FRMD7 Research Articles

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

A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus

Idiopathic infantile nystagmus (IIN) is a genetically heterogeneous disorder of eye movement that can be caused by mutations in the FRMD7 gene that encodes a FERM domain protein. FRMD7 is expressed in the brain and knock-down studies suggest it plays a role in neurite extension through modulation of the actin cytoskeleton, yet little is known about its precise molecular function and the effects of IIN mutations. Here, we studied four IIN-associated missense mutants and found them to have diverse effects on FRMD7 expression and cytoplasmic localization. The C271Y mutant accumulates in the nucleus, possibly due to disruption of a nuclear export sequence located downstream of the FERM-adjacent domain. While overexpression of wild-type FRMD7 promotes neurite outgrowth, mutants reduce this effect to differing degrees and the nuclear localizing C271Y mutant acts in a dominant-negative manner to inhibit neurite formation. To gain insight into FRMD7 molecular function, we used an IP-MS approach and identified the multi-domain plasma membrane scaffolding protein, CASK, as a FRMD7 interactor. Importantly, CASK promotes FRMD7 co-localization at the plasma membrane, where it enhances CASK-induced neurite length, whereas IIN-associated FRMD7 mutations impair all of these features. Mutations in CASK cause X-linked mental retardation. Patients with C-terminal CASK mutations also present with nystagmus and, strikingly, we show that these mutations specifically disrupt interaction with FRMD7. Together, our data strongly support a model whereby CASK recruits FRMD7 to the plasma membrane to promote neurite outgrowth during development of the oculomotor neural network and that defects in this interaction result in nystagmus.

Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus

Congenital nystagmus (NYS) is characterized by bilateral, spontaneous, and involuntary movements of the eyeballs that most commonly presents between 2 and 6 months of life. To date, 44 different FRMD7 gene mutations have been found to be etiological factors for the NYS1 locus at Xq26-q27. The aim of this study was to find the FRMD7 gene mutations in a large eleven-generation Indian pedigree with 71 members who are affected by NYS. Mutation analysis of the entire coding region and splice junctions of the FRMD7 gene revealed a novel missense mutation, c.A917G, predicts a substitution of Arg for Gln at codon 305 (Q305R) within exon 10 of FRMD7. The mutation was detected in hemizygous males, and in homozygous and heterozygous states in affected female members of the family. This mutation was not detected in unaffected members of the family or in 100 unrelated control subjects. This mutation was found to be at a highly conserved residue within the FERM-adjacent domain in affected members of the family. Structure prediction and energetic analysis of wild-type FRMD7 compared with mutant (Q305R) revealed that this change in amino acid led to a change in secondary structure predicted to be an energetically unstable protein. The present study represents the first confirmation of FRMD7 gene mutations in a multigenerational Indian family and expands the mutation spectrum for this locus.

A Novel Missense Mutation, R279S, in FRMD7 Gene in a Chinese Family with X-linked Infantile Nystagmus

Purpose: To identify the gene mutations causing an X-linked Chinese Family with infantile nystagmus. Methods: Families were ascertained and patients underwent complete ophthalmological examinations. Blood samples were collected and DNA was extracted. Four microsatellites were amplified by PCR reaction for linkage study. FRMD7 gene was sequenced and mutations analyzed. Results: A significant lod score of 2.4 was yielded at the microsatellite marker DXS1001. Sequencing of FRMD7 gene showed a nucleotide change of c. 837G>C in the exon9 of FRMD7 gene in the patients, which predicted to result in an R279S amino acid change. This novel mutation was absent in 100 normal Han Chinese controls. Conclusions: We identified a novel mutation, c. 837G>C (p. R279S), in a Han Chinese family with Infantile nystagmus. This mutation expands the mutation spectrum of FRMD7 and help to further study molecular pathogenesis of FRMD7.

