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201.
BMC Genomics ; 22(1): 543, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34271866

RESUMO

BACKGROUND: Most plants rely on photosynthesis; therefore, albinism in plants with leaves that are white instead of green causes slow growth, dwarfing, and even death. Although albinism has been characterized in annual model plants, little is known about albino trees. Jackfruit (Artocarpus heterophyllus) is an important tropical fruit tree species. To gain insight into the mechanisms underlying the differential growth and development between albino jackfruit mutants and green seedlings, we analyzed root, stem, and leaf tissues by combining PacBio single-molecule real-time (SMRT) sequencing, high-throughput RNA-sequencing (RNA-seq), and metabolomic analysis. RESULTS: We identified 8,202 differentially expressed genes (DEGs), including 225 genes encoding transcription factors (TFs), from 82,572 full-length transcripts. We also identified 298 significantly changed metabolites (SCMs) in albino A. heterophyllus seedlings from a set of 692 metabolites in A. heterophyllus seedlings. Pathway analysis revealed that these DEGs were highly enriched in metabolic pathways such as 'photosynthesis', 'carbon fixation in photosynthetic organisms', 'glycolysis/gluconeogenesis', and 'TCA cycle'. Analysis of the metabolites revealed 76 SCMs associated with metabolic pathways in the albino mutants, including L-aspartic acid, citric acid, succinic acid, and fumaric acid. We selected 225 differentially expressed TF genes, 333 differentially expressed metabolic pathway genes, and 76 SCMs to construct two correlation networks. Analysis of the TF-DEG network suggested that basic helix-loop-helix (bHLH) and MYB-related TFs regulate the expression of genes involved in carbon fixation and energy metabolism to affect light responses or photomorphogenesis and normal growth. Further analysis of the DEG-SCM correlation network and the photosynthetic carbon fixation pathway suggested that NAD-ME2 (encoding a malic enzyme) and L-aspartic acid jointly inhibit carbon fixation in the albino mutants, resulting in reduced photosynthetic efficiency and inhibited plant growth. CONCLUSIONS: Our preliminarily screening identified candidate genes and metabolites specifically affected in albino A. heterophyllus seedlings, laying the foundation for further study of the regulatory mechanism of carbon fixation during photosynthesis and energy metabolism. In addition, our findings elucidate the way genes and metabolites respond in albino trees.


Assuntos
Albinismo , Artocarpus , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Metaboloma , Folhas de Planta/genética , Plântula/genética , Transcriptoma
202.
Acta Derm Venereol ; 101(7): adv00506, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34230975

RESUMO

The aim of this study was to assess the efficacy of non-cultured autologous epidermal cell grafting resuspended in hyaluronic acid, performed using a ready-to-use kit, compared with hyaluronic acid alone (neutral comparator) for repigmenting vitiligo and piebaldism lesions at 6 months. Two identified paired lesions per patient were randomized to be treated by either device. Devices with a ready-to-use kit were prepared by separate health professionals, to maintain blinding. A skin biopsy was digested using trypsin, and cells resuspended in hyaluronic acid solution. Among 38 patients screened, 36 (94.7%) patients, corresponding to 72 lesions, were analysed. For difficult-to-treat lesions, defined as those located on the wrist, elbow, and hands (n = 30), no repigmentation ≥ 50% was observed. For all other locations (n = 42), the success rate was significantly higher (p = 0.021) in the ready-to-use kit group (47.6% vs 9.5%) at 6 months and was maintained until 12 months. In conclusion, a single application of non-cultured epidermal cellular grafting using a ready-to-use kit was efficient at 6 months and at 1-year follow-up.


Assuntos
Piebaldismo , Vitiligo , Células Epidérmicas , Humanos , Ácido Hialurônico , Piebaldismo/cirurgia , Pigmentação da Pele , Transplante de Pele , Transplante Autólogo , Resultado do Tratamento , Vitiligo/diagnóstico , Vitiligo/terapia
203.
Ann Dermatol Venereol ; 148(4): 246-250, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34217528

