Absent Pigment Research Articles

The degradation of TYR variants derived from Chinese OCA families is mediated by the ERAD and ERLAD pathway

Oculocutaneous albinism (OCA) is a genetically heterogeneous group of autosomal recessive disorders, which presents with decreased or absent pigmentation in the hair, skin, and eyes. OCA1, as a subtype of OCA, is caused by mutations in the tyrosinase gene (TYR). In this study, we performed in vitro functional analysis of eight TYR variants (one frameshift variant: c.929dupC (p.Arg311Lysfs*7); seven missense variants: c.896G>A (p.Arg299His), c.1234C>A (p.Pro412Thr), c.1169A>G (p.His390Arg), c.937C>A (p.Pro313Thr), c.636A>T (p.Arg212Ser), c.623 T>G (p.Leu208Arg), c.1325C>A (p.Ser442Tyr)) identified in Chinese OCA families. TYR plasmids were transfected into HEK 293 T cells to explore the effects of TYR variants on their processing, protein expression, activity, and degradation. The results showed that all eight variants caused TYR to be retained in the endoplasmic reticulum (ER), processing was blocked, and TYR activity almost disappeared; the frameshift variant caused the size of the TYR protein to be reduced by about 30KD, and the protein expression of the remaining seven missense variants was reduced; the ER-associated degradation (ERAD) pathway mediates the degradation of TYR variants that occur on the Tyrosinase copper-binding domain, while the degradation of TYR variants that are not located on that domain may be mediated by a new degradation pathway——ER-to-lysosome-associated degradation (ERLAD). In summary, TYR variants affected their protein processing and activity, and may also induce ER stress and trigger degradation through the ERLAD pathway in addition to the ERAD degradation pathway, providing new insights into the potential pathogenic mechanism for OCA1 caused by TYR variants.

Dermoscopy as a Tool for Identifying Potentially Metastatic Thin Melanoma: A Clinical-Dermoscopic and Histopathological Case-Control Study.

Despite being early-stage tumors, thin cutaneous melanomas contribute significantly to mortality and have a rising incidence. A retrospective case-control study was performed to identify clinical-dermoscopic and histopathological variables linked to local and distant metastases in melanomas ≤0.8 mm. Data from 1 January 2000 to 22 June 2022 were analyzed from two Italian skin cancer referral centers. Sixteen patients with ≤0.8 mm melanomas developing metastases were studied compared to controls without metastases over 5 years. Statistical analysis involved Pearson's chi-squared test or Fisher's exact test. Of the 1396 cases, 1.1% progressed. The median diagnosis age was 49 (range 28-83), with 56.3% men and 43.7% women. The torso was the primary tumor site (43.7%). Clinically, lesions were pigmented (>10 mm diameter: 73.3%, ≥3 colors: 80%). Dermoscopically, the common features were white patches (73.3%), atypical vascular patterns (66.5%), blue-gray areas (60%) and absent pigment networks (60%). Histopathologically, all cases had adverse features like regression (87.4%), dermal mitoses (50%), a vertical growth phase (62.5%) and ulceration (12.5%). These findings were statistically significant compared to controls (p < 0.05). In ≤0.8 mm melanomas, specific clinical-dermoscopic traits might indicate higher metastatic potential when paired with adverse histopathological features.

Dermatoscopic Patterns in Vitiligo.

Vitiligo is a chronic, acquired autoimmune pigmentary skin disease, most times it can be diagnosed clinically. Dermoscopy can confirm vitiligo in a non-invasive way. It is a diagnostic technique that visualizes sub-macroscopic morphological structures which correspond with specific histological structures. It detects subtle changes in the pigment pattern, evaluates vitiligo activity, attempts of re-pigmentation, leucotrichia, and differentiates it from other hypo pigmentary disorders. Most dermatoscopic clues used to assess vitiligo activity are found at the perifollicular level in the center and edge of the lesion. Perifollicular pigmentation is present in both active lesions and treated pigmented lesions with treatment. However, perifollicular depigmentation represents poor response, in treated lesions, and poor prognosis in untreated ones. The center of the lesion has reduced and/or absent pigment network, in active and stable lesions. If on dermoscopy the center of the lesion shows islands of pigment, erythema, or telangiectasias, re-pigmentation is suggested. At the periphery of the lesion, unstable vitiligo usually shows up as a diffuse border, trichrome pattern, micro-Koebner/comet tail phenomenon, satellite lesions, or a tapioca sago pattern. In stable lesions it is more frequent to find well defined or trichromic border. Pigmented lesions commonly present sharp borders and marginal or perilesional hyperpigmentation.

