Idiopathic Congenital Nystagmus Research Articles

Electroretinography in congenital nystagmus patients with a normal fundus examination.

To identify the ophthalmic causes of congenital nystagmus with normal eye examination by electroretinography (ERG). Retrospective observational study. We reviewed the medical records of patients younger than 6months of age who presented between June 2008 and November 2011 with nystagmus and no other neurological signs following an otherwise normal eye examination. A complete ophthalmic examination and ERG (Nicolet Bravo system; Nicolet Biomedial & RETIscan; Roland Instruments), fundus photography, and Ishihara color test were performed to identify any ophthalmic causes of congenital nystagmus. Thirty-three patients met the criteria. Rod dysfunction was diagnosed in 4 patients (12.1%), cone dysfunction in 2 patients (6.1%), and cone-rod dysfunction in 1 patient (3.0%). The results of ERG were negative in 2 patients (6.1%). Idiopathic infantile nystagmus was diagnosed in the remaining 24 patients (72.7%) based on their normal ERG examination. In Korean congenital nystagmus patients with a normal fundus examination, achromatopsia and Leber's congenital amaurosis are uncommon causes. ERG is needed to make a definite diagnosis and provide prognostic information in congenital idiopathic nystagmus patients with a normal fundus examination.

Truncated FRMD7 proteins in congenital Nystagmus: novel frameshift mutations and proteasomal pathway implications

Idiopathic congenital nystagmus (ICN) manifests as involuntary and periodic eye movements. To identify the genetic defect associated with X-linked ICN, Whole Exome Sequencing (WES) was conducted in two affected families. We identified two frameshift mutations in FRMD7, c.1492dupT/p.(Y498Lfs*15) and c.1616delG/p.(R539Kfs*2). Plasmids harboring the mutated genes and qPCR analysis revealed mRNA stability, evading degradation via the NMD pathway, and corroborated truncated protein production via Western-blot analysis. Notably, both truncated proteins were degraded through the proteasomal (ubiquitination) pathway, suggesting potential therapeutic avenues targeting this pathway for similar mutations. Moreover, we conducted a comprehensive analysis, summarizing 140 mutations within the FRMD7 gene. Our findings highlight the FERM and FA structural domains as mutation-prone regions. Interestingly, exons 9 and 12 are the most mutated regions, but 90% (28/31) mutations in exon 9 are missense while 84% (21/25) mutations in exon 12 are frameshift. A predominant occurrence of shift code mutations was observed in exons 11 and 12, possibly associated with the localization of premature termination codons (PTCs), leading to the generation of deleterious truncated proteins. Additionally, our conjecture suggests that the loss of FRMD7 protein function might not solely drive pathology; rather, the emergence of aberrant protein function could be pivotal in nystagmus etiology. We propose a dependence of FRMD7 protein normal function primarily on its anterior domain. Future investigations are warranted to validate this hypothesis.

Novel mutations of the X-linked genes associated with early-onset high myopia in five Chinese families

