Decreased CREB phosphorylation impairs embryonic retinal neurogenesis in the Oa1-/- mouse model of Ocular albinism.

Mutations in the human Ocular albinism type-1 gene OA1 are associated with abnormal retinal pigment epithelium (RPE) melanogenesis and poor binocular vision resulting from misrouting of ipsilateral retinal ganglion cell (iRGC) axons to the brain. We studied the latter using wild-type (WT) and Oa1-/- mouse eyes. At embryonic stages, the WT RPE-specific Oa1 protein signals through cAMP/Epac1-Erk2-CREB. Following CREB phosphorylation, a pCREB gradient extends from the RPE to the differentiating retinal amacrine and RGCs. In contrast to WT, the Oa1-/- RPE and ventral ciliary-margin-zone, a niche for iRGCs, express less pCREB while their retinas have a disrupted pCREB gradient, indicating Oa1's involvement in pCREB maintenance. Oa1-/- retinas also show hyperproliferation, enlarged nuclei, reduced differentiation, and fewer newborn amacrine and RGCs than WT retinas. Our results demonstrate that Oa1's absence leads to reduced binocular vision through a hyperproliferation-associated block in differentiation that impairs neurogenesis. This may affect iRGC axon's routing to the brain.

Novel Variants of HPS6 Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of HPS6 Variants.

INTRODUCTION: Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of HPS6 variants and their genotype-phenotype correlations. METHODS: Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of family JX. The single coding exon of HPS6 was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of HPS6 reported in the literature were reviewed. RESULTS: We identified two different compound heterozygous truncating variants of HPS6 in probands with suspected OA from two independent families. The proband of family JX had c.1674dup and c.503-504del variants, and the other proband from family CZ had a nonsense variant of c.1114C>T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of HPS6 variants and revealed a significant overlap between CpG islands and the variants of HPS6, suggesting a potential link between DNA methylation and HPS6 variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease. CONCLUSION: Our research expands the spectrum of HPS6 variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.

Diagnostic Yield of Genetic Testing for Ocular and Oculocutaneous Albinism in a Diverse United States Pediatric Population.

The diagnostic yield of genetic testing for ocular/oculocutaneous albinism (OA/OCA) in a diverse pediatric population in the United States (U.S.) is unclear. Phenotypes of 53 patients who presented between 2006-2022 with OA/OCA were retrospectively correlated with genetic testing results. Genetic diagnostic yield was defined as detection of pathogenic/likely pathogenic variant(s) matching the anticipated inheritance for that gene-disease relationship. Variant reclassifications of those with variants of uncertain significance (VUS) and without positive diagnostic yield were completed. Overall initial genetic diagnostic yield of OA/OCA was 66%. There was no significant difference (p = 0.59) between race and ethnicities (Black (78%), White (59%), Hispanic/Latino (64%)); however, the diagnostic yield of OA (33%) was significantly lower (p = 0.007) than OCA (76%). Causative variants in OCA2 (28%) and TYR (20%) were most common. Further, Hermansky-Pudlak syndrome variants were identified in 9% of patients. Re-classification of VUS in non-diagnostic cases resulted in genetic diagnoses for 29% of individuals and increased overall diagnostic yield to 70% of all subjects. There is a high diagnostic yield of genetic testing of patients overall with OA/OCA in a diverse U.S. based pediatric population. Presence or absence of cutaneous involvement of albinism significantly affects genetic diagnostic yield.

Ocular findings and a comparative study of hair, skin and iris color in Chinese patients with albinism.