Mesenchymal stem cell-derived exosomes and skin photoaging: From basic research to practical application.

Skin photoaging is a condition caused by long-term exposure to ultraviolet irradiation, resulting in a variety of changes in the skin, such as capillary dilation, increased or absent pigmentation, dryness, sagging, and wrinkles. Stem cells possess a remarkable antioxidant capacity and the ability to proliferate, differentiate, and migrate, and their main mode of action is through paracrine secretion, with exosomes being the primary form of secretion. Stem cell-derived exosomes contain a variety of growth factors and cytokines and may have great potential to promote skin repair and delay skin ageing. This review focuses on the mechanisms of UV-induced skin photoaging, the research progress of stem cell exosomes against skin photoaging, emerging application approaches and limitations in the application of exosome therapy. Exosomes derived from various stem cells have the potential to prevent skin photoaging. The combination with novel materials may be a key step for their practical application, which could be an important direction for future basic research and practical applications.

Evaluation of serum vitamin D concentration and blood eosinophil and basophil counts in patients with vitiligo: cross-sectional study from Rafsanjan and Zarand, Iran

Objective: Vitiligo is a chronic autoimmune depigmenting skin disorder. In this disease, the destruction of functional melanocytes can lead to reduced or absent pigmentation of the skin. Vitamin D deficiency has been reported in some autoimmune diseases. The association of eosinophils and basophils with autoimmune diseases has also been recently examined. Methods: The present study was performed to evaluate the serum vitamin D concentration and blood eosinophil and basophil counts in patients with vitiligo. Results: This descriptive cross-sectional study involved 30 patients with vitiligo. The average serum vitamin D concentration was significantly lower in the case group than in the control group (P = 0.01). Furthermore, the mean serum vitamin D concentration was significantly lower in women than in men (P = 0.03). The average eosinophil and basophil counts were not significantly different between the case and control groups. Discussion: The results of this study showed that the serum vitamin D concentration is low in patients with vitiligo. However, whether this reduction is a factor in the promotion of vitiligo or occurs after the onset of vitiligo remains unknown. Further studies on the serum vitamin D concentration in patients with vitiligo are needed to clarity this issue and develop effective treatments.

Assessment of DUS Traits in Rajmash (Phaseolus vulgaris L.) Genotypes: A Comprehensive Study on Genetic Diversity and Morphological Characteristics

The study was conducted at Dry Land Agriculture Research Station (DARS), Rangreth, Srinagar, Jammu and Kashmir, India aimed to comprehensively assess 40 genotypes, alongside 5 checks, for Distinctness, Uniformity and Stability (DUS) characterization. Employing an Augmented Block Design in the field in kharif season of April-August, 2022 and a Completely Randomized Design (CRD) in the laboratory from September–March 2023, the genotypes underwent evaluation for 21 DUS traits and 43 morphological, maturity, yield and quality traits. The evaluation followed descriptors specific to rajmash genotypes, utilizing frequency distribution based on “state” and “code” for each trait. The results indicated that majority of genotypes exhibited early flowering (&lt;50 days), with 91% displaying an absence of anthocyanin coloration. Erect plant types were prevalent (51.11%), with 51% and 60% being viny and determinate, respectively. Most genotypes featured medium-sized, light green, ovate leaves (46.66%, 53%, and 22%, respectively). White-colored flowers (48.88%) with striped petal surfaces (57.77%) and medium curvature (40.00%) were predominant. Seed-related traits, such as cordate pod shapes (51%) and concave pod sutures (50%), along with acute pod distal shapes (69%), were observed. Pale green pods (57.77%) and 76% of genotypes exhibiting pod stringiness were noted. Seed shapes were mainly kidney-shaped (60%), and absent pigmentation in pod shells (73%) was observed. Large-sized seeds (40%) with dark red testa color (44%) were common, and seed testa variegation was “absent” in 75.55% of genotypes.