PurposeTo report novel pathogenic variants of X-linked genes in five Chinese families with early-onset high myopia (eoHM) by using whole-exome sequencing and analyzing the phenotypic features.Methods5 probands with X-linked recessive related eoHM were collected in Ningxia Eye Hospital from January 2021 to June 2022. The probands and their family members received comprehensive ophthalmic examinations,and DNA was abstracted from patients and family members. Whole-exome sequencing was performed on probands to screen the causative variants, and all suspected pathogenic variants were determined by Sanger sequencing and co-segregation analysis was performed on available family members. The pathogenicity of novel variants was predicted using silico analysis and evaluated according to ACMG guidelines. RT-qPCR was used to detect differences in the relative mRNAs expression of candidate gene in mRNAs available with the proband and family members in the pedigree 2. The relationship between genetic variants and clinical features was analyzed.ResultsAll probands were male, and all pedigrees conformed to an X-linked recessive inheritance pattern. They were diagnosed with high myopia at their first visits between 4 and 7 years old. Spherical equivalent ranged between − 6.00D and − 11.00D.The five novel hemizygous variants were found in the probands, containing frameshift deletion variant c.797_801del (p.Val266Alafs*75) of OPN1LW gene in the pedigree 1, nonsense variant c.513G > A (p.Trp171Ter)of RP2 gene in the pedigree 2, missense variant c.98G > T (p.Cys33Phe) of GPR143 gene in the pedigree 3, frameshift deletion variant c.1876_1877del (p.Met626Valfs*22) of FRMD7 gene in the pedigree 4 and inframe deletion variant c.670_ 675del (p.Glu192_ Glu193del) of HMGB3 gene in the pedigree 5. All variants were classified as pathogenic or likely pathogenic by the interpretation principles of HGMD sequence variants and ACMG guidelines. In family 2, RT-qPCR showed that the mRNA expression of RP2 gene was lower in the proband than in other normal family members, indicating that such variant caused an effect on gene function at the mRNA expression level. Further clinical examination showed that pedigrees 1, 2, 3, and 4 were diagnosed as X-linked recessive hereditary eye disease with early-onset high myopia, including quiescent cone dysfunction, retinitis pigmentosa, ocular albinism, and idiopathic congenital nystagmus respectively. The pedigree 5 had eoHM in the right eye and ptosis in both eyes.ConclusionIn this paper,we are the first to report five novel hemizygous variants in OPN1LW, RP2, GPR143, FRMD7, HMGB3 genes are associated with eoHM. Our study extends the genotypic spectrums for eoHM and better assists ophthalmologists in assessing, diagnosing, and conducting genetic screening for eoHM.

Disrupted voxel-mirrored homotopic connectivity in congenital nystagmus using resting-state fMRI.

Idiopathic congenital nystagmus (CN) is a rare eye disease that can cause early blindness (EB). CN deficits are observed most frequently with oculomotor dysfunction; however, it is still unclear what neuromechanics underly CN with EB. Based on that visual experience requires the functional integration of both hemispheres, we hypothesized that CN adolescents with EB might exhibit impaired interhemispheric synchrony. Our study aimed to investigate the interhemispheric functional connectivity alterations using voxel-mirrored homotopic connectivity (VMHC) and their relationships with clinical features in CN patients. This study included 21 patients with CN and EB, and 21 sighted controls (SC), who were matched for sex, age and educational level. The 3.0 T MRI scan and ocular examination were performed. The VMHC differences were examined between the two groups, and the relationships between mean VMHC values in altered brain regions and clinical variables in the CN group were evaluated by Pearson correlation analysis. Compared with the SC group, the CN had increased VMHC values in the bilateral cerebellum posterior and anterior lobes/cerebellar tonsil/declive/pyramis/culmen/pons, middle frontal gyri (BA 10) and frontal eye field/superior frontal gyri (BA 6 and BA 8). No particular areas of the brain had lower VMHC values. Furthermore, no correlation with the duration of disease or blindness could be demonstrated in CN. Our results suggest the existence of interhemispheric connectivity changes and provide further evidence for the neurological basis of CN with EB.

FRMD7 Gene Alterations in a Pakistani Family Associated with Congenital Idiopathic Nystagmus.

Congenital idiopathic nystagmus (CIN) is an oculomotor disorder characterized by repetitive and rapid involuntary movement of the eye that usually develops in the first six months after birth. Unlike other forms of nystagmus, CIN is widely associated with mutations in the FRMD7 gene. This study involves the molecular genetic analysis of a consanguineous Pakistani family with individuals suffering from CIN to undermine any potential pathogenic mutations. Blood samples were taken from affected and normal individuals of the family. Genomic DNA was extracted using an in-organic method. Whole Exome Sequencing (WES) and analysis were performed to find any mutations in the causative gene. To validate the existence and co-segregation of the FRMD7 gene variant found using WES, sanger sequencing was also carried out using primers that targeted all of the FRMD7 coding exons. Additionally, the pathogenicity of the identified variant was assessed using different bioinformatic tools. The WES results identified a novel nonsense mutation in the FRMD7 (c.443T>A; p. Leu148 *) gene in affected individuals from the Pakistani family, with CIN resulting in a premature termination codon, further resulting in the formation of a destabilized protein structure that was incomplete. Co-segregation analysis revealed that affected males are hemizygous for the mutated allele c.443T>A; p. Leu148 * and the affected mother is heterozygous. Overall, such molecular genetic studies expand our current knowledge of the mutations associated with the FRMD7 gene in Pakistani families with CIN and significantly enhance our understanding of the molecular mechanisms involved in genetic disorders.