BACKGROUND: Oculocutaneous albinism (OCA) could be either non-syndromic or syndromic. There are significant challenges in clinically recognizing and differentiating Hermansky-Pudlak syndrome (HPS) from non-syndromic OCA. MATERIALS AND METHODS: In a prospective consecutive case series, 63 patients (less than 18 years old) with a molecular genetic diagnosis of albinism (except OCA1A), Ocular albinism (OA) and Hermansky-Pudlak syndrome seen over a 3-year period were evaluated and analyzed. Hair colour, iris colour was graded, compared and correlated with the degree of fundus pigmentation and foveal development. RESULTS: A total of 63 patients were evaluated. Forty-five patients had non-syndromic OCA (11 OCA1B, 24 OCA2, 9 OCA4, and 1 OCA6), 5 patients had OA and 13 patients had HPS. All 3 BLOC-related HPS categories were seen (1 with BLOC1, 7 with BLOC-2 and 5 with BLOC-3 related HPS). All patients with OA were hyperopic, had darker fundus pigmentation, but had poor foveal development. All HPS patients had lighter fundus pigmentation. The degree of fundus pigmentation correlated positively with the iris pigmentation and also with the foveal development only in OCA2. CONCLUSIONS: Careful observation of the phenotype by comparison of the skin, hair, iris colour, with the degree of fundus pigmentation and foveal development may help clinically differentiate HPS from OCA patients of Chinese ethnicity even in the absence of any bleeding tendency.

Choroidal and retinal thickness variations in ocular albinism.

Purpose: To study the retinal and choroidal thickness variations on enhanced depth imaging optical coherence tomography scans in ocular albinism (OA) and compare with age-matched healthy subjects. Methods: This retrospective observational study had 48 eyes of 24 patients diagnosed clinically as OA and age, sex, and axial length-matched control healthy subjects. All patients underwent detailed ophthalmic examination and a single-line horizontal-raster enhanced depth imaging - optical coherence tomography scan (Spectralis, Heidelberg Engineering). Retinal and choroidal thickness was measured, compared, and analyzed between the two groups. Mann-Whitney U test was used for analysis between the two groups. P < 0.05 was considered significant. Results: The mean age was 28.3 ± 11.6 and 29.9 ± 10.6 years in the OA group and control group, respectively. Spherical equivalents ranged from -8.5D to +10.5D in the OA group and from -8.0D to +10.0D in the control group. The mean axial length between the two groups (P = 0.652) were comparable. The average retinal thickness (272 ± 34.3 vs. 213 ± 13.8 µm; P < 0.001) was greater in the OA group as compared to controls. The mean choroidal thickness (184 ± 78.4 vs. 287 ± 46.4 µm; P < 0.001) was significantly thinner in the OA group. Conclusion: Acquisition of OCT scans in OA can be challenging. This study showed that the subfoveal retinal thickness and choroidal thickness measured across the scans were significantly different in the OA group compared to controls. In the future, more studies are required to evaluate the role of the choroid and its relationship to emmetropization in albinism.

The Many Faces of G Protein-Coupled Receptor 143, an Atypical Intracellular Receptor.

GPCRs transform extracellular stimuli into a physiological response by activating an intracellular signaling cascade initiated via binding to G proteins. Orphan G protein-coupled receptors (GPCRs) hold the potential to pave the way for development of new, innovative therapeutic strategies. In this review we will introduce G protein-coupled receptor 143 (GPR143), an enigmatic receptor in terms of classification within the GPCR superfamily and localization. GPR143 has not been assigned to any of the GPCR families due to the lack of common structural motifs. Hence we will describe the most important motifs of classes A and B and compare them to the protein sequence of GPR143. While a precise function for the receptor has yet to be determined, the protein is expressed abundantly in pigment producing cells. Many GPR143 mutations cause X-linked Ocular Albinism Type 1 (OA1, Nettleship-Falls OA), which results in hypopigmentation of the eyes and loss of visual acuity due to disrupted visual system development and function. In pigment cells of the skin, loss of functional GPR143 results in abnormally large melanosomes (organelles in which pigment is produced). Studies have shown that the receptor is localized internally, including at the melanosomal membrane, where it may function to regulate melanosome size and/or facilitate protein trafficking to the melanosome through the endolysosomal system. Numerous additional roles have been proposed for GPR143 in determining cancer predisposition, regulation of blood pressure, development of macular degeneration and signaling in the brain, which we will briefly describe as well as potential ligands that have been identified. Furthermore, GPR143 is a promiscuous receptor that has been shown to interact with multiple other melanosomal proteins and GPCRs, which strongly suggests that this orphan receptor is likely involved in many different physiological actions.

Long-term vision outcomes for patients with albinism and diabetic retinopathy.