Molecular genetic characterization of Congolese patients with oculocutaneous albinism

BackgroundOculocutaneous albinism (OCA) is an autosomal recessive genetic disorder associated with reduced or absent pigmentation in the skin, hair and eyes. OCA type 2 (OCA2) is the most common type in Sub-Saharan Africa, related to a recurrent 2.7 kb intragenic deletion. Genomic data from Congolese patients are lacking. We aimed to describe genetic causes of OCA2 in a cohort of Congolese persons with OCA, and explore possible genotype-phenotype correlations. MethodsA cross sectional study was conducted from January 2015 to December 2017 in Kinshasa, Democratic Republic of Congo (DRC). 165 Congolese unrelated families with non-syndromic OCA, identified through patients' associations, consented to participate to this study. All index cases were tested for the known 2.7 kb deletion involving the exon 7 of the OCA2 gene. Patients heterozygous for the deletion underwent Sanger sequencing of all exons and flanking sequences in the OCA2 gene. Family segregation was performed for candidate pathogenic variants. ResultsThe 2.7 kb deletion in the OCA2 gene was identified in 136/165 (82.4%) index cases, including 113 (68.5%) homozygotes and 23 (13.9%) heterozygotes. Sanger sequencing identified a pathogenic or likely pathogenic variant in the OCA2 gene in 12 out of 23 heterozygotes investigated (52.1%). Segregation analysis allowed us to locate the point mutation on the trans allele in the three patients from whom parental DNA was available. ConclusionThe OCA2 2.7 kb deletion is the major cause of non-syndromic OCA in Congolese patients recruited in this study, confirming results from other Sub-Saharan African populations. Several additional mutations were detected in OCA patient's heterozygote for the deletion, with to date no evidence for a second frequent founder mutation. The confirmation of a single mutation as the major cause will facilitate genetic counselling in this country.

Hypopigmented variant of intraoral common blue nevus. A rare entity

<h3>Objectives</h3> Blue nevus (BN) represents a clinicopathologically distinctive subset of benign melanocytic proliferations that may affect the oral mucosa. While diagnosis of conventional BN is usually straightforward, some of its rare variants may cause significant overlap with other entities, causing diagnostic pitfalls. Herein we present a case of hypopigmented variant of common BN and discuss the diagnostic challenges. <h3>Findings</h3> A 52 year-old male of unremarkable medical history was referred for the evaluation of a painless palatal lesion of unknown duration. The clinical examination revealed a well-circumscribed, slightly elevated lesion of normal hue with bluish halo involving the hard palate. With a provisional diagnosis of BN an excisional biopsy was decided. Histopathologically, a proliferation composed of scattered elongated, finely branching melanocytes, located deeply within the lamina propria with non-infiltrating pattern and associated with a variably desmoplastic stroma, was observed. Cytoplasmic pigmentation was detected only in a small subset of dendritic processes after serial sectioning. Minimal cytologic atypia and mild nuclear pleomorphism were also present in the absence of mitotic activity. In order to rule out malignant melanocytic tumors, especially desmoplastic melanoma, extensive immunohistochemical examination was performed. Melanocytes were strongly and diffusely positive for Melan-A, HMB-45, SOX-10, S-100, p16, and vimentin. The proliferation index Ki-67 was <5%. A final diagnosis of hypopigmented common BN was rendered. No signs of recurrence were noted during follow-up. <h3>Conclusions</h3> To this date, few cases of BN with minimal or absent pigmentation have been reported in the literature. However, this pattern is extremely rare in lesions affecting the oral mucosa. Hypopigmented BN lesions require careful evaluation to be distinguished primarily from desmoplastic melanoma. Immunohistochemistry may be helpful, especially when tumors with atypia, pleomorphism, infiltrative pattern and/or mitoses are encountered.

Mutations in TYR and OCA2 associated with oculocutaneous albinism in Pakistani families

