A novel frame-shift mutation in FRMD7 causes X-linked idiopathic congenital nystagmus in a Chinese family.
ABSTRACT To screen mutations in the FERM domain-containing 7 (FRMD7) gene in a Chinese family with X-linked idiopathic congenital nystagmus (ICN).
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.
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.
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.
- SourceAvailable from: Eric H Souied[show abstract] [hide abstract]
ABSTRACT: Congenital nystagmus (CN) is a common oculomotor disorder (frequency of 1/1,500 live births) characterized by bilateral uncontrollable ocular oscillations, with onset typically at birth or within the first few months of life. This condition is regarded as idiopathic, after exclusion of nervous and ocular diseases. X-linked, autosomal dominant, and autosomal recessive modes of inheritance have been reported, but X-linked inheritance is probably the most common. In this article, we report the mapping of a gene for X-linked dominant CN (NYS1) to the short arm of chromosome X, by showing close linkage of NYS1 to polymorphic markers on chromosome Xp11.4-p11.3 (maximum LOD score of 3.20, over locus DXS993). Because no candidate gene, by virtue of its function, has been found in this region of chromosome Xp, further studies are required, to reduce the genetic interval encompassing the NYS1 gene. It is hoped that the complete gene characterization will address the complex pathophysiology of CN.The American Journal of Human Genetics 05/1999; 64(4):1141-6. · 11.20 Impact Factor
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ABSTRACT: Infantile nystagmus (IN) is an inherited disorder characterized by bilateral ocular oscillatory movements. Recently, mutations in FRMD7 were found to be responsible for X-linked idiopathic infantile nystagmus . We investigated the role of the FRMD7 gene mutations in seven Chinese families with infantile nystagmus. Linkage analysis was performed with fluorescently labeled microsatellite markers, DXS1001 and DXS1047. Analysis of FRMD7 gene mutations was performed by direct sequence to the whole coding regions and exon-intron boundaries of FRMD7 gene in all affected members in seven families with IN. Five novel FRMD7 gene mutations, 70 G>T(p.G24W) in exon 2, c.689-690delAG (p.Ser232del) in exon8, c. 782G>A (p.R260Q) and c. 812G>T (p. C271F) in exon 9, and c. 910C>T (R303X) in exon 10, were identified in five of seven Chinese families with X-linked infantile nystagmus. But we didn't detect the FRMD7 gene mutation in one of seven families, although a positive LOD score of 2.42 (thetamax=0.1) was obtained at DXS1047 . We also found the same mutation, which is c. 782G>A (p.R260Q), occurred in two different families. This is first report that five kinds of FRMD7 gene mutation types occurred in Chinese families with IN, which further support that FRMD7 gene mutations are the underlying pathogenesis of the molecular mechanism for infantile nystagmus.Molecular vision 01/2008; 14:733-8. · 1.99 Impact Factor
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ABSTRACT: To identify the gene mutations causing X-linked infantile nystagmus in two Chinese families (NYS003 and NYS008), of which the NYS003 family was assigned to the FERM domain-containing 7 (FRMD7) gene linked region in our previous study, and no mutations were found by direct sequencing. Two microsatellites, DXS1047 and DXS1001, were amplified using a PCR reaction for the linkage study in the NYS008 family. FRMD7 was sequenced and mutations were analyzed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect FRMD7 mutations in the NYS003 family. The NYS008 family yielded a maximum logarithm of odds (LOD) score of 1.91 at θ=0 with DXS1001. FRMD7 sequencing showed a nucleotide change of c. 623A>G in exon7 of the patients' FRMD7 gene, which was predicted to result in an H208R amino acid change. This novel mutation was absent in 100 normal Han Chinese controls. No FRMD7 gene mutations were detected by MLPA in the NYS003 family. We identified a novel mutation, c. 623A>G (p. H208R), in a Han Chinese family with infantile nystagmus. This mutation expands the mutation spectrum of FRMD7 and contributes to the research on the molecular pathogenesis of FRMD7.Molecular vision 01/2011; 17:461-8. · 1.99 Impact Factor