PURPOSE: Albinism defines a group of genetic diseases which result from disordered melanin biosynthesis. Proliferative diabetic retinopathy (PDR) results from poorly controlled type 1 or 2 diabetes mellitus (DM) and can lead to blindness due to progressive neovascularisation. However, the treatment of PDR in patients with ocular/oculocutaneous albinism may be more challenging. In this study, we compared a group of patients with albinism and PDR, to a group with albinism and diabetes mellitus but no PDR, to examine the long-term implications. METHODS: Retrospective observational study included all patients with ocular albinism (OA) or oculocutaneous albinism (OCA) and DM who presented at a single specialist centre. Participants were allocated into either group 1 (eyes with PDR) or group 2 (all eyes without PDR). Statistical analysis was performed using SPSS V26.0. Between-group differences were investigated. RESULTS: Outcome data was available for 5 eyes from 3 participants in group 1 and 26 eyes from 13 participants in group 2. Despite interventions, a large and significant difference in vision at follow-up was observed between group 1 and group 2 (mean change in visual acuity: 1.11 (± 1.00) versus - 0.15 (± 0.46), respectively; p = < 0.0001). CONCLUSION: PDR is associated with poor long-term prognosis despite interventions for patients with albinism. Those without PDR appear to maintain stable vision. Alternative treatments for PDR and its complications may be required in this population. Measures to prevent the development of diabetic eye disease and progression towards PDR should be employed at an early stage.

GPR143 genotypic and ocular phenotypic characterisation in a Chinese cohort with ocular albinism.

PURPOSE: Ocular albinism type I (OA1) is caused by mutations in the GPR143 gene. The purpose of this study was to describe the clinical and genetic findings in 13 patients from 12 unrelated Chinese pedigrees with a pathogenic variant of the GPR143 gene. METHODS: Most patients underwent clinical examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, spectral domain optical coherence tomography, and full-field electroretinograms (ERG). A combination of molecular screening procedures, consisting of Sanger-DNA sequencing of GPR143 and targeted next-generation sequencing, was performed to identify each mutation. In silico programs were utilized to evaluate the pathogenicity of all the variants. RESULTS: The 13 patients (mean age 21.75 ± 16.63 years, range 1-54 years) all presented with congenital nystagmus, different extents of visual impairment, and severe foveal hypoplasia. Their BCVA was between 0.05 and 0.3 (decimal notation). The patients and obligate carriers exhibited different extents of mild depigmentation of the iris and fundus. We detected 11 distinct mutations in this patient cohort, including 7 novel mutations. Most (82%) were null mutations and included frameshift indel, nonsense, splicing effect, and large genomic DNA deletions, while missense mutations only accounted for 18%. CONCLUSIONS: Patients with GPR143 mutations all have congenital nystagmus, visual impairment, and foveal hypoplasia, whereas hypopigmentation in their iris and fundus is mild. They exhibit no evident genotype-phenotype correlations. GPR143 mutation screening is very important for establishing a precise diagnosis and for providing genetic counseling for patients and their families.

Prospective Study of the Phenotypic and Mutational Spectrum of Ocular Albinism and Oculocutaneous Albinism.

Albinism encompasses a group of hereditary disorders characterized by reduced or absent ocular pigment and variable skin and/or hair involvement, with syndromic forms such as Hermansky-Pudlak syndrome and Chédiak-Higashi syndrome. Autosomal recessive oculocutaneous albinism (OCA) is phenotypically and genetically heterogenous (associated with seven genes). X-linked ocular albinism (OA) is associated with only one gene, GPR143. We report the clinical and genetic outcomes of 44 patients, from 40 unrelated families of diverse ethnicities, with query albinism presenting to the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between November 2017 and October 2019. Thirty-six were children (≤ 16 years) with a median age of 31 months (range 2-186), and eight adults with a median age of 33 years (range 17-39); 52.3% (n = 23) were male. Genetic testing using whole genome sequencing (WGS, n = 9) or a targeted gene panel (n = 31) gave an overall diagnostic rate of 42.5% (44.4% (4/9) with WGS and 41.9% (13/31) with panel testing). Seventeen families had confirmed mutations in TYR (n = 9), OCA2, (n = 4), HPS1 (n = 1), HPS3 (n = 1), HPS6 (n = 1), and GPR143 (n = 1). Molecular diagnosis of albinism remains challenging due to factors such as missing heritability. Differential diagnoses must include SLC38A8-associated foveal hypoplasia and syndromic forms of albinism.