BackgroundOculocutaneous albinism (OCA) is a genetically heterogeneous disorder of abnormal melanin synthesis, resulting in decreased or absent pigmentation of eyes, skin and hair. OCA has been classified based on genetic findings into seven subtypes (OCA 1–7). OCA1 is the most common subtype, accounting for 50% of cases worldwide (Hutton and Spritz, 2008; Rooryck et al., 2008), and is caused by mutations in the tyrosinase (TYR) gene. This study describes genetic investigations in 11 families from Pakistan with individuals with OCA. MethodsWhole genome SNP genotyping for autozygosity mapping was undertaken using the Illumina Human CytoSNP-12 array, and exome sequencing performed using the Illumina TruSight One sequencing panel. For individuals putatively linked to the TYR gene, dideoxy sequencing of TYR was performed using primers targeting all five coding exons and intron-exon splice sites to identify mutations in individuals diagnosed with OCA. Dideoxy sequencing was also performed to confirm the presence and cosegregation of TYR and OCA2 variants identified via exome sequencing. ResultsWe identified new and previously reported variations in TYR and OCA2 genes in 11 OCA families from Pakistan. One novel missense variant in TYR (NM_000372.4: c.240G>C; p.Trp80Cys), and three novel variants in OCA2 (missense variants NM_000275.2: c.2458T>C; p.Ser820Pro and c.1762C>T; p.Arg588Trp, as well as a frameshift variant c.408_409delTT; p.Arg137Ilefs*83), were observed in five OCA families. In addition, four previously identified variants in TYR (c.649C>T; p.Arg217Trp, c.1255G>A; p.Gly419Arg, c.832C>T; p.Arg278Ter, and c.132T>A p.Ser44Arg) and three previously identified variants in OCA2 (c.1045-15T>G, c.2020C>G; p.Leu674Val and c.1327G>A; p.Val443Ile) were identified in eight OCA families. All affected individuals displayed the cardinal features of OCA with white hair, pale skin, nystagmus and decreased vision. ConclusionsOur findings broaden the molecular spectrum associated with TYR and OCA2 mutations in Pakistani families, aiding the development and refinement of genetic diagnostic and counselling services in Pakistan.

A Novel Deletion Mutation of the TYR Gene in a Patient With Oculocutaneous Albinism Type 1A

Introduction: Oculocutaneous albinism (OCA) is a genetically heterogeneous autosomal recessive genetic disorder that is characterized by reduced or completely absent pigmentation in the hair, skin, and eyes. Case Presentation: In the present study, in order to verify OCA type 1A in a patient with clinical symptoms, and to study the variations of the TYR gene for the first time in southwest Iran, this gene was entirely sequenced. Conclusions: A novel homozygous mutation, the deletion of exons 1 - 5 on the TYR gene, was found on the molecular genetic testing of this patient. Exon 1 - 5 deletion on TYR causes a lack of the tyrosinase enzyme and disturbs the melanin biosynthesis process.

Changes of Epidermal Thickness in Vitiligo

The stratum corneum and epidermal pigmentation have protective roles against ultraviolet radiation. Because vitiligo skin lacks melanocytes and has no potential to produce pigment, some studies suggested that the epidermis in vitiligo skin is thicker than in normal skin. However, only a few studies investigated epidermal thickness changes in vitiligo, and some of these had relatively small sample sizes. Thus, this study aimed to compare epidermal thickness between vitiligo skin and adjacent normal-appearing skin in a large cohort. Photos of hematoxylin and eosin–stained slides of vitiligo skin and adjacent normal-appearing skin were taken under a microscope. The thicknesses of the stratum corneum, viable epidermis, and full epidermis were then measured by a computerized image analyzer. A total of 206 patients (412 sections) were included. There were significant differences between vitiligo skin and adjacent normal-appearing skin in the thickness of the stratum corneum (P = 0.009), viable epidermis (P = 0.001), and total epidermis (P = 0.001). An analysis comparing skin biopsied from a sun-exposed area versus a sun-protected area showed that the stratum corneum, viable epidermis, and total epidermis were significantly thicker in vitiligo skin than in normal-appearing skin in sun-exposed areas (P < 0.05), but not in sun-protected areas. We revealed that the epidermis was thicker in vitiligo skin than in normal-appearing skin, especially on sun-exposed skin, and that this may represent a photoprotective role compensating for absent pigmentation.

Adrenal Insufficiency Overview

Since Thomas Addison first reported adrenal insufficiency in the 19th century till nowadays still this entity shows challenging scenarios and recurrently reported as missed cases diagnosed retrograde after substantial delay. This is due to the wide variety and non-specific manifestations such as fatigue, malaise, loss of energy, loss of appetite and even occasionally present with mood disorders. Also there are exceptions for cardinal features of adrenal insufficiency such as absent pigmentation in secondary and some primary cases of Adrenal Insufficiency (A.I) and the cosyntropin test may give normal response if done early in secondary A.I. So in this article there is extensive literature review of the adrenal insufficiency covering a wide spectrum of areas starting from physiology back ground till the management lines and raising some important points such as the regenerative potential of the adrenal glands, the variety of presentations, the entity of pseudo-hypoadrenalism, some pitfalls in the diagnosis, possible self-recovery and management lines.

