Comparing myopic error in patients with basic and convergence insufficiency intermittent exotropia in China.

PURPOSE: To compare the degree of myopia between the dominant and non-dominant eyes in teenagers with intermittent exotropia (IXT) in China. METHODS: A total of 199 IXT patients with myopia were included in this retrospective study and were divided into two groups according to the difference between near and distance exodeviation: basic IXT and convergence insufficiency (CI) IXT. Refractive errors were analyzed by spherical equivalent (SE) values. Patients were further stratified into anisometropia group and non-anisometropia group based on binocular SE values difference greater than 1.0D or not. RESULTS: There were 127 patients in the CI IXT group, with a near deviation of 46.94 ± 20.53 prism diopters (PD) and a distance deviation of 28.36 ± 14.34 PD, and there were 72 (36.2%) patients in the basic IXT group, with a near deviation of 37.68 ± 22.21 PD and a distance deviation angle of 33.21 ± 23.96 PD. The near exodeviation was significantly larger in the CI group than in the basic IXT group(P < 0.001). In the CI IXT group, the mean SE was - 2.09 ± 1.45 diopters (D) in the dominant eye and - 2.53 ± 1.44D in the non-dominant eye, while in the basic IXT group, the mean SE was - 2.46 ± 1.56D in the dominant eye and - 2.89 ± 1.37D in the non-dominant eye. The anisometropia group included 43 patients, while non-anisometropia group included 156 patients. The near and distance exodeviation in the anisometropia group were 45.26 ± 24.41 PD and 33.53 ± 23.31 PD, respectively, and those in the non-anisometropia group were 43.42 ± 20.69 PD and 29.07 ± 16.84 PD, respectively. There were no significant differences in near and distance deviation (P = 0.78 and P = 0.73 respectively) between the two groups. The SE of the dominant eye was less myopic than of the non-dominant eyes in both the CI and anisometropia groups (P = 0.002 and P < 0.001, respectively). CONCLUSIONS: Our study revealed that convergence insufficiency IXT is more common than the basic type in pediatric myopic population and is characterized by higher inter-eye differences of myopia. The dominant eye was found to be less myopic in IXT patients, particularly in those with convergence insufficiency and anisometropia.

Choroidal thickness, myopia, and myopia control interventions in children: a Meta-analysis and systemic review.

AIM: To investigate changes of choroidal thickness (ChT) in children with myopia and the effect of current myopia control interventions on ChT. METHODS: Major literature databases were searched for studies relevant to myopia in children. All studies used swept-source optical coherence tomography (SS-OCT) or enhanced depth imaging optical coherence tomography (EDI-OCT) to measure the ChT value. The weighted mean difference (WMD) and 95% confidence interval (CI) were pooled to evaluate ChT in myopia children. RESULTS: A total of 11 eligible articles, including 1693 myopic and 1132 non-myopic eyes, were included in the first Meta-analysis. The sub-foveal choroidal thickness (SFCT; WMD=-40.06, 95%CI, -59.36 to -20.75, P<0.001) and ChT at other sectors were significantly thinner in myopic eyes compared with the non-myopic eyes. The Meta-analysis revealed that the ChT decreased horizontally from the temporal sector toward the nasal sector in the pediatric myopia population. Another 11 studies reporting the effect of myopia control interventions were included in the second Meta-analysis for the relationship between myopia control treatments and ChT. SFCT significantly increased after orthokeratology (OK) treatment and OK combined with 0.01% atropine (OKA) treatment (WMD=19.47, 95%CI, 15.96 to 22.98, P<0.001; WMD=21.81, 95%CI, 12.92 to 29.70, P<0.001, respectively). The forest plots showed that SFCT changed little in myopic children receiving 0.01% atropine (P=0.30). Furthermore, the Meta-analysis showed that OK treatment had a stronger effect on the value of SFCT in myopic children as compared with 0.01% atropine (WMD=9.86; 95%CI, -0.21 to 19.93, P=0.05). There is no difference between the treatment with OK and OKA treatment in ChT in myopic children (P=0.37). CONCLUSION: The ChT in myopic eyes is thinner than that in non-myopic eyes in pediatric population. Myopia control interventions including OK and OKA lead to ChT thickening, but other treatments such as 0.01% atropine did not show an increase in ChT.