Genotype-phenotype associations in Danish patients with ocular and oculocutaneous albinism.

BACKGROUND: The study aimed to describe genotype-phenotype associations in patients with oculocutaneous and ocular-only albinism and to evaluate a set of diagnostic criteria proposed recently by Kruijt et al. MATERIALS AND METHODS: Genotype-phenotype associations in patients with a clinical diagnosis of albinism were studied based on imaging of hair and ocular features (nystagmus, iris color and translucency, fundus pigmentation and foveal development) and self-evaluated skin type. Patients were sub-grouped based on genetic findings. RESULTS: Patients with biallelic variants in TYR (n = 29), OCA2 (n = 22), other albinism genes (n = 13) or monoallelic variants in GPR143 (n = 13) were included as were 15 patients with a pure clinical diagnosis but no genetic findings. In descending order the most common findings were: foveal hypoplasia (any hypoplasia 95.2%, severe 88.0%), nystagmus (93.5%), iris translucency (any translucency 80.2%, moderate to severe 31.5%), misrouting on VEP (80.0%): fundus hypopigmentation (any hypopigmentation: 75.8%, severe 30.1%), fair skin type (73.8%), blue irides (62.0%), blonde hair (57.5%), and unpigmented eye lashes (39.1%). There were no phenotypic differences between the different genetic subgroups of albinism but patients with a pathogenic haplotype in TYR in combination with a classic variant had less iris translucency than patients with two classic variants in TYR. CONCLUSIONS: Ocular developmental features were the most common findings whereas phenotypic features related to pigmentation were less common findings but there were no genotype-phenotype correlations. All patients with a genetically confirmed diagnosis of albinism fulfilled the diagnostic criteria by Kruijt irrespective of genetic subtype.

Nistagmo secundario a albinismo con compromiso ocular en paciente femenina: un desafío diagnóstico / Nystagmus secondary to albinism with ocular involvement in a female: a diagnostic challenge

INTRODUCCIÓN: El nistagmo infantil es infrecuente y representa un desafío diagnóstico para el pediatra. El albinismo es una de sus principales causas, siendo difícil de sospechar en ausencia de compromiso cutáneo evidente, especialmente en pacientes femeninas, debido a que tipo de herencia del albinismo ocular. OBJETIVO: Describir un caso de nistagmo secundario a albinismo con compromiso ocular aislado en paciente femenina, para discutir el enfoque diagnóstico pediátrico. CASO CLÍNICO: Paciente fe menino de 3 semanas de vida, sin antecedentes mórbidos, derivada a neuropediatra y oftalmólogo por movimientos oculares paroxísticos desde las 2 semanas, con estudio con electroencefalograma e imágenes cerebrales normales. A los 3 meses se confirmó translucencia iridiana, nistagmo y astigmatismo hipermetrópico. La valuación dermatológica descartó compromiso cutáneo. Evolucionó con inclinación cefálica hacia abajo y retraso del desarrollo de la coordinación, fue manejada con lentes de corrección y kinesioterapia. A los 3 años, destacaba mejoría de la agudeza visual, disminución del nistagmo y neurodesarrollo normal. La evaluación oftalmológica de ambos padres fue normal y no había antecedentes de nistagmo o albinismo en la familia. Por decisión de los padres no se realizó estudio genético. CONCLUSIÓN: El diagnóstico de nistagmo secundario a compromiso ocular del albinismo, aún en ausencia de afección cutánea, es clínico; el estudio genético permite confirmar la etiología, sin ser un examen imprescindible, a menos que se considere la planificación familiar. La pesquisa oportuna e intervención multidisciplinaria determinan un mejor pronóstico.