Tyrosinase gene mutations in the Chinese Han population with OCA1.

Oculocutaneous albinism (OCA) is a heterogeneous autosomal recessive genetic disorder that affects melanin synthesis. OCA results in reduced or absent pigmentation in the hair, skin and eyes. Type 1 OCA (OCA1) is the result of tyrosinase (TYR) gene mutations and is a severe disease type. This study investigated TYR mutations in a Chinese cohort with OCA1. This study included two parts: patient genetic study and prenatal genetic diagnosis. A total of 30 OCA1 patients were subjected to TYR gene mutation analysis. Ten pedigrees were included for prenatal genetic diagnosis. A total of 100 unrelated healthy Chinese individuals were genotyped for controls. The coding sequence and the intron/exon junctions of TYR were analysed by bidirectional DNA sequencing. In this study, 20 mutations were identified, four of which were novel. Of these 30 OCA1 patients, 25 patients were TYR compound heterozygous; two patients carried homozygous TYR mutations; and three were heterozygous. Among the ten prenatally genotyped fetuses, three fetuses carried compound heterozygous mutations and seven carried no mutation or only one mutant allele of TYR and appeared normal at birth. In conclusion, we identified four novel TYR mutations and showed that molecular-based prenatal screening to detect TYR mutations in a fetus at risk for OCA1 provided essential information for genetic counselling of couples at risk.

Hypothyroidism Complicating Nephropathy in a Diabetes Patient

We describe a patient with type 2 diabetes mellitus and autoimmune hypothyroidism who presented with elevated serum creatinine possibly due to subclinical rhabdomyolysis induced by hypolipidemic drug therapy in the background of diabetic nephropathy. Both hypothyroidism and rhabdomyolysis were asymptomatic in this case as evidenced by lack of classical clinical features of hypothyroidism despite elevated serum TSH and absent pigment cast in renal biopsy. The combination of diabetes mellitus and hypothyroidism is common in the general population and should not be forgotten in patients with diabetes and kidney disease.

Ocular Straylight in Albinism

Albinism is an inherited disorder that affects the melanin biosynthesis pathway, which results in reduced or absent pigment formation. This may lead to increased light transmission through the iris and more reflected light from the fundus. Both these effects contribute to the occurrence of ocular straylight. One aim of this study is to determine whether and how increased iris transmission and fundus reflection in subjects with albinism contributes to the occurrence of ocular straylight. The other aim is to determine the effect that an iris print-contact lens (CL) could have in terms of reducing the occurrence of ocular straylight. Ocular straylight was quantified by means of the straylight parameter s and measured as a function of angle and wavelength in 17 subjects with different types of albinism, none of whom wore an iris print-CL. The measurements were then repeated with the subjects wearing an iris print-CL to reduce the iris transmission component and thus the occurrence of ocular straylight. The contributions of transmission and reflectance components were estimated for each individual. Straylight level increase varied from normal (s ≈9) to severe (8x). In 15 cases, the reflectance component contributed s >3 to up to s = 17. In eight cases, the transmission component contributed s >3 to up to s = 101. A significant reduction in straylight was observed using an iris print-CL in six subjects with elevated straylight values. In the other 11 subjects with albinism, the iris print-CL had no significant effect on straylight because of the low values of the transmission component. This study gives insight into the effects of transmission and reflectance on the total measured straylight occurrence in subjects with albinism. Subjects experiencing increased ocular straylight values may benefit significantly from wearing iris print-CLs because transmission of light through the natural iris may cause a significant increase in straylight.

Telediagnosis and face‐to‐face diagnosis reliability for melanocytic and non‐melanocytic ‘pink’ lesions

Telemedicine is a worldwide healthcare practice that, during the last years, has dramatically reduced the time of consultation for patients. Teledermoscopy aids in the current management of skin cancers in general and particularly of melanoma; telemedicine and teledermoscopy give the chance to provide consultations with experts also by long distance. The purpose of this study is to determine the diagnostic reliability, according to interobserver agreement, between clinical and dermoscopic diagnosis of lesions with poor and/or absent pigmentation, comparing face-to-face diagnosis and telediagnosis. Forty-four lesions were examined by two different dermatologists with good and similar experience in the clinical field and dermoscopy. A store-and-forward teledermatological system, based on clinical and dermoscopic images, was done by the two skilled dermatologists. Our results underline that teledermoscopy of 'pink' lesions does not provide a similar degree of diagnostic accuracy as otherwise in face-to-face diagnosis perhaps due to the absence of typical criteria. Atypical skin lesions are characterized by the absence of typical dermoscopic patterns, and their teleconsultation does not always increase the diagnostic accuracy.