Molecular genetics advances of congenital idiopathic nystagmus

Congenital idiopathic nystagmus (CIN) is genetically heterogeneous. Autosomal dominant, autosomal recessive and X-linked patterns of inheritance have described. At least three distinct loci are related to autosomal dominant and X-linked patterns. One causative gene for X-linked form has been identified (FRMD7, Xq26.2) through linkage analysis. The molecular genetics advances of the congenital idiopathic nystagmus (CIN) are reviewed.

The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus.

Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.

Current advance in molecular genetics of congenital idiopathic nystagmus

Congenital idiopathic nystagmus (CIN) is characterized by monoocular or biocular involuntary,rhythmical,repeated oscillations.CIN is often referred to congenital 'motor' nystagmus since nystagmus occurs in the absence of a clinically demonstrable defect in the visual sensory system.CIN is genetically heterogeneous,and patterns of its inheritance have been well-known to include autosomal dominant.autosomal recessive and X-linked patterns.In recent years, many different genetic loci for CIN have been mapped,and researchers have found some candidate causing-disease genes.This review focuses on the recent advances of gene mapping and candidate gene analysis for molecular research of CIN. Key words: Nystagmus/congenital idiopathic; Gene; FRMD7gene; GPR143 gene; Inheritance

Novel Intragenic FRMD7 Deletion in a Pedigree with Congenital X-Linked Nystagmus

Objective: To identify the disease-causing mutation in a large 3 generation pedigree of X-linked congenital nystagmus.Methods: Twenty-three members of a single pedigree, including 7 affected males, 2 affected females, 5 obligate carriers, and 9 unaffected family members were tested for mutations in the FRMD7 gene using PCR-based DNA sequencing assays and multiplex PCR assays for deletions.Results: A hemizygous deletion of exons 2, 3, and 4 of FRMD7 was detected in all affected males in the family and was absent from 40 control subjects.Conclusions: A range of missense, nonsense, frameshift, and splicing mutations in FRMD7 have been shown to cause X-linked congenital nystagmus. Here we show for the first time that large intragenic deletions of FRMD7 can also cause this form of nystagmus.

The nystagmus-associated FRMD7 gene regulates neuronal outgrowth and development

Mutations in the gene encoding FERM domain-containing 7 protein (FRMD7) are recognized as an important cause of X-linked idiopathic infantile nystagmus (IIN). However, the precise role of FRMD7 and its involvement in the pathogenesis of IIN are not understood. In the present study, we have explored the role of FRMD7 in neuronal development. Using in situ hybridization and immunohistochemistry, we reveal that FRMD7 expression is spatially and temporally regulated in both the human and mouse brain during embryonic and fetal development. Furthermore, we show that FRMD7 expression is up-regulated upon retinoic acid (RA)-induced differentiation of mouse neuroblastoma NEURO2A cells, suggesting FRMD7 may play a role in this process. Indeed, we demonstrate, for the first time, that knockdown of FRMD7 during neuronal differentiation results in altered neurite development. Taken together, our data suggest that FRMD7 is involved in multiple aspects of neuronal development, and have direct importance to further understanding the pathogenesis of IIN.

A Novel Frameshift Mutation in FRMD7 Causing X-Linked Idiopathic Congenital Nystagmus

Idiopathic congenital nystagmus (ICN) is a common oculomotor disorder characterized by bilateral involuntary, periodic, and predominantly ocular oscillations. X-linked ICN (XLICN) with incomplete penetrance in females is the most common inheritance form, and FERM domain containing (FRMD7) mutation is the major reason for XLICN families. To date, 39 FRMD7 mutations have been identified, and 50% of the XLICN pedigrees have yielded FRMD7 mutations in the Western population. In this study, we identified a novel frameshift mutation (c.1274-1275delTG) in the FRMD7 gene in six XLICN pedigrees. Incorporated with data reported from other two Chinese groups, approximately 47% XLICN pedigrees were caused by the FRMD7 mutation in China. Therefore, this study showed that mutation analysis of the FRMD7 gene had diagnostic value not only in the Western population but also in one of the biggest Eastern populations, Chinese XLICN families. In addition, the results indicated the type of FRMD7 mutation associated with the penetrance of female carriers of XLICN.

