ABCB6 mutations cause ocular coloboma.

Ocular coloboma is a developmental defect of the eye and is due to abnormal or incomplete closure of the optic fissure. This disorder displays genetic and clinical heterogeneity. Using a positional cloning approach, we identified a mutation in the ATP-binding cassette (ABC) transporter ABCB6 in a Chinese family affected by autosomal-dominant coloboma. The Leu811Val mutation was identified in seven affected members of the family and was absent in six unaffected members from three generations. A LOD score of 3.2 at θ = 0 was calculated for the mutation identified in this family. Sequence analysis was performed on the ABCB6 exons from 116 sporadic cases of microphthalmia with coloboma (MAC), isolated coloboma, and aniridia, and an additional mutation (A57T) was identified in three patients with MAC. These two mutations were not present in the ethnically matched control populations. Immunostaining of transiently transfected, Myc-tagged ABCB6 in retinal pigment epithelial (RPE) cells showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells. RT-PCR of ABCB6 mRNA in human cell lines and tissue indicated that ABCB6 is expressed in the retinae and RPE cells. Using zebrafish, we show that abcb6 is expressed in the eye and CNS. Morpholino knockdown of abcb6 in zebrafish produces a phenotype characteristic of coloboma and replicates the clinical phenotype observed in our index cases. The knockdown phenotype can be corrected with coinjection of the wild-type, but not mutant, ABCB6 mRNA, suggesting that the phenotypes observed in zebrafish are due to insufficient abcb6 function. Our results demonstrate that ABCB6 mutations cause ocular coloboma.

Retrospective reversal of extinction of conditioned fear by instruction.

In the present study, we examined the impact of verbal instruction during extinction of human fear-conditioning. We extended the study of Raes, De Houwer, Verschuere, and De Raedt (2011) by controlling for context conditioning and recording unconditioned stimulus expectancy online in a within-subject design. We informed participants of an alternative reason for the absence of the aversive unconditioned stimulus after extinction had been carried out, to see if such instruction could induce retrospective protection from extinction. The results demonstrated that both the expectancy of an aversive outcome and conditioned skin conductance were significantly increased for the conditioned stimulus targeted by the instruction. Thus extinction was reversed by the concurrent presence of an alternative cause for the absence of the unconditioned stimulus.

A new novel mutation in FBN1 causes autosomal dominant Marfan syndrome in a Chinese family.

PURPOSE: Screening of mutations in the fibrillin-1 (FBN1) gene in a Chinese family with autosomal dominant Marfan syndrome (MFS). METHODS: It has been reported that FBN1 mutations account for approximately 90% of Autosomal Dominant MFS. FBN1 mutations were analyzed in a Chinese family of 36 members including 13 MFS patients. The genomic DNAs from blood leukocytes of the patients and their relatives were isolated and the entire coding region of FBN1 was amplified by PCR. The sequence of FBN1 was dertermined with an ABI 3100 Genetic Analyzer. RESULTS: A previously unreported the missense mutation G214S (caused by a 640 A→G heterozygous change) in FBN1 was identified in the Chinese family. The mutation was associated with the disease phenotype in patients, but not detected in their relatives or in the 100 normal controls. CONCLUSIONS: This is the first report of molecular characterization of FBN1 in the MFS family of Chinese origin. Our results expand the spectrum of FBN1 mutations causing MFS and further confirm the role of FBN1 in the pathogenesis of MFS. Direct sequencing of the mutation in FBN1 may be used for diagnosis of MFS.

A novel frame-shift mutation in FRMD7 causes X-linked idiopathic congenital nystagmus in a Chinese family.

PURPOSE: To screen mutations in the FERM domain-containing 7 (FRMD7) gene in a Chinese family with X-linked idiopathic congenital nystagmus (ICN). METHODS: It has been reported that FRMD7 mutations account for approximately 47% of X-linked nystagmus in Chinese patients. We collected 5 ml of blood samples from members of a family with X-linked ICN and 100 normal controls. Mutations in FRMD7 were determined by sequencing PCR products. RESULTS: We identified a previously unreported 4 bp deletion in FRMD7 (c.1486-1489 del TTTT) in a Chinese family. The mutation co-segregated with the disease phenotype in patients and female carriers, while it was not detected in other relatives or in the 100 normal controls. CONCLUSIONS: Our results expand the spectrum of FRMD7 mutations causing ICN, and further confirm the role of FRMD7 in the pathogenesis of ICN. Direct sequencing of FRMD7 could be used as a diagnostic testing of idiopathic congenital nystagmus.

Modified Posterior Scleral Reinforcement as a Treatment for High Myopia in Children and Its Therapeutic Effect.