RESUMO

BACKGROUND: Long-term and ongoing support in accordance with the changing needs of patients and their families is one of the main components of patient care, including therapeutic patient education (TPE). OBJECTIVE: To co-construct a TPE program for albinism with all those involved in the management of albinism patients. METHODS: Eight steps have been defined for the co-construction process: 1) identify all the relevant experts and invite them to participate in the construction of a TPE program to improve care for and support of patients with albinism, 2) review and analyse all publications regarding TPE for albinism, 3) conduct semi-structured interviews with the patients' parents, 4) conduct brainstorming meetings with the participating experts for an exchange of experience and expertise, 5) elaborate the program's concrete content with the experts, 6) draw up a TPE skills checklist, 7) create TPE educational tools to facilitate learning, 8) review and summarize each step of the co-construction protocol. RESULTS: Co-construction of a TPE program for children, adolescents, and young adults with albinism, and their parents. CONCLUSION: Strengths and advantages of the co-construction process include: i) highlighting of the experiential knowledge mentioned in the repository, ii) multiplicity of points of view and perspectives, iii) rapid improvement in TPE training both for the association and the patients, iv) awareness of the shift caregivers' position with regards to TPE and recognition of the polysemy of their discourse. The TPE program for albinism has been authorized since 2018.


Assuntos
Albinismo , Educação de Pacientes como Assunto , Adolescente , Criança , Humanos , Pais
204.
Ophthalmic Genet ; 42(5): 539-552, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34251969

RESUMO

Purpose: To correlate clinical features, molecular genetic findings, and visual acuity in a cohort of patients clinically diagnosed with oculocutaneous albinism.Design: Retrospective chart reviewMethods: 58 charts met the inclusion criteria. Clinical examination, ancillary testing, and molecular genetic diagnoses were extracted. A novel clinical albinism score (CAS) was developed.Results: A least one likely pathogenic mutation was found in 44/58 (75.9%) patients. Mutations in the OCA1 gene were the most common (52.3%), followed by OCA2 (34%), OCA4 (2.3%), OA1 (6.8%), and HPS (4.5%). Thirty-four percentage of patients had a complete genotype, 41% had one mutation found and 24% had negative genetic testing. CAS was statistically significantly higher in patients with complete genotype, versus patients with one or no mutations found (p < .01). Better visual acuity was associated with lower CAS and fewer disease-causing mutations (p < .01). Foveal defects and iris transillumination were associated with a higher number of mutations (p < .01). Patients with nystagmus or anomalous optic nerves had worse visual acuity than those who did not (p < .01, p < .05).Conclusions: Patients with a complete genotype were more likely to have higher CAS. Vision loss correlated with complete phenotype and higher CAS, the presence of nystagmus and anomalous optic nerves. Patients with features of albinism in whom an incomplete genotype was found had better vision than those with complete genotype, suggesting a mild occult mutation or modifier variant. Genetic diagnosis is vital for complete diagnosis, counseling, and family planning.


Assuntos
Albinismo Oculocutâneo/diagnóstico , Nistagmo Patológico/diagnóstico , Doenças do Nervo Óptico/diagnóstico , Acuidade Visual/fisiologia , Albinismo Oculocutâneo/genética , Albinismo Oculocutâneo/fisiopatologia , Antígenos de Neoplasias/genética , Criança , Proteínas do Olho/genética , Feminino , Testes Genéticos , Genótipo , Humanos , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Mutação , Nistagmo Patológico/fisiopatologia , Doenças do Nervo Óptico/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Tirosina/genética
205.
Hum Mutat ; 42(10): 1239-1253, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34246199

RESUMO

Oculocutaneous albinism (OCA) is a heritable disorder of pigment production that manifests as hypopigmentation and altered eye development. Exon sequencing of known OCA genes is unsuccessful in producing a complete molecular diagnosis for a significant number of affected individuals. We sequenced the DNA of individuals with OCA using short-read custom capture sequencing that targeted coding, intronic, and noncoding regulatory regions of known OCA genes, and genome-wide association study-associated pigmentation loci. We identified an OCA2 complex structural variant (CxSV), defined by a 143 kb inverted segment reintroduced in intron 1, upstream of the native location. The corresponding CxSV junctions were observed in 11/390 probands screened. The 143 kb CxSV presents in one family as a copy number variant duplication for the 143 kb region. In the remaining 10/11 families, the 143 kb CxSV acquired an additional 184 kb deletion across the same region, restoring exons 3-19 of OCA2 to a copy-number neutral state. Allele-associated haplotype analysis found rare SNVs rs374519281 and rs139696407 are linked with the 143 kb CxSV in both OCA2 alleles. For individuals in which customary molecular evaluation does not reveal a biallelic OCA diagnosis, we recommend preliminary screening for these haplotype-associated rare variants, followed by junction-specific validation for the OCA2 143 kb CxSV.