The critical role of m6A methylation in the pathogenesis of Graves' ophthalmopathy.

PURPOSE: To investigate the role of N6-methyladenosine (m6A) RNA modification in the pathogenesis of Graves' ophthalmopathy (GO). METHODS: Surgically excised extraocular muscles from 7 patients with GO and 5 subjects without GO were used. The global m6A levels in the specimens were determined using an m6A RNA methylation quantification kit. RNA sequencing (RNA-seq) was used to analyze the molecules involved in the regulation of m6A RNA methylation and the differential expression of mRNAs between the two groups (4 eyes, respectively). The expression of m6A RNA modification genes was evaluated by real-time PCR. The functional implications of the gene alterations between the GO and control specimens were determined by Gene Ontology analysis. RESULTS: The m6A level was significantly increased in the specimens of GO patients compared to the control specimens (P < 0.05). The expression of m6A methylation regulators, such as WT1 associated protein (WTAP), alkylation repair homolog protein 5 (ALKBH5), E74 like ETS transcription factor 3 (ELF3), YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), YTHDF3 and YTH domain containing 2 (YTHDC2), was significantly upregulated (P < 0.05). Gene Ontology enrichment analysis showed that the most highly upregulated genes and biological pathways were related to the immune response and inflammatory processes such as lymphocyte activation, leukocyte differentiation, cytokine production and cytokine-mediated signaling pathways. CONCLUSIONS: Our results suggest that m6A methylation may play a critical role in the pathogenesis of GO and that targeting genes that regulate m6A methylation may provide a new therapeutic approach for GO.

p.His16Arg of STXBP1 (MUNC18-1) Associated With Syntaxin 3B Causes Autosomal Dominant Congenital Nystagmus.

Congenital nystagmus (CN) is an ocular movement disorder manifested as involuntary conjugated binocular oscillation and usually occurs in early infancy. The pathological mechanism underlying CN is still poorly understood. We mapped a novel genetic locus 9q33.1-q34.2 in a larger Chinese family with autosomal dominant CN and identified a variant (c.47A>G/p.His16Arg) of STXBP1 by exome sequencing, which fully co-segregated with the nystagmus phenotype in this family and was absent in 571 healthy unrelated individuals. The STXBP1 encodes syntaxin binding protein 1 (also known as MUNC18-1), which plays a pivotal role in neurotransmitter release. In unc-18 (nematode homolog of MUNC18-1) null Caenorhabditis elegans, we found that the p.His16Arg exhibits a compromised ability to rescue the locomotion defect and aldicarb sensitivity, indicating a functional defect in neurotransmitter release. In addition, we also found an enhanced binding of the p.His16Arg mutant to syntaxin 3B, which is a homolog of syntaxin 1A and specifically located in retinal ribbon synapses. We hypothesize that the variant p.His16Arg of STXBP1 is likely to affect neurotransmitter release in the retina, which may be the underlying etiology of CN in this family. Our results provide a new perspective on understanding the molecular mechanism of CN.

Ultrathin and Robust Micro-Nano Composite Coating for Implantable Pressure Sensor Encapsulation.