INTRODUCTION: Infantile nystagmus is an infrequent condition that represents a diagnostic challenge for the pediatri cian. Albinism is one of its main causes, being difficult to suspect in the absence of evident cutaneous involvement, especially in female patients, due to the inheritance type of ocular albinism. OBJECTIVE: To describe a case of nystagmus secondary to albinism with isolated ocular involvement in a female patient, in order to provide tools for pediatric approach and diagnosis. CLINICAL CASE: Three- weeks-old female patient, without morbid history, referred to a pediatric neurosurgeon and ophthal mologist due to paroxysmal eye movements since 2 weeks of age. The electroencephalogram and brain images were normal. In follow-up monitoring at 3 months, iris translucency, nystagmus, and hypermetropic astigmatism were confirmed. Dermatologic evaluation ruled out cutaneous invol vement. The patient developed cephalic downward inclination and coordination development de lay was confirmed, the patient was handled with corrective lenses and kinesiotherapy. In follow-up monitoring at 3 years, there was an improvement in visual acuity, decreased nystagmus and normal neurodevelopment. The ophthalmological evaluation of both parents was normal and there was no history of nystagmus or albinism in the family. Upon her parents' decision, no genetic study was ca rried out. CONCLUSION: The diagnosis of nystagmus secondary to ocular albinism, even in the absence of cutaneous involvement, is clinical. The genetic study allows confirming the etiology, without being an essential examination, unless family planning is considered. Timely research and multidisciplinary intervention determine a better prognosis.

A novel GPR143 mutation in a Chinese family with X­linked ocular albinism type 1.

Ocular albinism type 1 (OA1) is a genetic disorder characterized by reduced eye pigmentation and nystagmus, which is often accompanied by decreased visual acuity, strabismus and other symptoms, whereas skin and hair color remain normal. The present study aimed to assess the clinical features and perform genotype analysis of a family with OA1, and to determine the disease­causing mutation. A total of 18 family members (nine affected patients and nine normal subjects) from Hainan, China, were recruited to the present study in December 2017. A detailed clinical ophthalmic examination was performed for all participants, including a visual acuity test, anterior segment slit lamp examination, eye fundus examination and optical coherence tomography. Mutations in the G protein­coupled receptor 143 (GPR143) gene were determined by DNA sequencing assays and polymerase chain reaction assays for deletions; all exon coding sequences, exons at the 5'­ and 3'­ends, and non­coding region sequences of intron splicing were assessed. Within the family, nine male patients exhibited disease occurrence at the age of 0­6 months. All patients presented with different degrees of iris depigmentation, horizontal jerk nystagmus, foveal hypoplasia and reduced visual acuity. The fundus of only one patient exhibited choroid coloboma; in the remaining patients, their fundi exhibited different degrees of irregular retinal depigmentation. The mutation c.360+5G>T in the GPR143 gene was identified in this family. In conclusion, the present study identified the splicing mutation c.360+5G>T in the GPR143 gene in a Chinese family with OA1 and successfully identified the site. To the best of our knowledge, there have been no previous reports regarding this mutation in any major genome databases; therefore, this outcome may enrich the mutation spectrum of the GPR143 gene.

Overexpression of the gene product of ocular albinism 1 (GPR143/OA1) but not its mutant forms inhibits neurite outgrowth in PC12 cells.

Neurite outgrowth is a complex differentiation process regulated by external and/or internal mechanisms. Among external mechanisms, G-protein coupled receptors (GPCRs) have been implicated in this process, but the pathways involved are not fully understood. L-3,4-dihydroxyphenylalanine (l-DOPA) is considered to be inert by itself, and to relieve Parkinson's disease through its conversion to dopamine. We have proposed that l-DOPA acts as a neurotransmitter. GPR143, the gene product of ocular albinism 1 (OA1), was identified as a receptor for l-DOPA. OA1 is an X-linked disorder characterized by all typical visual anomalies associated with hypopigmentation and optic misrouting, resulting in severe reduction of visual acuity. However, the molecular basis for this phenotype remains unknown. To study the function of GPR143, we investigated the phenotypic effect of overexpression of GPR143 in pheochromocytoma (PC12) cells treated with nerve growth factor. Overexpression of mouse GPR143 inhibited neurite outgrowth, and the effect was mitigated by l-DOPA cyclohexylester, an antagonist for l-DOPA. Furthermore, knockdown of G-protein Gα13 attenuated mouse GPR143 induced inhibition of neurite outgrowth. Human wild-type (wt) GPR143 also inhibited neurite outgrowth, but its mutants did not mimic the effect of wt GPR143. Our results provide a mechanism for axon guidance phenotype in ocular albinism 1.