Assuntos
Albinismo Oculocutâneo , Estudo de Associação Genômica Ampla , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/genética , Alelos , Humanos , Proteínas de Membrana Transportadoras/genética , Mutação
206.
Curr Biol ; 31(16): 3694-3701.e4, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34293332

RESUMO

Adaptation to novel environments often involves the evolution of multiple morphological, physiological, and behavioral traits. One striking example of multi-trait evolution is the suite of traits that has evolved repeatedly in cave animals, including regression of eyes, loss of pigmentation, and enhancement of non-visual sensory systems.1,2 The Mexican tetra, Astyanax mexicanus, consists of fish that inhabit at least 30 caves in Mexico and ancestral-like surface fish that inhabit the rivers of Mexico and southern Texas.3 Cave A. mexicanus are interfertile with surface fish and have evolved a number of traits, including reduced pigmentation, eye loss, and alterations to behavior.4-6 To define relationships between different cave-evolved traits, we phenotyped 208 surface-cave F2 hybrid fish for numerous morphological and behavioral traits. We found differences in sleep between pigmented and albino hybrid fish, raising the possibility that these traits share a genetic basis. In cavefish and other species, mutations in oculocutaneous albinism 2 (oca2) cause albinism.7-12 Surface fish with mutations in oca2 displayed both albinism and reduced sleep. Further, this mutation in oca2 fails to complement sleep loss when surface fish harboring this engineered mutation are crossed to independently evolved populations of albino cavefish with naturally occurring mutations in oca2. Analysis of the oca2 locus in wild-caught cave and surface fish suggests that oca2 is under positive selection in 3 cave populations. Taken together, these findings identify oca2 as a novel regulator of sleep and suggest that a pleiotropic function of oca2 underlies the adaptive evolution of albinism and sleep loss.


Assuntos
Albinismo , Characidae , Proteínas de Peixes/genética , Sono , Animais , Evolução Biológica , Characidae/genética , Olho , Pigmentação/genética
207.
J AAPOS ; 25(4): 220.e1-220.e8, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34280564

RESUMO

PURPOSE: To present a series of patients diagnosed with oculocutaneous albinism (OCA) based on clinical presentation who were later proven to have a different diagnosis. METHODS: The medical records of patients seen at the Pediatric Inherited Eye Disease Clinic of the University of Iowa from 1980 to 2018 who were eventually discovered to have an incorrect diagnosis of OCA were reviewed retrospectively. RESULTS: Eight pediatric patients presenting with clinical features suggestive of OCA which changed to a different diagnosis over time were identified. Presenting clinical features included fair pigmentation of the skin and adnexa (8/8), congenital nystagmus (6/8), decreased visual acuity (8/8), iris transillumination defects (8/8), and foveal hypoplasia (7/8). Of the 8 patients, 4 manifested progressive, preschool-age-onset myopia. Other associated clinical features included hearing loss (3), seizures (1), abnormal chest x-ray (1) and easy bruising (2). During follow-up, additional clinical features and genetic testing proved that they have different clinical entities, namely, Knobloch syndrome, Jeune syndrome, Donnai-Barrow syndrome, Waardenburg syndrome, Aniridia syndrome, Stickler syndrome, and Hermansky-Pudlak syndrome, one of the syndromic types of OCA. CONCLUSIONS: Clinical features used to diagnose OCA also occur in other disorders. For a definitive diagnosis of OCA, ancillary/genetic testing must be performed. Clinical features not typically found in association with albinism, such as hearing loss, or early onset, or progressive myopia, may indicate the need for more extensive investigation.


Assuntos
Albinismo Oculocutâneo , Albinismo , Síndrome de Hermanski-Pudlak , Nistagmo Congênito , Albinismo Oculocutâneo/genética , Criança , Pré-Escolar , Humanos , Fenótipo , Estudos Retrospectivos
208.
Rev. peru. biol. (Impr.) ; 28(3)jul. 2021.
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1508869

RESUMO

Se documenta el primer registro de albinismo de vizcacha (Lagidium viscacia) con base en dos individuos avistados en el departamento de Apurímac, en Perú. Este registro representa el primer reporte de albinismo en la familia Chinchillidae.