Nystagmus-related FRMD7 gene influences the maturation and complexities of neuronal processes in human neurons.

AimsIdiopathic congenital nystagmus (ICN) is an oculomotor disorder caused by the defects in the ocular motor control regions of the brain. Mutations in FRMD7, a member of the FERM family of proteins, associated with cytoskeletal dynamics, are the most frequent causes of X‐linked ICN. Previous studies illustrated that FRMD7 is involved in the elongation of neurites during neuronal development; however, almost all the studies were performed on mice cell models. The complexity in the human neuronal network might suggest a unique vulnerability of human neurons to FRMD7 mutations.MethodsHerein, we successfully established human neuronal cell models with FRMD7 mutations, from fibroblasts‐reprogrammed neurons (iNs). In these neurons, the complexity of the neuronal processes was measured by the induced ratio, total neurite length, the number of terminals, and the number of maturation neurons.ResultsThe complexity of the neuronal processes was greatly reduced during various reprogramming stages in the presence of FRMD7 mutations. Consistently, the expression of the three main Rho GTPases was significantly increased by FRMD7 mutations. Interestingly, a slightly diverse phenotype is observed in different derived neurons.ConclusionWe established ideal human neuron models and confirmed that the mutation in FRMD7 influences the maturation and complexities of neuronal processes, which might be involved with the Rho GTPase signaling.

Mutations analysis of FRMD7 gene in idiopathic congenital nystagmus families

Objective To reveal the pathogenic mutations in Chinese families with idiopathic congenital nystagmus(ICN) Methods Six families with ICN were recruited from Subei People's Hospital.DNA was extracted from peripheral blood samples of all participants.All coding and exon-intronic boundary regions of the targeted gene FRMD7 were amplified with PCR and sequenced using Sanger sequencing to detect potential pathogenic mutations.This study followed the Helsinki Declaration and was approved by the Ethics Committee of Subei People's Hospital (NO.2015KY-126). All patients or their guardians signed informed consent. Results Three mutations (c.902A>G, c.1944T>A and 1945G>T) were screened in two families after co-segregation validation of intrafamilial genotype-phenotype, c.1944T>A and 1945G>T were newly detected mutations which were not detected in 100 normal controls.No significant mutations were found in the FRMD7 coding region and adjacent splicing sites in the probands of the other four families. Conclusions Two novel pathogenic mutations of FRMD7 are discovered, which expands the pathogenic mutational spectrum of FRMD7 gene causing ICN. Key words: Idiopathic congenital nystagmus; FRMD7 gene; Missense mutation; Nonsense mutation

Identification and functional characterization of a novel missense mutation in FRMD7 responsible for idiopathic congenital nystagmus.

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder which seriously reduces childhood visual acuity. X-linked inheritance is the most common pattern, and mutations in FERM domain-containing protein 7 (FRMD7) are the major cause. Here, we recruited a four-generation Chinese family with X-linked ICN for the causative mutational screening of FRMD7. A novel missense variant, c.805 A > C, was identified in the proband. The mutation was confirmed in all the affected individuals but was not detected in unaffected family members or 100 unrelated Chinese male controls. The mutation causes a substitution of lysine to glutamine at position 269 (p.Lys269Gln, K269Q). The FRMD7 mutant inhibits the formation and extension of neurites. Moreover, the mutation disrupts FRMD7 interaction with calcium/calmodulin-dependent serine protein kinase and neurite formation. Together, our data expand the mutation spectrum of FRMD7 causing ICN and provide an insight into the pathogenesis of nystagmus.