Ocular albinism with mutation in GPR143: Findings in wide-field autofluorescence and optical coherence tomography. / Albinismo ocular con mutación en GPR143: hallazgos en autofluorescencia de campo amplio y tomografía de coherencia óptica.

A 12 year-old boy who consulted due to nystagmus and low vision from birth. His mother also consulted for low vision of the right eye since she was a child, which worsened recently. The physical examination revealed no alterations in skin and hair pigmentation. In the examination of the anterior segment of the child, areas of slight circumferential hypopigmentation were observed in the iris in both eyes. The fundus examination revealed a choroidal fundus due to the absence of melanin in the retinal pigment epithelium. In the autofluorescence, an absence of physiological macular hypo-autofluorescence was observed and, in optical coherence tomography, foveal hypoplasia was observed in both eyes. In the ocular fundus examination of the mother, slight macular pigmentary changes were observed in the right eye, with hyperpigmented radiated spots in the retinal periphery of both eyes, which were hypo-autofluorescent in the wide-field autofluorescence. In the optical coherence tomography of the right eye, a cavitation of the outer retinal layers was observed in the fovea. The genetic study by nucleotide sequencing was performed on the mother and the child. In the mutation found in the GPR143 gene, the son was hemizygous and the mother was heterozygous. X-linked ocular albinism was diagnosed and the genetic counselling was carried out. Ocular albinism linked to X is the most frequent genetic variant of this disease. Peripheral pigment alterations in heterozygous mothers have been previously described in the literature, but there are no reports of cavitations in the external retinal layers using optical coherence tomography.

Successful treatment of aggressive posterior retinopathy of prematurity with diode laser in ocular albinism: A case report.

Oculocutaneous albinism is characterized by partial or complete absence of melanin in retinal pigment epithelium (RPE) and uveal melanocytes. Absence of typical fundal background from RPE and choroid makes it difficult to diagnose retinal disorders in ocular albinism. Lack of melanin in RPE makes the laser photocoagulation very challenging in these cases. This report presents a unique case of preterm infant of oculocutaneous albinism diagnosed as aggressive posterior retinopathy of prematurity (APROP), which was successfully treated with diode laser photocoagulation. The parameters of the laser used in this case were higher than usual, just enough to achieve blanching of retina. This report highlights the fact that the diagnosis of APROP and its treatment with laser is challenging in the presence of oculocutaneous albinism, but it is possible to achieve complete regression using diode laser at higher parameters.

Ocular albinism with infertility and late-onset sensorineural hearing loss.

Ocular albinism type 1 (OA1) is caused by mutations in the GPR143 gene located at Xp22.2. The manifestations, which are due to hypopigmentation, are confined to the eyes and optic pathway. OA1 associated with late-onset sensorineural hearing loss was previously reported in a single family and hypothesized to be caused by a contiguous gene deletion syndrome involving GPR143 and the adjacent gene, TBL1X. Here, we report on a family with OA1, infertility, late-onset sensorineural hearing loss, and a small interstitial Xp microdeletion including the GPR143, TBL1X, and SHROOM2 genes. In addition, we re-examined a patient previously described with OA1, infertility and a similar Xp deletion with audiologic follow-up showing a late-onset sensorineural hearing loss. Our results raise an intriguing question about the possibility for TBL1X (absence) involvement in this type of hearing loss. However, our study cannot claim a causative relationship and more convincing evidence is needed before the hypothesis can be accepted that TBL1X could be involved in late-onset sensorineural hearing loss and that ocular albinism with late-onset sensorineural hearing loss can present itself as a contiguous gene deletion/microdeletion syndrome. The finding of infertility in all affected male patients demonstrates that this deletion, including the SHROOM2 gene, may be a potentially causative X-linked genetic factor of male infertility.