A Tyrosinase missense mutation causes albinism in the Wistar rat

Tyrosinase serves as a key enzyme in the synthesis of melanin. In humans mutations in the TYR gene are associated with type 1 oculocutaneous albinism (OCA1) that leads to reduced or absent pigmentation of skin, hair and eye. Various mutations causing OCA in man, mouse, rabbit and cattle have been identified throughout the Tyrosinase gene including nonsense, missense, frameshift and splice site alterations. Here we report a missense substitution at codon R299H in exon 2 of the Tyr gene in the albino Wistar rat. As this very exchange has already been described in OCA patients, our findings reinforce the significance of this region for normal catalytic activity of tyrosinase protein.

Microphthalmia-associated transcription factor (MITF) locus lacks linkage to human vitiligo or osteopetrosis: an evaluation.

The microphthalmia-associated transcription factor (MITF) locus has been mapped to human chromosome 3p12-p14.1, and encodes a basic helix-loop-helix zipper (bHLH-ZIP) protein homologous to a number of transcription factors. Numerous mutations at the mouse microphthalmia (mi) locus have been described, and all have reduced or absent pigmentation of the eyes, ears, and/or pelage, with some genotypes exhibiting small or absent eyes and osteopetrosis. The mivit/vit mutation at the mouse mi locus produces a postnatal depigmentation that resembles human vitiligo. The mice homozygous for this mi allele show a progressive loss of cutaneous, hair and ocular pigmentation with age. Vitiligo, an acquired depigmentary disorder, is characterized by patchy depigmentation of skin that generally begins around puberty and tends to become more progressive over time. There is suggestive evidence that human vitiligo may be inherited; however, the mode of inheritance is still debated and the pathogenesis is not clearly delineated. The human disorder osteopetrosis is characterized by a generalized net accumulation of skeletal mass and results from reduced osteoclast function in the bone. This is an inherited disorder and has been associated with mi in a mutant mouse. Therefore, the possible involvement of the MITF locus in the pathogenesis of either familial vitiligo or osteopetrosis was investigated. Linkage analysis was performed using microsatellite polymorphic markers D3S2465, D3S1261, and D3S1766 on genomic DNA from 26 families with vitiligo/osteopetrosis. D3S1261 is physically located at or near the MITF locus, while D3S2465 and D3S1766 are flanking the locus at about 17.5 cM genetic distance each side. Evidence from LOD score analysis surprisingly indicated that none of the families with vitiligo or osteopetrosis are linked to these short tandem repeat polymorphisms (STRPs). Thus, the human homolog (MITF) of the mouse mi gene, a good candidate gene at the phenotypic level, may not be involved in the pathogenesis of familial human vitiligo or osteopetrosis.

Ectopic expression of RET results in microphthalmia and tumors in the retinal pigment epithelium.

The retinal pigment epithelium (RPE) is essential for eye development by interacting with the overlaying neuroepithelium. Regulatory sequences of the gene encoding for tyrosinase-related protein 1 (TRP-1), linked to the lacZ reporter gene, lead to strong and specific beta-galactosidase expression in the RPE. We asked how the oncogene ret would affect this epithelial cell type during mouse development. We used the TRP-1 promoter to express ret in the developing RPE, and obtained transgenic mouse lines, which showed mild to severe microphthalmia. During development, the RPE changed to a stratified epithelium with reduced or absent pigmentation from E10.5 onward. In addition, proliferation of RPE cells and tumor formation were observed from E12.5 onward. These early events prevent closure of choroid fissure and lead to microphthalmia and secondary malformations after birth. We conclude that ret transgene expression in the RPE prevents normal differentiation of this epithelial layer and induces proliferation and tumor formation. The appearance of the microphthalmic phenotype underlines the requirement of a normally developed RPE for eye development.