We report the first record of albinism in vizcacha (Lagidium viscacia) based on two adult individuals sighted in department of Apurímac, in Peru. This record represents the first report of albinism in Chinchillidae.

209.
BMC Pediatr ; 21(1): 253, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34058999

RESUMO

BACKGROUND: Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disease caused by mutations in RAB27A gene. It is primarily characterized by a combination of partial albinism, hemophagocytic lymphohistiocytosis (HLH) or other immunodeficiency. However, neurological involvement at onset in GS2 and treatment has rarely been described. CASE PRESENTATION: We describe a 3-year-old boy with GS2 in an Asian Chinese family. He presented with progressive neurological abnormalities following unremitting fever at onset. He developed HLH during the clinical course. A novel homozygous mutation (c.1 A > G) in RAB27A gene was subsequently identified. He was then treated by HLH-1994 protocol combined with ruxolitinib and experienced a dramatic remission. He subsequently underwent a successful haploidentical hematopoietic stem cell transplantation and stayed at a good condition. CONCLUSIONS: We reported an atypical form of GS2 manifesting as severe central nervous system involvement at onset and subsequent HLH, which was successfully rescued in time. This case also highlights the need for early consideration of immunologic and genetic evaluation for HLH in unexplained neuroinflammation in the diagnostic work up.


Assuntos
Linfo-Histiocitose Hemofagocítica , Piebaldismo , Doenças da Imunodeficiência Primária , Pré-Escolar , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/terapia , Masculino , Piebaldismo/complicações , Piebaldismo/diagnóstico , Piebaldismo/genética , Proteínas rab27 de Ligação ao GTP/genética
210.
Am J Med Genet A ; 185(11): 3350-3358, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34165242

RESUMO

From Sir Archibald Garrod's initial description of the tetrad of albinism, alkaptonuria, cystinuria, and pentosuria to today, the field of medicine dedicated to inborn errors of metabolism has evolved from disease identification and mechanistic discovery to the development of therapies designed to subvert biochemical defects. In this review, we highlight major milestones in the treatment and diagnosis of inborn errors of metabolism, starting with dietary therapy for phenylketonuria in the 1950s and 1960s, and ending with current approaches in genetic manipulation.


Assuntos
Albinismo/terapia , Alcaptonúria/terapia , Cistinúria/terapia , Erros Inatos do Metabolismo/terapia , Albinismo/genética , Albinismo/metabolismo , Albinismo/patologia , Alcaptonúria/genética , Alcaptonúria/metabolismo , Alcaptonúria/patologia , Erros Inatos do Metabolismo dos Carboidratos/genética , Erros Inatos do Metabolismo dos Carboidratos/metabolismo , Erros Inatos do Metabolismo dos Carboidratos/patologia , Erros Inatos do Metabolismo dos Carboidratos/terapia , Cistinúria/genética , Cistinúria/metabolismo , Cistinúria/patologia , Humanos , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Fenilcetonúrias/genética , Fenilcetonúrias/metabolismo , Fenilcetonúrias/patologia , Fenilcetonúrias/terapia , Desidrogenase do Álcool de Açúcar/deficiência , Desidrogenase do Álcool de Açúcar/genética , Desidrogenase do Álcool de Açúcar/metabolismo , Xilulose/genética , Xilulose/metabolismo
211.
Sci Rep ; 11(1): 11572, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078970

RESUMO

To describe the phenotype of Dutch patients with oculocutaneous albinism type 4 (OCA4), we collected data on pigmentation (skin, hair, and eyes), visual acuity (VA), nystagmus, foveal hypoplasia, chiasmal misrouting, and molecular analyses of nine Dutch OCA4 patients from the Bartiméus Diagnostic Center for complex visual disorders. All patients had severely reduced pigmentation of skin, hair, and eyes with iris transillumination over 360 degrees. Three unrelated OCA4 patients had normal VA, no nystagmus, no foveal hypoplasia, and no misrouting of the visual pathways. Six patients had poor visual acuity (0.6 to 1.0 logMAR), nystagmus, severe foveal hypoplasia and misrouting. We found two novel variants in the SLC45A2 gene, c.310C > T; (p.Pro104Ser), and c.1368 + 3_1368 + 9del; (p.?). OCA4 patients of this Dutch cohort all had hypopigmentation of skin, hair, and iris translucency. However, patients were either severely affected with regard to visual acuity, foveal hypoplasia, and misrouting, or visually not affected at all. We describe for the first time OCA4 patients with an evident lack of pigmentation, but normal visual acuity, normal foveal development and absence of misrouting. This implies that absence of melanin does not invariably lead to foveal hypoplasia and abnormal routing of the visual pathways.