Implantable pressure sensors enable more accurate disease diagnosis and real-time monitoring. Their widescale usage is dependent on a reliable encapsulation to protect them from corrosion of body fluids, yet not increasing their sizes or impairing their sensing functions during their lifespans. To realize the above requirements, an ultrathin, flexible, waterproof while robust micro-nano composite coating for encapsulation of an implantable pressure sensor is designed. The composite coating is composed of a nanolayer of silane-coupled molecules and a microlayer of parylene polymers. The mechanism and principle of the composite encapsulation coating with high adhesion are elucidated. Experimental results show that the error of the sensors after encapsulation is less than 2 mmHg, after working continuously for equivalently over 434 days in a simulated body fluid environment. The effects of the coating thickness on the waterproof time and the error of the sensor are also studied. The encapsulated sensor is implanted in an isolated porcine eye and a living rabbit eye, exhibiting excellent performances. Therefore, the micro-nano composite encapsulation coating would have an appealing application in micro-nano-device protections, especially for implantable biomedical devices.

Young patients with divergence insufficiency related to excessive near work.

The purpose of this study is to explore the relationships between excessive near work and divergence insufficiency esotropia in young adults. A prospective study described a series of young patients with divergence insufficiency esotropia related to excessive near work between 2012 and 2017. The medical records of twelve young patients with divergence insufficiency esotropia and a history of excessive near work were reviewed, and the duration of near work, angle of primary position deviations at distance and at near, and angle of primary position deviations after refraining from near work for 3 months were analyzed. All patients with divergence insufficiency esotropia (age range: 21-35 years) showed an initial esodeviation ranging from 18 to 35 prism diopters for distance fixation and ranging from 8 to 20 prism diopters for near. Neurological evaluation in all cases was normal. Myopic refractive errors were detected in twelve patients. Every patient persisted near work for more than 6 h a day over a period of several months (minimum 4 months). Reductions in esodeviation were noted in twelve patients after refraining from near work for more than 3 months. Only one patient was diplopia free in all positions of gaze. The remaining eleven patients were treated successfully, six with prisms and five with surgery. They were all orthophoric and demonstrated restored binocularity at the post-treatment examinations. Our findings suggested that excessive near work might influence the development of divergence insufficiency esotropia in young adults. Refraining from excessive near work could decrease the degree of esodeviation in these patients.

FRMD7 Mutations Disrupt the Interaction with GABRA2 and May Result in Infantile Nystagmus Syndrome.

Purpose: To identify the pathogenic gene of infantile nystagmus syndrome (INS) in three Chinese families and explore the potential pathogenic mechanism of FERM domain-containing 7 (FRMD7) mutations. Methods: Genetic testing was performed via Sanger sequencing. Western blotting was used to analyze protein expression of FRMD7. Glutathione S-transferase pull-down and immunoprecipitation were conducted to investigate the proteins interacting with FRMD7. Rescue assays were performed in Caenorhabditis elegans to explore the potential role of FRMD7 in vivo. Results: We recruited three Chinese families with X-linked INS and identified a duplication and two missense mutations in FRMD7: c.998dupA/p.His333Glnfs*2, c.580G>A/p.Ala194Thr, and c.973A>G/p.Arg325Gly (one in each family). Expression levels of three mutants were similar to that of wild-type FRMD7 in vitro. Interestingly, the mutant p.His333Glnfs*2 exhibited a predominantly nuclear location, whereas wild-type FRMD7 localized to the cytoplasm. In addition, we found FRMD7 to directly interact with the loop between transmembrane domains 3 and 4 of GABRA2, a type A gamma-aminobutyric acid (GABA) receptor (GABAARs) subunit critical for receptor transport and localization, whereas the mutants p.Ala194Thr and p.Arg325Gly exhibited decreased binding to GABRA2. In frm-3 (a nematode homologue of FRMD7) null C. elegans, we found that FRMD7 mutants exhibited a poor rescue effect on the defects of locomotion and fluorescence recovery after photobleaching of GABAARs. Conclusions: Our findings identified three FRMD7 mutants in three Chinese families with X-linked INS and confirmed GABRA2 as a novel binding partner of FRMD7. These findings suggest that FRMD7 plays an important role by targeting GABAARs.

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 novel deletion downstream of the PAX6 gene identified in a Chinese family with congenital aniridia.

