-genetics

Pastural, E., Barrat, F. J., Dufourcq Lagelouse, R., Certain, S., Sanal, O., Jabado, N., Seger, R., Griscelli, C., Fischer, A., & de Saint Basile, G. (1997). Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nat Genet, 16(3), 289-92 Issn: 1061-4036. Griscelli disease (OMIM 214450) is a rare autosomal recessive disorder characterized by pigmentary dilution, variable cellular immunodeficiency and onset of acute phases of uncontrolled lymphocyte and macrophage activation, leading to death in the absence of bone-marrow transplantation. The pigmentary dilution is characterized by a diffuse skin pigmentation, silvery hair, large clumps of pigments in the hair shafts (Fig. 1) and an accumulation of melanosomes in melanocytes, with abnormal transfer of the melanin granules to the keratinocytes. Immunological abnormalities are characterized by absent delayed-type cutaneous hypersensitivity and an impaired natural-killer cell function. A similar disorder has been described in the dilute lethal mouse--which, however, differs by the occurrence of a severe neurological disorder. The dilute locus encodes myosin-Va, a member of the unconventional myosin family. Myosins bind actin and produce mechanical force through ATP hydrolysis. Some members of this family are thought to participate in organelle-transport machinery. Because of the phenotype resulting in the dilute mouse and because of their potential role in intracellular transport, unconventional myosin-encoding genes were regarded as candidate genes for Griscelli disease. Here we report that the Griscelli disease locus co-localizes on chromosome 15q21 with the myosin-Va gene, MYO5a, and that mutations of this gene occur in two patients with the disease. Griscelli disease is therefore a human equivalent of dilute expression in the mouse. MIME: Cells,-Cultured; Chromosome-Mapping; Disease-Models,-Animal; Haplotypes-; Hypersensitivity,-Delayed; Mice-; Mice,-Mutant-Strains; Molecular-Sequence-Data; Mutation-genetics; Myosin-chemistry; Pedigree-; Sequence-Analysis,-DNA MJME: *Albinism-genetics; *Chromosomes,-Human,-Pair-15-genetics; *Immunologic-Deficiency-Syndromes-genetics; *Myosin-genetics

Potterf, S. B., Furumura, M., Sviderskaya, E. V., Santis, C., Bennett, D. C., & Hearing, V. J. (1998). Normal tyrosine transport and abnormal tyrosinase routing in pink-eyed dilution melanocytes. Exp Cell Res, 244(1), 319-26 Issn: 0014-4827. The pink-eyed dilution phenotype in mice arises from mutations in the p gene; in humans, analogous mutations in the P gene result in oculocutaneous albinism type 2. Although the molecular mechanisms which underlie this phenotype remain obscure, it has been postulated that mutations in p result in defective tyrosine transport into murine melanosomes, resulting in hypopigmentation and diminished coat color. However, we previously reported no difference in melanosomal tyrosine transport in unpigmented, melanoblast-like pink-eyed dilution (pcp/pcp), and in pigmented (melan-a) murine melanocytes. In this study, we utilized melan-p1 cells, more differentiated pink-eyed dilution (pcp/p25H) melanocytes which can be induced to produce melanin, to characterize the melanogenic lesion(s) more definitively. Uptake of [3H]tyrosine into melan-a melanosomes did not differ significantly from uptake into melanosomes derived from melan-p1 melanocytes, further arguing against its critical role as a tyrosine transporter. Pink-eyed dilution melanocytes incubated in high tyrosine concentrations became extremely pigmented as they became confluent and secreted large amounts of black material into the medium. Total cellular tyrosinase activity in melan-p1 melanocytes was significantly higher than that in melan-a melanocytes (which are wild-type at the p locus), but the localization of tyrosinase to melanosomes was impaired in melan-p1 melanocytes compared to melan-a melanocytes. These results indicate that mechanisms other than deficient tyrosine transport are involved in the pink-eyed dilution phenotype and that this protein may serve a chaperone-like or stabilizing function in melanocytes. Copyright 1998 Academic Press. MIME: Albinism,-Oculocutaneous-genetics; Biological-Transport; Cell-Line; Melanins-biosynthesis; Melanocytes-enzymology; Mice-; Mice,-Inbred-C57BL; Mutation-; Phenotype-; Pigmentation-genetics; Subcellular-Fractions-enzymology; Tyrosine-physiology MJME: *Melanocytes-metabolism; *Membrane-Proteins-genetics; *Monophenol-Monooxygenase-metabolism; *Tyrosine-metabolism