Assuntos
Albinismo Oculocutâneo/epidemiologia , Transtornos da Pigmentação/epidemiologia , Adolescente , Adulto , Albinismo Oculocutâneo/genética , Albinismo Oculocutâneo/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Países Baixos , Nistagmo Patológico/complicações , Acuidade Visual
213.
Rev Assoc Med Bras (1992) ; 67(1): 77-82, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34161467

RESUMO

OBJECTIVE: Oculocutaneous albinism describes a group of pigmentary disorders that lead to skin sensitivity and predisposition to skin malignances. AIMS: To analyze clinical and epidemiological data in oculocutaneous albinism patients and to determine the prevalence of malignant skin lesions, assessing possible risk factors for skin cancer. METHODS: Cross-sectional study evaluating epidemiological data, habits of sun exposure and sun protection, and clinical examination of albino patients followed in a reference dermatology outpatient clinic in Brasil. Our primary outcome was the occurrence of malignant skin lesions in biopsied tissues. RESULTS: Of 74 patients analyzed, 11 (15%) had one or more suspicious lesions and were biopsied, of which 8 (72.7%) patients presented with basal cell carcinomas, 7 (63.3%) presented with squamous cell carcinoma, and 1 (9%) presented with melanoma. Moreover, 32(43%) patients presented with actinic keratosis. Age, female gender, previous history of sunburn, history of malignant lesions and history of sun exposure without photoprotection were associated with the presence of malignant lesions. LIMITATIONS: Unicentric, non-aleatory sample. CONCLUSIONS: There was a high prevalence of malignant and pre-malignant lesions in this population. Some potentially modifiable risk factors were associated with the occurrence of malignant skin lesions.


Assuntos
Albinismo Oculocutâneo , Neoplasias Cutâneas , Queimadura Solar , Albinismo Oculocutâneo/epidemiologia , Brasil/epidemiologia , Estudos Transversais , Feminino , Humanos , Prevalência , Neoplasias Cutâneas/epidemiologia , Queimadura Solar/complicações , Queimadura Solar/epidemiologia
215.
Transl Vis Sci Technol ; 10(6): 22, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-34111268

RESUMO

Purpose: Adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in patients with achromatopsia (ACHM) and albinism is not always successful. Here, we tested whether optical coherence tomography (OCT) measures of foveal structure differed between patients for whom AOSLO images were either quantifiable or unquantifiable. Methods: The study included 166 subjects (84 with ACHM; 82 with albinism) with previously acquired OCT scans, AOSLO images, and best-corrected visual acuity (BCVA, if available). Foveal OCT scans were assessed for outer retinal structure, outer nuclear layer thickness, and hypoplasia. AOSLO images were graded as quantifiable if a peak cone density could be measured and/or usable if the location of peak density could be identified and the parafoveal mosaic was quantifiable. Results: Forty-nine percent of subjects with ACHM and 57% of subjects with albinism had quantifiable AOSLO images. Older age and better BCVA were found in subjects with quantifiable AOSLO images for both ACHM (P = 0.0214 and P = 0.0276, respectively) and albinism (P = 0.0073 and P < 0.0004, respectively). There was a significant trend between ellipsoid zone appearance and ability to quantify AOSLO (P = 0.0028). In albinism, OCT metrics of cone structure did not differ between groups. Conclusions: Previously reported AOSLO-based cone density measures in ACHM may not necessarily reflect the degree of remnant cone structure in these patients. Translational Relevance: Until AOSLO is successful in all patients with ACHM and albinism, the possibility of the reported data from a particular cohort not being representative of the entire population remains an important issue to consider when interpreting results from AOSLO studies.