PURPOSE: Congenital aniridia, a severe bilateral panocular visual disorder, is an autosomal dominantly inherited eye anomaly. Mutations in the paired box 6 gene (PAX6) have been shown to be responsible for congenital aniridia in most patients. The purpose of the present study was to report clinical features of a Chinese family with congenital aniridia and to screen novel genetic mutations for congenital aniridia. METHODS: All members of a three-generation family underwent comprehensive ophthalmic examination, and 8 of its 25 members were diagnosed with congenital aniridia. The proband was analyzed by exome sequencing and whole genome sequencing, and linkage analysis was performed for the family. The mutation was confirmed by direct DNA sequencing. RESULTS: Using Illumina's Human Linkage-12 beadchip microarray (including 6090 SNPs) whole genome scan, the LOD score value showed that the interval on chromosome 11 between rs1389423 to rs910090 exhibited a strong linkage. A novel heterozygous 469 kb deletion mutation within the downstream region of PAX6 (chr11:31189937-31659379) was identified in all affected family members, but not in unaffected family members or 2000 ethnically matched controls. CONCLUSION: A novel deletion mutation was identified within the PAX6 downstream region that results in congenital aniridia.

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.

A novel splice donor site mutation in EPHA2 caused congenital cataract in a Chinese family.

BACKGROUND: Congenital cataract is a rare disorder characterized by crystallin denaturation, which becomes a major cause of childhood blindness. Although more than fifty pathogenic genes for congenital cataract have been reported, the genetic causes of many cataract patients remain unknown. In this study, the aim is to identify the genetic cause of a five-generation Chinese autosomal dominant congenital cataract family. METHODS: Whole exome sequencing (WES) was performed on three affected and one unaffected member of the family, known causative genes were scanned first. Sanger sequencing was used to validate co-segregation of the candidate variant in the family. The impact on the transcript and amino acid sequences of the variant was further analyzed. RESULTS: We identified a novel splice donor site mutation c. 2825+1G >A in EPHA2 that was absent in public and in-house databases and showed co-segregation in the family. This variant resulted in an altered splice that led to protein truncation. CONCLUSIONS: The mutation we identified was responsible for congenital cataract in our studied family. Our findings broaden the spectrum of causative mutations in EPHA2 gene for congenital cataract and suggest that WES is an efficient strategy to scan variants in known causative genes for genetically heterogeneous diseases.

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.

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.

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.

[Linkage analysis of a Chinese family with autosomal dominant congenital retinaochoroidal coloboma].

OBJECTIVE: To map the candidate gene by linkage analysis in a Chinese family with autosomal dominant congenital retinaochoroidal coloboma. METHODS: A detailed clinical examination was performed for all patients in the family. The genomic DNA of all family members was extracted from peripheral blood leukocytes. Linkage analysis and genome-wide linkage screening was conducted using fluorescent detection of 398 microsatellite markers representing all autosomes at an average resolution of approximately 10 cM. Polymerase chain reaction was carried out to amplify all 398 microsatellite markers. The allele sizes were determined on ABI 3130-Avant genetic analyzer according to an internal size standard, and the results were analyzed using Genescan 3.1 and Genotyper 2.0 software. RESULTS: Linkage analysis showed the markers D2S2382-D2S301-D2S2244-D2S163 co-segregated with the disease locus in all affected members. The maximum Lod score was 3.01(D2S2382). CONCLUSION: The candidate region of the disease gene in the family was located in 2q34-2q35.

Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death.