Identification of a novel idiopathic congenital nystagmus‑causing missense mutation, p.G296C, in the FRMD7 gene.

Exploring the genetic basis for idiopathic congenital nystagmus is critical for improving our understanding of its molecular pathogenesis. In the present study, direct sequencing using gene specific primers was performed in order to identify the causative mutations in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. A comprehensive ophthalmological examination, including eye movement recordings, fundus examination, and retinal optical coherence tomography imaging was also conducted, to characterize the disease phenotype. The results revealed that the two brothers exhibited clear signs of nystagmus without any other ocular anomalies. Direct sequencing revealed a G to T transition (c.886G>T) in exon 9 of the four-point-one, ezrin, radixin, moesin domain-containing 7 (FRMD7) gene, which resulted in a conservative substitution of glycine to cysteine at codon 296 (p.G296C), leading to idiopathic congenital nystagmus in the two affected brothers. c.886G>T is a novel idiopathic congenital nystagmus-inducing mutation in the FRMD7 gene. This finding expands the spectrum of known gene mutations in idiopathic congenital nystagmus, and may be useful for faster gene diagnosis, prenatal testing, the development of potential gene therapies, and for improving the understanding of the molecular pathogenesis of idiopathic congenital nystagmus.

Stable cell lines of human SH-SY5Y uniformly expressing wild-type or mutant-type FERM domain containing 7 gene

It has been reported that FERM domain containing 7 (FRMD7) may cause X-linked idiopathic congenital nystagmus (ICN). A total of >40 mutations of the FRMD7 gene have been identified, however their pathogenic role remains unclear. In the present study, enhanced green fluorescent protein-tagged wild-type (WT) and mutant (MT) FRMD7 (c. C781>G) were expressed in stably expressing human neuroblastoma SH-SY5Y cells following viral transfection and antibiotic selection. Uniform expression of the FRMD7 fusion proteins was confirmed via fluorescence microscopy and western blotting. The expression profiles of neuron-specific proteins and Rho guanine triphosphatases (GTPases) differed significantly between the wild-type and mutant cell lines. Levels of Mtap2, NF-M, nestin, GAP43 and Rac1 mRNA were significantly increased in MT-FRMD7 cells compared with controls (P<0.01). However, the expression of Rac1 protein did not differ significantly among the two cell lines. Taken together, the results of the current study suggest that MT-FRMD7 influences the expression of neuron-specific genes and Rho GTPases, which may be involved in the pathogenesis of ICN. The FRMD7 stable expression cell line may facilitate future studies investigating the role of this protein in neuronal development.

The Effect of Acupuncture on Visual Function in Patients with Congenital and Acquired Nystagmus.

