RESUMO
Hereditary retinal degenerations encompass a group of genetic diseases characterized by extreme clinical variability. Following next-generation sequencing and autozygome-based screening of patients presenting with a peculiar, recessive form of cone-dominated retinopathy, we identified five homozygous variants [p.(Asp594fs), p.(Gln117*), p.(Met712fs), p.(Ile756Phe), and p.(Glu543Lys)] in the polyglutamylase-encoding gene TTLL5, in eight patients from six families. The two male patients carrying truncating TTLL5 variants also displayed a substantial reduction in sperm motility and infertility, whereas those carrying missense changes were fertile. Defects in this polyglutamylase in humans have recently been associated with cone photoreceptor dystrophy, while mouse models carrying truncating mutations in the same gene also display reduced fertility in male animals. We examined the expression levels of TTLL5 in various human tissues and determined that this gene has multiple viable isoforms, being highly expressed in testis and retina. In addition, antibodies against TTLL5 stained the basal body of photoreceptor cells in rat and the centrosome of the spermatozoon flagellum in humans, suggesting a common mechanism of action in these two cell types. Taken together, our data indicate that mutations in TTLL5 delineate a novel, allele-specific syndrome causing defects in two as yet pathogenically unrelated functions, reproduction and vision.
Assuntos
Proteínas de Transporte/genética , Distrofias de Cones e Bastonetes/enzimologia , Expressão Gênica , Infertilidade Masculina/enzimologia , Mutação , Adolescente , Adulto , Idoso , Animais , Distrofias de Cones e Bastonetes/genética , Análise Mutacional de DNA , Modelos Animais de Doenças , Proteínas do Olho/genética , Feminino , Homozigoto , Humanos , Infertilidade Masculina/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Especificidade de Órgãos , Linhagem , Células Fotorreceptoras de Vertebrados/enzimologia , Ratos , Motilidade dos Espermatozoides , Espermatozoides/enzimologia , Testículo/enzimologiaRESUMO
BACKGROUND: The genetic background of retinal vein occlusion (RVO) remains unclear. In the current study, we aimed to replicate polymorphisms related to thrombophilia/hypofibrinolysis in a Greek population and also systematically summarize current evidence available on the topic. MATERIALS AND METHODS: A total of 48 RVO patients and 53 controls were genotyped for factor V H1299R and V Leiden, ß-fibrinogen G455A, PAI-1 4G/5G, ACE I/D, HPA1, prothrombin G20210A, factor XIII Val34Leu, MTHFR A1298C and C677T polymorphisms. We examined the association between RVO and the above polymorphisms under a per-allele genetic model in a Greek unrelated case/control population. Additionally, searching PubMed up to January 2012, we identified existing evidence on these polymorphisms and performed meta-analyses. RESULTS: A total of three polymorphisms had nominally significant associations with RVO. These associations pertained to ACE D allele (odds ratio, OR, 2.08 [95% CI, 1.12-3.85], p = 0.02); factor XIII 34Leu allele (OR = 0.41 [95% CI, 0.18-0.95], p = 0.037] and MTHFR 677T variant (OR = 2.20 [95% CI 1.10-4.40], p = 0.026). We performed a meta-analysis on the associations between RVO and PAI-1 (n = 5), factor V Leiden (n = 21), MTHFR C677T (n = 19) and prothrombin G20210A (n = 21). We observed nominally significant associations only for PAI-1 (OR = 1.27 [95% CI, 1.02-1.60, p = 0.036]) (I(2) = 44.7%), and factor V Leiden (OR = 1.40 [95% CI, 1.07-1.84, p = 0.015]) (I(2) = 3.6%) using random effects model. CONCLUSIONS: Our results suggest that there may be an association between increased risk for RVO and ACE I/D, MTHFR C677T, PAI-1 4G/5G and factor V Leiden polymorphisms, whereas the Val34Leu variant may exert a protective effect.
Assuntos
Fator V/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Peptidil Dipeptidase A/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo Genético , Oclusão da Veia Retiniana/genética , Idoso , Alelos , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Genótipo , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de ChancesRESUMO
BACKGROUND AND OBJECTIVE: To investigate the morphological substrate of the changes in visual function in eyes with retinitis pigmentosa and good visual acuity using spectral-domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: A total of 30 eyes of 17 patients with retinitis pigmentosa and visual acuity of 20/40 or better underwent contrast sensitivity and color vision testing. The retinal thickness at the fovea and macula and the length of the photoreceptor inner/outer segment (IS/OS) junction were assessed by SD-OCT. Structural-functional correlations were investigated. RESULTS: Contrast sensitivity correlated well with IS/OS length (Spearman r = 0.719, P < .001) and foveal thickness (r = 0.672, P < .001) and moderately with macular thickness (r = 0.422, P = .025). Moreover, color vision correlated significantly with IS/OS length (r = -0.725, P < .001) and foveal thickness (r = -0.661, P < .001). CONCLUSION: In eyes with retinitis pigmentosa and good visual acuity, the structural changes observed on OCT scans correspond well to subtle measures of central visual function, complementary to visual acuity testing.