Seldenrijk, R., Huijsman, K. G., Heussen, A. M., & van de Veerdonk, F. C. (1982). A comparative ultrastructural and physiological study on melanophores of wild-type and periodic albino mutants of Xenopus laevis. Cell Tissue Res, 222(1), 1-9 Issn: 0302-766x. Pigment of tail-fin melanophores in periodic albino Xenopus laevis tadpoles is dispersed in response to darkness and to alpha-MSH in a manner similar to wild-type melanophores. However, periodic albino tadpoles lack the response to different background conditions and the melatonin-induced aggregation in darkness. The tyrosinase activity in cells of the latter type tadpoles is weak compared to the wild-type cells. Ultrastructural examination of melanophores from periodic albino mutants and cells from wild-type tadpoles shows similar organelles at corresponding sites. A morphological difference can be observed in the fine structure of the melanosomes, which in albinos resembles an earlier stage of development. It is postulated that periodic albino Xenopus laevis possess the cellular mechanism to disperse pigment in the melanophores, but that under physiological conditions the release of alpha-MSH appears to be absent or scarce. MIME: Albinism-genetics; Albinism-veterinary; Light-; Melanins-biosynthesis; Monophenol-Monooxygenase-metabolism; Mutation-; MSH-physiology; Skin-Pigmentation MJME: *Albinism-pathology; *Melanophores-ultrastructure; *Xenopus-laevis-genetics

Semkin, V. I., & Mikhailov, I. N. (1984). [Skin changes in albinism in persons of the Negroid race (light- and electron-microscopy studies]. Arkh Patol, 46(6), 52-6 Issn: 0004-1955. The skin of the negroid race albinos is studied light- and electron-microscopically. Morphological alterations, as compared to control, consist of the horny layer thickening, increase of the cellularity in the epidermis, appearance of numerous pronounced tonofibrillar-keratohyaline complexes in the granular cells and a well developed network of dense bundles of tonofibrils in the spinous layer. Melanocytes and Langerhans cells are similar by their structure and number to those in the control. The protein skeletons of melanosomes in keratinocytes and melanocytes are practically unchanged but they are completely deprived of melanine biopolymer. The dermal macrophages do not contain a melanin pigment. The morphological features of the albinos epidermis, particularly the horny layer thickening, increase of the cellularity and the presence of pronounced tonofibrillar-keratohyaline complexes represent most likely a compensatory protective mechanism against ultraviolet radiation. MIME: Cell-Count; English-Abstract; Epidermis-ultrastructure; Langerhans-Cells-ultrastructure; Melanins-deficiency; Melanocytes-metabolism; Melanocytes-ultrastructure; Microscopy,-Electron MJME: *Albinism-pathology; *Epidermis-pathology; *Langerhans-Cells-pathology; *Melanocytes-pathology; *Negroid-Race

Shimizu, H., Ishiko, A., Kikuchi, A., Akiyama, M., Suzumori, K., & Nishikawa, T. (1994). Prenatal diagnosis of tyrosinase-negative oculocutaneous albinism by an electron microscopic dopa reaction test of fetal skin. Prenat Diagn, 14(6), 442-50 Issn: 0197-3851. An electron microscopic DOPA reaction test of fetal skin was used for the prenatal diagnosis of tyrosinase-negative oculocutaneous albinism (OCA). The subject was a 34-year-old Japanese woman in her second pregnancy. Her first child, born in 1982, had been previously examined and confirmed to have tyrosinase-negative OCA. The parents requested a prenatal diagnosis and we sampled skin from the upper trunk of the fetus. On conventional electron microscopy, the development of melanosomes in interfollicular melanocytes had progressed no further than stage II. Fetal skin samples incubated with L-DOPA solution indicated a lack of tyrosinase activity and showed that the melanosomes had not progressed beyond stage II. In skin samples from the trunks of three Japanese fetuses aborted for other reasons at 19-20 weeks of gestation, most premature melanosomes were further melanized to stage IV after incubation with L-DOPA solution. A prenatal diagnosis of tyrosinase-negative OCA was made. The parents requested a termination and skin biopsies of the abortus confirmed the diagnosis. This study shows that tyrosinase is normally present in melanocytes of the fetal epidermis at 20 weeks' gestation, and that the electron microscopic DOPA reaction test of a fetal skin biopsy specimen is safe and practical, and provides reliable information for making a prenatal diagnosis of tyrosinase-negative OCA in the second trimester. MIME: Adult-; Child-; Melanocytes-enzymology; Melanocytes-ultrastructure; Pregnancy-; Pregnancy-Outcome; Skin-enzymology; Skin-ultrastructure MJME: *Albinism,-Oculocutaneous-diagnosis; *Dopa-; *Microscopy,-Electron; *Prenatal-Diagnosis; *Skin-embryology

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