Atrial fibrillation (AF) is the most common form of sustained clinical arrhythmia. We previously mapped an AF locus to chromosome 5p13 in an AF family with sudden death in early childhood. Here we show that the specific AF gene underlying this linkage is NUP155, which encodes a member of the nucleoporins, the components of the nuclear pore complex (NPC). We have identified a homozygous mutation, R391H, in NUP155 that cosegregates with AF, affects nuclear localization of NUP155, and reduces nuclear envelope permeability. Homozygous NUP155(-/-) knockout mice die before E8.5, but heterozygous NUP155(+/-) mice show the AF phenotype. The R391H mutation and reduction of NUP155 are associated with inhibition of both export of Hsp70 mRNA and nuclear import of Hsp70 protein. These human and mouse studies indicate that loss of NUP155 function causes AF by altering mRNA and protein transport and link the NPC to cardiovascular disease.

Identification of a genetic locus for autosomal dominant infantile cataract on chromosome 20p12.1-p11.23 in a Chinese family.

PURPOSE: To map a gene responsible for infantile cataract in a large four-generation, non-consanguineous Chinese family. METHODS: Twenty-two family members including 17 cataract patients in the Chinese family were analyzed clinically. All family members were genotyped with 382 microsatellite markers that provide genome-wide coverage every 10 cM. Linkage analysis was performed to identify the chromosomal location of the infantile cataract gene in the family. Candidate genes were studied by direct DNA sequence analysis. RESULTS: Genome-wide linkage analysis provided evidence for a genetic locus for infantile cataract on chromosome 20p12.2-20p11.23. The maximum LOD score was 5.15 for marker D20S471 at a recombination fraction of 0. Fine mapping defined the cataract gene within a 7.4 Mb interval between markers D20S915 and D20S912. No mutation was detected in potential candidate genes, BFSP1 and CHMP4B. CONCLUSIONS: Our results suggest that there is a new gene for infantile cataract on chromosome 20p12.2-p11.23. Our results suggest that new genes for infantile cataract could be found through further study of candidate genes at the 20q locus, which may provide insights into the pathogenic mechanisms of cataracts.

T14484C and T14502C in the mitochondrial ND6 gene are associated with Leber's hereditary optic neuropathy in a Chinese family.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited ocular disease which has been associated with three primary mitochondrial DNA mutations: G3640A, G11778A, and T14484C. In this study, we clinically characterized a Chinese family with complete penetrance of LHON. The patients in the family presented with variable clinical features. By direct DNA sequence analysis, we identified both T14484C mutation and a nearby T to C variant at nucleotide 14502 of mitochondria DNA. The T14502C variant altered I58 to V of the protein ND6, which was present in all patients of the family, but not in four unaffected family members and 200 normal controls. The co-existence of both T14484C mutation and T14502C substitution in all patients from the same LHON family suggests that T14502C may play a synergistic role with the primary mutation T14484C. The two variants together may account for the complete penetrance and absence of marked gender bias and visual recovery in the Chinese LHON family although we cannot exclude the possibility of simultaneous involvement of additional mitochondrial variant(s).

Identification of a novel GPR143 mutation in a large Chinese family with congenital nystagmus as the most prominent and consistent manifestation.

Congenital nystagmus is characterized by involuntary, rhythmical, repeated oscillations of one or both eyes. We studied a large Chinese family with nystagmus as a prominent and consistent manifestation phenotype in nine patients to map and identify a disease-causing gene for nystagmus. X-linked recessive inheritance was observed in the family, and foveal hypoplasia was detected in some of the nine patients. The disease gene was mapped to an approximately 10.6 Mb region flanked by DXS996 and DXS7593 on Xp22 with a significant peak multipoint LOD score. Analysis of 21 candidate genes in the region revealed a novel p.S89F mutation in the second transmembrane domain of GPR143, a G protein-coupled receptor which causes ocular albinism when mutated. All male patients in the family were hemizygous for the mutation; the female carriers were heterozygous for the mutation. The p.S89F mutation was not identified in 100 normal females or 100 normal males. Our results indicate that a mutation in the GPR143 gene can cause a variant form of ocular albinism, with congenital nystagmus as the most prominent and only consistent finding in all patients in this Chinese family. These results expand the spectrum of clinical phenotypes associated with GPR143 mutations.