A comparison of clinical and eye movement characteristics between albinism and idiopathic infantile nystagmus with and without mutations in the FRMD7 gene

Abstract Purpose Nystagmus consists of involuntary to and fro oscillations of the eyes. The differences between nystagmus associated with albinism and idiopathic infantile nystagmus (IIN) are unclear. Recently mutations in a novel gene called FRMD7 have been found to underlie a significant proportion of X‐linked IIN. Phenotypic variations in eye movements between FRMD7 and non‐FRMD7 types have also been recently described. We have compared clinical and eye movement characteristics between albinism and IIN with and without mutations in the FMRD7 gene. Methods Clinical features and eye movement were recorded from 37 albino subjects, 83 subjects with the FRMD7 mutation and 45 subjects without the FRMD7 mutation. Results Mean visual acuity was significantly worse in albinos compared to IIN patients (p<<0.0001). Although there was no significant differences between the groups (p>0.05) for nystagmus amplitude or foveation, the frequency of nystagmus was significantly slower in albinism (p<<0.0001). In addition, nystagmus associated with albinism was significantly more likely to be jerk nystagmus rather than pendular nystagmus compared to FRMD7 group (p<<0.0001). The most common waveform associated with albinism was pure jerk nystagmus, whereas non‐FRMD7 was more likely to be associated with jerk with extended foveation. Conclusion Contrary to available literature, nystagmus associated with albinism shows distinct differences to IIN both with and without FRMD7 mutations. This suggests the possibility of different underlying mechanisms to albinism and IIN in generating eye oscillations although these are yet to be elucidated

Study of gene mutation in a Chinese family with X-linked congenital nystagmus

To study the disease-causing gene for a Chinese family with X-linked congenital idiopathic nystagmus. It was a retrospective study. The phenotype of a Chinese family with congenital nystagmus was identified by investigating the history and the clinical features of each family member. The mode of inheritance in this family was ascertained by the pedigree analysis. Linkage analysis was performed to identify the possible locus harboring the disease-causing gene. Direct DNA sequence analysis was performed to find the mutation responsible for this disease. The positive LOD score was obtained for 10 microsatellite makers on chromosome Xq25-Xq27, and the maximum LOD score with DXS1211 was 3.91. A 2-bp deletion in exon 8 of FRMD7 was detected after direct DNA sequence analysis, which was cosegregated with all patients in this family. Congenital nystagmus is a clinically and genetically heterogeneous ocular movement disease. Mutation of the FRMD7 gene is the cause of congenital nystagmus in this family.

Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene

Aims:This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family.Methods:Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons...

Allelic Variation of the FRMD7 Gene in Congenital Idiopathic Nystagmus

To perform a genotype-phenotype correlation study in an X-linked congenital idiopathic nystagmus pedigree (pedigree 1) and to assess the allelic variance of the FRMD7 gene in congenital idiopathic nystagmus. Subjects from pedigree 1 underwent detailed clinical examination including nystagmology. Screening of FRMD7 was undertaken in pedigree 1 and in 37 other congenital idiopathic nystagmus probands and controls. Direct sequencing confirmed sequence changes. X-inactivation studies were performed in pedigree 1. The nystagmus phenotype was extremely variable in pedigree 1. We identified 2 FRMD7 mutations. However, 80% of X-linked families and 96% of simplex cases showed no mutations. X-inactivation studies demonstrated no clear causal link between skewing and variable penetrance. We confirm profound phenotypic variation in X-linked congenital idiopathic nystagmus pedigrees. We demonstrate that other congenital nystagmus genes exist besides FRMD7. We show that the role of X inactivation in variable penetrance is unclear in congenital idiopathic nystagmus. Clinical Relevance We demonstrate that phenotypic variation of nystagmus occurs in families with FRMD7 mutations. While FRMD7 mutations may be found in some cases of X-linked congenital idiopathic nystagmus, the diagnostic yield is low. X-inactivation assays are unhelpful as a test for carrier status for this disease.