Background: The aim of this study is to examine the short-term effect of visual function following acupuncture treatment in patients with congenital idiopathic nystagmus and acquired nystagmus (CIN and AN). Methods: An observational pilot study on six patients with confirmed diagnosis of nystagmus (three CIN and three AN patients (2♀, 4♂; mean age 42.67; SD ± 20.57 y)), was performed. Acupuncture treatment was done following a standardized protocol applying needle-acupuncture on the body and the ears. The treatment was scheduled with 10 sessions of 30 min duration over five weeks. To assess the effect of the treatment, we performed before, between, and after acupuncture objective measurement of the BCVA (EDTRS charts), contrast vision (CSV-1000, Vector Vision), nystagmography (Compact Integrated Pupillograph), complemented by evaluation questionnaires. A placebo non-acupuncture control group (Nr: 11, 22 eyes; 8♀, 3♂; mean age: 33.34 y (SD ± 7.33 y)) was taken for comparison. Results: The results showed that, following acupuncture treatment, CIN and AN patients showed improvement (SD± mean) in their binocular BCVA (baseline: 0.45 ± 0.36; between: 0.53 ± 0.34 and post-treatment: 0.51 ± 0.28), and in their monocular contrast sensitivity (baseline: 11.29 ± 12.35; between: 11.43 ± 11.45 and post-treatment: 14.0 ± 12.22). The post-/baseline-difference showed a significant improvement in contrast vision and in BCVA for CIN and AN patients, but not for controls (p = 0.029 and p = 0.007, respectively). The effect of the eye showed also, within CIN and AN, significant values for the examined parameters in the post-/baseline difference (p = 0.004 and p ≤ 0.001). Evaluated only binocularly, the respective between-/baseline and post-/baseline difference in the CIN and AN group showed significant values (p < 0.045). Two AN patients reported reduction of oscillations. Among general subjective symptoms, our patients reported reduction of tiredness and headache attacks, improvement of vision, and shorter sleep onset time. Conclusion: The applied acupuncture protocol showed improvement in the visual function of nystagmus patients and thus, in their quality of life. Further studies are mandatory to differentiate which group of nystagmus patients would benefit more from acupuncture.

Ultrastructural alteration of extraocular muscle proprioceptor in congenital idiopathic nystagmus

Objective: To explore the ultrastructural alteration of extraocular muscle proprioceptor in congenital idiopathic nystagmus (CIN). Methods: Case-control study. Ten extraocular muscle samples were collected from five CIN children who underwent nystagmus surgeries in Beijing Children's Hospital from March 2015 to March 2016. Another ten extraocular muscle specimens were collected from five strabismus children in surgery at the same period as normal contrast. There were 3 male patients and 2 female patients of CIN with age of 61-147 months (median age: 91 months). The ultrastructure of extraocular muscle proprioceptors was compared between these two groups by transmission electron microscope. Results: Twenty-three proprioceptors were found in extraocular muscle specimens of CIN children, whereas thirty-three proprioceptors were detected in strabismus children. The ultrastructure of extraocular muscle proprioceptor of CIN altered greatly comparing with that of the control. Fourteen extraocular muscle proprioceptors of CIN were discovered much smaller and vacuolated not only at inner capsules but also at the space between inner and outer capsules with lipofuscins and myeloid bodies in the intrafusal muscle fibers. Sensory nerve fibers degenerated greatly with a lot of lipofuscins and myeloid bodies in these sensory nerve fibers. Demyelination also appeared in some severe cases. Nine extraocular muscle proprioceptors of CIN showed significant dissolving degeneration of myofibrils and proliferation of collagen fibrils. The normal structures could not be distinguished in these proprioceptors. And these structural disorders also appeared in extrafusal muscle fibers and nerve endings. Conclusion: The ultrastructure of extraocular muscle proprioceptor in CIN turned much smaller and had significantly structural disorder.(Chin J Ophthalmol, 2017, 53: 136-139).

Clinical characteristics and surgical treatment of idiopathic congenital nystagmus in 224 patients

To study clinical characteristics and surgical treatment of idiopathic congenital nystagmus (ICN). A retrospective study was conducted in 224 patients with ICN in Tianjin eye hospital from July 2007 to February 2013. There were 224 patients, 158 (70.54%) males and 66 (29.5%) females, mean age was (11.6±8.4) years and (11.4±6.4) years separately. Horizontal nystgamus happened in 215 cases, 3 cases were vertical type and 6 cases were mixed. 214 cases were with no history of operation and 10 patients had ever underwent surgeries before. Furthermore, 151 patients combined with strabismus and refractive error, anterior segment or retinal disorders, which accounting for 67.4% of all the patients. 48 patients were associated myopia, 30 patients with hyperopia, 43 patients with strabismus. Among them, 153 cases of compensatory head position direction were horizontal with face turn, 43 cases (43/153, 28.1%) showed face turning to the left, 110 cases (110/153, 71.9%) showed face turning to the right. Surgeries were designed according to the compensatory head position and head retroversion angle. For 15 patients with double intermediate zones, the position which was often used with good visual function was chosen for operation design. As for the patients with nystagmus and strabismus, the transfer null zone to primary position for the dominant eye and strabismus surgery for the other eye was chosen. And for complicated patients with compensative head position, the dominant head posture were designed for surgery. ICN is dominated by male with variable clinical manifestations. Surgical choice for ICN depends on the direction of head position and if there is strabismus accompanying it.The aim of ocular muscle surgery is to transfer null zone to primary position. (Chin J Ophthalmol, 2016, 52: 574-578).