Ocular Albinism Type 1 Regulates Melanogenesis in Mouse Melanocytes.

To investigate whether ocular albinism type 1 (OA1) is differentially expressed in the skin of mice with different coat colors and to determine its correlation with coat color establishment in mouse, the expression patterns and tissue distribution characterization of OA1 in the skin of mice with different coat colors were qualitatively and quantitatively analyzed by real-time quantitative PCR (qRT-PCR), immunofluorescence staining and Western blot. The qRT-PCR analysis revealed that OA1 mRNA was expressed in all mice skin samples tested, with the highest expression level in brown skin, a moderate expression level in black skin and the lowest expression level in gray skin. Positive OA1 protein bands were also detected in all skin samples by Western blot analysis. The relative expression levels of OA1 protein in both black and brown skin were significantly higher than that in gray skin, but there was no significant difference between black and brown mice. Immunofluorescence assays revealed that OA1 was mainly expressed in the hair follicle matrix, the inner and outer root sheath in the skin tissues with different coat colors. To get further insight into the important role of OA1 in the melanocytes' pigmentation, we transfected the OA1 into mouse melanocytes and then detected the relative expression levels of pigmentation-related gene. Simultaneously, we tested the melanin content of melanocytes. As a result, the overexpression of OA1 significantly increased the expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein 1 (TRP1) and premelanosome protein (PMEL). However, the tyrosinase-related protein 2 (TRP2) level was attenuated. By contrast, the level of glycoprotein non-metastatic melanoma protein b (GPNMB) was unaffected by OA1 overexpression. Furthermore, we observed a significant increase in melanin content in mouse melanocyte transfected OA1. Therefore, we propose that OA1 may participate in the formation of coat color by regulating the level of MITF and the number, size, motility and maturation of melanosome.

A Case of a Newborn with Agenesis of the Corpus Callosum Complicated with Ocular Albinism.

PURPOSE: To report a case of ocular albinism found in a newborn infant in whom agenesis of the corpus callosum (ACC) was indicated in utero. CASE REPORT: This study involved a female newborn who was delivered after a gestational period of 41 weeks. The patient was referred to the Obstetrics Department at Takatsuki Hospital, Takatsuki City, Japan, after the indication of ACC by magnetic resonance imaging (MRI) at a nearby clinic during the fetal period. At birth, the baby's weight was 2,590 g, and ACC and ventricular enlargement were found by cranial sonography and cranial MRI. While initial ophthalmic findings noted partial loss of pigmentation of the iris and hypopigmentation of broad areas of the fundus in both eyes, nystagmus was not observed. The patient's hair pigment was slightly diluted, and the color of her skin was slightly off-white. At 2 years after birth, obvious mental retardation was observed. With regard to other systemic findings, no apparent heart, kidney, or immune system abnormalities were found. CONCLUSION: Although the patient in question is presently growing without any major systemic problems, it will be necessary in the future to pay attention to any changes in systemic and ophthalmic findings.

Role of ocular albinism type 1 (OA1) GPCR in Asian gypsy moth development and transcriptional expression of heat-shock protein genes.

The ocular albinism type 1 gene, named OA1, is a coding pigment cell-specific G protein-coupled receptor exclusively localized in intracellular organelles. However, the function of OA1 in insects remains generally unknown. In the present study, we explore for the first time the function of LdOA1 in the Asian gypsy moth, Lymantria dispar. To identify the function of LdOA1 gene in the development and growth of the Asian gypsy moth, the LdOA1 gene in third instar larvae was knocked down by RNAi. Compared with the controls, the knockdown of LdOA1 increased larval mortality but did not significantly affect their utilization of nutrition. Moreover, LdOA1 was stably transformed into the third chromosome of Drosophila melanogaster. The LdOA1 gene in the transformed D. melanogaster modulated the expression of heat-shock protein (hsp) and increased the expression of hsp genes under deltamethrin stress, which indicates that LdOA1 is involved in the regulation of hsp gene expression. These results deepen our understanding of the molecular function of OA1 in insects.