Assuntos
Albinismo , Defeitos da Visão Cromática , Idoso , Albinismo/genética , Benchmarking , Defeitos da Visão Cromática/diagnóstico , Humanos , Oftalmoscopia , Acuidade Visual
216.
J Eur Acad Dermatol Venereol ; 35(7): 1449-1459, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34042219

RESUMO

Albinism is a worldwide genetic disorder caused by mutations in at least 20 genes, identified to date, that affect melanin production or transport in the skin, hair and eyes. Patients present with variable degrees of diffuse muco-cutaneous and adnexal hypopigmentation, as well as ocular features including nystagmus, misrouting of optic nerves and foveal hypoplasia. Less often, albinism is associated with blood, immunological, pulmonary, digestive and/or neurological anomalies. Clinical and molecular characterizations are essential in preventing potential complications. Disease-causing mutations remain unknown for about 25% of patients with albinism. These guidelines have been developed for the diagnosis and management of syndromic and non-syndromic forms of albinism, based on a systematic review of the scientific literature. These guidelines comprise clinical and molecular characterization, diagnosis, therapeutic approach and management.


Assuntos
Albinismo Oculocutâneo , Albinismo , Nistagmo Patológico , Albinismo/genética , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/genética , Albinismo Oculocutâneo/terapia , Humanos , Melaninas , Guias de Prática Clínica como Assunto , Revisões Sistemáticas como Assunto , Transtornos da Visão
217.
Pigment Cell Melanoma Res ; 34(4): 786-799, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33960688

RESUMO

Oculocutaneous albinism (OCA) is the most frequent presentation of albinism, a heterogeneous rare genetic condition generally associated with variable alterations in pigmentation and with a profound visual impairment. There are non-syndromic and syndromic types of OCA, depending on whether the gene product affected impairs essentially the function of melanosomes or, in addition, that of other lysosome-related organelles (LROs), respectively. Syndromic OCA can be more severe and associated with additional systemic consequences, beyond pigmentation and vision alterations. In addition to OCA, albinism can also be presented without obvious skin and hair pigmentation alterations, in ocular albinism (OA), and a related genetic condition known as foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA). In this review, we will focus only in the genetics of skin pigmentation in OCA, both in human and mouse, updating our current knowledge on this subject.


Assuntos
Albinismo Oculocutâneo/genética , Predisposição Genética para Doença , Animais , Modelos Animais de Doenças , Humanos , Melaninas/metabolismo , Camundongos , Síndrome
218.
J Vis ; 21(5): 19, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-34007988

RESUMO

Retinotopic organization is a fundamental feature of visual cortex thought to play a vital role in encoding spatial information. One important aspect of normal retinotopy is the representation of the right and left hemifields in contralateral visual cortex. However, in human albinism, many temporal retinal afferents decussate aberrantly at the optic chiasm resulting in partially superimposed representations of opposite hemifields in each hemisphere of visual cortex. Previous functional magnetic resonance imaging (fMRI) studies in human albinism suggest that the right and left hemifield representations are superimposed in a mirror-symmetric manner. This should produce imaging voxels which respond to two separate locations mirrored across the vertical meridian. However, it is not yet clear how retino-cortical miswiring in albinism manifests at the level of single voxel population receptive fields (pRFs). Here, we used pRF modeling to fit both single and dual pRF models to the visual responses of voxels in visual areas V1 to V3 of five subjects with albinism. We found that subjects with albinism (but not controls) have sizable clusters of voxels with unequivocal dual pRFs consistently corresponding to, but not fully coextensive with, regions of hemifield overlap. These dual pRFs were typically positioned at locations roughly mirrored across the vertical meridian and were uniquely clustered within a portion of the visual field for each subject.