GPR143 Gene Mutations in Five Chinese Families with X-linked Congenital Nystagmus.

The ocular albinism type I (OA1) is clinically characterized by impaired visual acuity, nystagmus, iris hypopigmentation with translucency, albinotic fundus, and macular hypoplasia together with normally pigmented skin and hair. However, it is easily misdiagnosed as congenital idiopathic nystagmus in some Chinese patients with OA1 caused by the G-protein coupled receptor 143 (GPR143) gene mutations. Mutations in the FERM domain–containing 7 (FRMD7) gene are responsible for the X-linked congenital idiopathic nystagmus. In this study, five Chinese families initially diagnosed as X-linked congenital nystagmus were recruited and patients underwent ophthalmological examinations. After direct sequencing of the FRMD7 and GPR143 genes, five mutations in GPR143 gene were detected in each of the five families, including a novel nonsense mutation of c.333G>A (p.W111X), two novel splicing mutations of c.360+1G>C and c.659-1G>A, a novel small deletion mutation of c.43_50dupGACGCAGC (p.L20PfsX25), and a previously reported missense mutation of c.703G>A (p.E235K). Optical coherence tomography (OCT) examination showed foveal hypoplasia in all the affected patients with nystagmus. Our study further expands the GPR143 mutation spectrum and contributes to the study of GPR143 molecular pathogenesis. Molecular diagnosis and optical coherence tomography (OCT) are two useful tools for differential diagnosis.

Quantitative assess the efficacy of congenital idiopathic nystagmus surgery by digital eye tracker

To evaluate the feasibility of independently developed digital eye tracker in determining the efficacy of congenital idiopathic nystagmus (CIN) surgery. Aprospective selfpairing study. The surgical efficacy was evaluated by independently developed eye tracker in 16 CIN patients. The null zone and the frequency, amplitude, intensity of nystagmus in various gazing position were recorded with eye tracker pre and post operatively. The consistency of null zone determined by digital eye tracker and clinical investigation were evaluated. The preoperative and postoperative rectification of horizontal and vertical nystagmus in the horizontal direction of individual patient were compared by paired samples t-test. The improvement or aggravation quantity were recorded by comparing preoperative and postoperative intensity of nystagmus every 5° within 25°. The null zone got from digital eye tracker and clinical investigation were highly consistent (r = 0.952, P < 0.01). The horizontal and vertical intensity improved in 9 patients (t = 2.335-6.609, P < 0.05) and 5 patients (t = 2.176-5.471, P < 0.05) respectively after surgery. There were 67.63% (117/173) horizontal intensity and 69.94% (121/173) vertical intensity improvement. The independently developed digital eye tracker can quantitatively evaluate the pre and post-operative nystagmus and analyze the surgical efficacy for CIN patients.

A novel mutation in FRMD7 causes X-linked idiopathic congenital nystagmus in a North Indian family