PURPOSE: To investigate the safety and therapeutic effect of a modified posterior scleral reinforcement (PSR) in treating high myopia. METHODS: A total of 85 highly myopic eyes in 47 children (6.3±3.6 years of age, range from 3 years to 15 years) who underwent this modified PSR were included in this study. Axial length, refractive error, best-corrected visual acuity (BCVA), macular scans, and adverse events were recorded before the operation (as a baseline) and in postoperative reviews taken yearly for 5 years. RESULTS: This was a 5-year research: 50% of the children (20 children, 40 eyes) participated in the 6-month review, 41% of the children (17 children, 33 eyes) participated in the 1-year review, 26% of the children (11 children, 21 eyes) participated in the 2-year review, 16% of the children (7 children, 13 eyes) participated in the 3-year review, 13% of the children (5.3 children, 11 eyes) participated in the 4-year review, and 8% of the children (3.3 children, 7 eyes) participated in the 5-year review. Compared with the baseline, axial elongation was significantly changed (P<0.05) over the 5-year period in all of the children: 6-month (P=0.003), 1-year (P=0), 2-year (P=0), 3-year (P=0), 4-year (P=0), and 5-year (P=0). The axial length was extended. No significant difference was found in refractive error between measurements taken at baseline and at the 5-year postoperative visit in all of the children: 6-month (P=0.51), 1-year (P=0.50), 2-year (P=0.46), 3-year (P=0.56), 4-year (P=0.30), and 5-year (P=0.16). There were significant differences in BCVA between measurements taken at baseline and at the postoperative 5-year visit in all the children: 6-month (P=0), 1-year (P=0), 2-year (P=0), 3-year (P=0), 4-year (P=0), and 5-year (P=0). BCVA improved in 71 eyes (83.52%), remained stable in 14 eyes (16.47%), and declined in none of the children. No serious adverse events occurred before the operation and during the 5-year follow-up period. CONCLUSION: This modified PSR could be a therapeutic treatment for high myopia.

A previously unidentified deletion in G protein-coupled receptor 143 causing X-linked congenital nystagmus in a Chinese family.

BACKGROUND: Congenital nystagmus (CN) is characterized by conjugated, spontaneous, and involuntary ocular oscillations. It is an inherited disease and the most common inheritance pattern is X-linked CN. In this study, our aim is to identify the disease-causing mutation in a large sixth-generation Chinese family with X-linked CN. METHODS: It has been reported that mutations in four-point-one, ezrin, radixin, moesin domain-containing 7 gene (FRMD7) and G protein-coupled receptor 143 gene (GPR143) account for the majority patients of X-linked nystagmus. We collected 8 ml blood samples from members of a large sixth-generation pedigree with X-linked CN and 100 normal controls. FRMD7 and GPR143 were scanned by polymerase chain reaction (PCR)-based DNA sequencing assays, and multiplex PCR assays were applied to detect deletions. RESULTS: We identified a previously unreported deletion covering 7 exons in GPR143 in a Chinese family. The heterozygous deletion from exon 3 to exon 9 of GPR143 was detected in all affected males in the family, while it was not detected in other unaffected relatives or 100 normal controls. CONCLUSIONS: This is the first report of molecular characterization in GPR143 gene in the CN family. Our results expand the spectrum of GPR143 mutations causing CN and further confirm the role of GPR143 in the pathogenesis of CN.

Unconditioned stimulus revaluation to promote conditioned fear extinction in the memory reconsolidation window.

The retrieval-extinction paradigm, which disrupts the reconsolidation of fear memories in humans, is a non-invasive technique that can be used to prevent the return of fear in humans. In the present study, unconditioned stimulus revaluation was applied in the retrieval-extinction paradigm to investigate its promotion of conditioned fear extinction in the memory reconsolidation window after participants acquired conditioned fear. This experiment comprised three stages (acquisition, unconditioned stimulus revaluation, retrieval-extinction) and three methods for indexing fear (unconditioned stimulus expectancy, skin conductance response, conditioned stimulus pleasure rating). After the acquisition phase, we decreased the intensity of the unconditioned stimulus in one group (devaluation) and maintained constant for the other group (control). The results indicated that both groups exhibited similar levels of unconditioned stimulus expectancy, but the devaluation group had significantly smaller skin conductance responses and exhibited a growth in conditioned stimulus + pleasure. Thus, our findings indicate unconditioned stimulus revaluation effectively promoted the extinction of conditioned fear within the memory reconsolidation window.

The therapeutic impact of perceptual learning on juvenile amblyopia with or without previous patching treatment.

PURPOSE: To investigate the therapeutic impact of perceptual learning on juvenile amblyopia that is no longer responsive to patching treatment (PT group) or was never patch treated (NPT group). METHODS: Ten PT and 13 NPT subjects aged 8 to 17 years were trained with a grating acuity task for 40 to 60 sessions. Half in each group were further trained with single or crowded tumbling E acuity tasks for 8 to 10 sessions. RESULTS: Training improved grating acuity by -2.1% in the PT eyes and 36.1% in the NPT eyes, along with a boost of single and crowded E acuities by 0.9 or 0.7 lines in the PT eyes and 1.5 and 1.2 lines in the NPT eyes, in contrast to a nearly 5-line improvement in the same PT eyes after previous patching treatment. Stereoacuity was improved in some PT and NPT eyes. The single and crowded E acuity improvements were not significantly dependent on the pretraining acuity. The single and crowded E acuity and stereoacuity improvements were uncorrelated with grating acuity improvement, suggesting some random training impacts on different tasks and individuals. Further direct single and crowded E acuity training generated an additional 0.2- and 0.2-line boost for PT eyes and a 0.4- and 0.5-line boost for NPT eyes, resulting in overall single and crowded E acuity gains of 1.4 and 1.0 lines for PT eyes and 2.2 and 1.8 lines for NPT eyes. CONCLUSIONS: Perceptual learning has a small but significant therapeutic impact on both PT and NPT juvenile eyes, which is most likely to have clinical values for eyes with mild amblyopia. Early diagnosis and treatment are most important and effective.