Assuntos
Albinismo , Córtex Visual , Mapeamento Encefálico , Humanos , Imageamento por Ressonância Magnética , Quiasma Óptico , Córtex Visual/diagnóstico por imagem , Campos Visuais , Vias Visuais
219.
Stem Cell Res Ther ; 12(1): 287, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33985578

RESUMO

BACKGROUND: Griscelli syndrome type 2 (GS-2) is a rare, autosomal recessive immune deficiency syndrome caused by a mutation in the RAB27A gene, which results in the absence of a protein involved in vesicle trafficking and consequent loss of function of in particular cytotoxic T and NK cells. Induced pluripotent stem cells (iPSC) express genes associated with pluripotency, have the capacity for infinite expansion, and can differentiate into cells from all three germ layers. They can be induced using integrative or non-integrative systems for transfer of the Oct4, Sox2, Klf4, and cMyc (OSKM) transcription factors. To better understand the pathophysiology of GS-2 and to test novel treatment options, there is a need for an in vitro model of GS-2. METHODS: Here, we generated iPSCs from 3 different GS-2 patients using lentiviral vectors. The iPSCs were characterized using flow cytometry and RT-PCR and tested for the expression of pluripotency markers. In vivo differentiation to cells from all three germlines was tested using a teratoma assay. In vitro differentiation of GS-2 iPSCs into hematopoietic stem and progenitor cells was done using Op9 feeder layers and specified media. RESULTS: All GS-2 iPSC clones displayed a normal karyotype (46XX or 46XY) and were shown to express the same RAB27A gene mutation that was present in the original somatic donor cells. GS-2 iPSCs expressed SSEA1, SSEA4, TRA-1-60, TRA-1-81, and OCT4 proteins, and SOX2, NANOG, and OCT4 expression were confirmed by RT-PCR. Differentiation capacity into cells from all three germ layers was confirmed using the teratoma assay. GS-2 iPSCs showed the capacity to differentiate into cells of the hematopoietic lineage. CONCLUSIONS: Using the lentiviral transfer of OSKM, we were able to generate different iPSC clones from 3 GS-2 patients. These cells can be used in future studies for the development of novel treatment options and to study the pathophysiology of GS-2 disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células-Tronco Pluripotentes Induzidas , Diferenciação Celular , Células Alimentadoras , Humanos , Fator 4 Semelhante a Kruppel , Linfo-Histiocitose Hemofagocítica , Piebaldismo , Doenças da Imunodeficiência Primária
220.
Hum Genet ; 140(8): 1157-1168, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33959807

RESUMO

Infantile nystagmus syndrome (INS) denominates early-onset, involuntary oscillatory eye movements with different etiologies. Nystagmus is also one of the symptoms in oculocutaneus albinism (OCA), a heterogeneous disease mainly caused by defects in melanin synthesis or melanosome biogenesis. Dopachrome tautomerase (DCT, also called TYRP2) together with tyrosinase (TYR) and tyrosin-related protein 1 (TYRP1) is one of the key enzymes in melanin synthesis. Although DCT´s role in pigmentation has been proven in different species, until now only mutations in TYR and TYRP1 have been found in patients with OCA. Detailed ophthalmological and orthoptic investigations identified a consanguineous family with two individuals with isolated infantile nystagmus and one family member with subtle signs of albinism. By whole-exome sequencing and segregation analysis, we identified the missense mutation c.176G > T (p.Gly59Val) in DCT in a homozygous state in all three affected family members. We show that this mutation results in incomplete protein maturation and targeting in vitro compatible with a partial or total loss of function. Subsequent screening of a cohort of patients with OCA (n = 85) and INS (n = 25) revealed two heterozygous truncating mutations, namely c.876C > A (p.Tyr292*) and c.1407G > A (p.Trp469*), in an independent patient with OCA. Taken together, our data suggest that mutations in DCT can cause a phenotypic spectrum ranging from isolated infantile nystagmus to oculocutaneous albinism.


Assuntos
Albinismo Oculocutâneo/genética , Oxirredutases Intramoleculares/genética , Melaninas/biossíntese , Mutação de Sentido Incorreto , Nistagmo Congênito/genética , Adolescente , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/enzimologia , Albinismo Oculocutâneo/patologia , Sequência de Bases , Calnexina/genética , Calnexina/metabolismo , Criança , Estudos de Coortes , Consanguinidade , Feminino , Regulação da Expressão Gênica , Células HEK293 , Homozigoto , Humanos , Oxirredutases Intramoleculares/deficiência , Masculino , Melaninas/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Nistagmo Congênito/diagnóstico , Nistagmo Congênito/enzimologia , Nistagmo Congênito/patologia , Oxirredutases/genética , Oxirredutases/metabolismo , Linhagem , Sequenciamento do Exoma , Adulto Jovem
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