Idiopathic congenital nystagmus (ICN) is the most common form of oculomotor disorder characterized by involuntary bilateral ocular oscillations. Primarily the disease is an ocular anomaly but the pathophysiology is associated with neuronal cytoskeletal dynamics in the brain. In the current study, a three generation North Indian family affected with X-linked idiopathic congenital nystagmus (XLICN) was recruited. Our aim was to identify the causal mutation for ICN in the family by screening the candidate gene, FERM domain containing-7 (FRMD7). This gene has been implicated in XLICN as it regulates neuronal cytoskeletal proteins and neurite outgrowth in the developing brain. Therefore, the entire protein coding region, including splice junctions, 5′ UTR and 3′ UTR of FRMD7 was screened by PCR-Sanger sequencing. Targeted sequencing revealed a novel A to G transition in the exon seven (c.556A>G), resulting in a conservative substitution of methionine by valine at codon 186 (p.M186V). A cohort of healthy individuals was also checked for presence of the putative causal variant by allele specific PCR. All the affected males and carriers in the family shared this variant; however, this was absent in the unaffected males as well as 100 unrelated healthy individuals. Further, protein homology modeling revealed that the change p.M186V might destabilize the interaction between the FERM-M and FERM-C domains. The in silico prediction supports pathogenicity of the mutation; nevertheless it needs in vivo validation in the future. This is the first genetic investigation of XLICN in a North Indian family where we report a novel causal mutation c.556A>G (p.M186V) in the gene FRMD7.

A FRMD7 variant in a Japanese family causes congenital nystagmus.

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder that causes a large proportion of childhood visual impairment. Here we describe a missense variant (p.L292P) within a mutation-rich region of FRMD7 detected in three affected male siblings in a Japanese family with X-linked ICN. Combining sequence analysis and results from structural and functional predictions, we report p.L292P as a variant potentially disrupting FRMD7 function associated with X-linked ICN.

Expression of a novel splice variant of FRMD7 in developing human fetal brains that is upregulated upon the differentiation of NT2 cells.

FRMD7 mutations are associated with X-linked idiopathic congenital nystagmus (ICN); however, the underlying mechanisms whereby mutations of FRMD7 lead to ICN remain unclear. In a previous study, the first FRMD7 splice variant (FRMD7-S) was cloned and identified, and FRMD7-S was hypothesized to play a significant role in neuronal differentiation and development. The present study investigated a novel multiple exon-skipping mRNA splice variant of FRMD7, termed FRMD7_SV2, which was detected in NT2 cells using northern blotting. The mRNA expression levels of FRMD7_SV2 in the developing human fetal brain were examined using reverse transcription polymerase chain reaction (PCR), while the expression levels in NT2 cells treated with retinoid acid (RA) or bone morphogenetic protein-2 were investigated using quantitative PCR. The results revealed that the expression of FRMD7_SV2 was spatially and temporally restricted in human fetal brain development, and was upregulated upon RA-induced neuronal differentiation of the NT2 cells. These results indicated that as a novel splice variant of FRMD7, FRMD7_SV2 may play a role in neuronal development.

Identification of Three Novel Mutations in the FRMD7 Gene for X-linked Idiopathic Congenital Nystagmus

Idiopathic congenital nystagmus (ICN) consists of involuntary and periodic ocular motility, often with seriously reduced visual acuity. To identify the genetic defects associated with X-linked ICN, we performed PCR-based DNA direct sequencing of two candidate genes, FRMD7 and GPR143, in four families. Mutation analysis led to identification of three novel mutations, p.S260R, p.Q487X, and p.V549Y fsX554, in FRMD7 in three of the recruited families. Results from structural modeling indicated that the p.S260R may potentially disrupt FRMD7 function through loss of a phosphorylation site and/or interference with protein-protein interactions. Both p.Q487X, and p.V549Y fsX554 mutations were predicted to generate nonfunctional truncated proteins. Using a capture next generation sequencing method, we excluded CASK as the responsible gene for the remaining family. Combining sequence analysis and structural modeling, we report three novel mutations in FRMD7 in three independent families with XLICN, and provide molecular insights for future XLICN diagnosis and treatment.

Erratum to: Novel mutation c.980_983delATTA compound with c.986C>A mutation of the FRMD7 gene in a Chinese family with X-linked idiopathic congenital nystagmus

Erratum to: Novel mutation c.980_983delATTA compound with c.986C>A mutation of the FRMD7 gene in a Chinese family with X-linked idiopathic congenital nystagmus