A novel frame-shift mutation in FRMD7 causes X-linked idiopathic
congenital nystagmus in a Chinese family
Wei Du,1 Juan Bu,1 Jiamei Dong,1,2 Yanlei Jia,3 Jing Li,4 Chen Liang,1 Shancheng Si,1 Lejin Wang1
(The first three authors contributed equally to this work)
1Department of Ophthalmology, Peking University 3rd Hospital, Beijing, P.R. China; 2Department of Cardiology, Party School of
Central Committee of C.P.C., Beijing, P.R. China; 3Department of Ophthalmology, The Municipal Hospital of ZaoZhuang,
Shandong, P.R. China; 4Department of Ophthalmology, Beijing Ji Shui Tan Hospital, Beijing, P.R. China
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
Idiopathic congenital nystagmus (ICN) is primarily a
disorder of neurologic control system that stabilizes the eyes
defined as conjugated, spontaneous, and involuntary ocular
oscillations. The symptoms appear at birth or during the first
three months of life. Many of the patients show X-linked
inheritance. Three disease loci of X-linked ICN have been
mapped to chromosome Xq26.2, Xp11.4 and Xp22.3 [1-3]. In
2006, Tarpey et al.  reported a new member of the FERM
family (4.1 protein, ezrin, radixin, moesin) that mapped to
chromosome Xq26.2, FERM
(FRMD7), which was associated with X-linked ICN.
Mutations associated with ICN include missense mutations,
null mutations, deletions, and frame-shift mutations [1,4-14].
Mutations in FRMD7 are major causes of Chinese familial X-
linked congenital nystagmus and account for approximately
47% of Chinese patients with the disorder .
FRMD7 contains 12 exons and encodes a protein with
714 amino acids. In this study, we present a previously
unreported mutation in the 12th exon of FRMD7 in a Chinese
family with ICN. We found a 4 bp deletion (c.1486–1489 del
TTTT), resulting in a predicted truncation at amino acid
residue 523. Our data expands on the spectrum of FRMD7
Correspondence to: Lejin Wang, Department of Ophthalmology,
Peking University 3rd Hospital, 49 North Garden Rd, Haidian,
Beijing, 100191, P.R. China; Phone: +86-010-82266563; FAX:
+86-010-82089951; email: firstname.lastname@example.org
mutations causing ICN, and further confirm the role of
FRMD7 in the pathogenesis of ICN.
Clinical data and 5 ml of blood samples were collected from
a Chinese Han family with ICN. The Institutional Review
Board approved the project and investigators followed the
principles of the Declaration of Helskinki. Informed consent
was obtained from each person.
Human genomic DNA was isolated from blood
lymphocytes according to standard protocol (Roche
Diagnostics Corporation, Shanghai, China), using the DNA
Isolation Kits for Mammalian Blood according to the
manufacturer’s instructions (Roche Diagnostics Corporation,
Indianapolis, IN). PCR-amplification of FRMD7’s 12 exons
and exon-intron boundaries was performed using a standard
40 μl PCR buffer system with primers listed in Table 1. DNA
sequence analysis was determined by BigDye™ terminator
cycle sequencing with an ABI-3130 Genetic Analyzer (ABI
Corporation, Carlsbad, CA).
Molecular Vision 2011; 17:2765-2768 <http://www.molvis.org/molvis/v17/a299>
Received 13 August 2011 | Accepted 18 October 2011 | Published 22 October 2011
© 2011 Molecular Vision
The family from Shandong Province, China, included 4 male
patients and 5 female patients who were carriers (Figure 1).
All patients in this family had various reduced visual acuity
with a similar pattern of nystagmus.
Sequencing of the 12 coding exons of FRMD7 in one of
the patients revealed a deletion in exon 12 (c.1486–
1489delTTTT: Figure 2), which resulted in frame-shift at
codon 497 and a putative stop codon 26 amino acids
downstream in the translated protein (p.F497fs26X). The
mutation was confirmed, and was further extended to other
family members. The mutation co-segregated with the disease
phenotype in male patients and heterozygous female
individuals, while it was not found in other unaffected
relatives or in the 100 normal controls.
FRMD7 shows a strong sequence homology with 2 other
FERM family members, FERM, RhoGEF and pleckstrin
domain protein 1 (FARP1) and FARP2, which are known to
promote the dendritic growth of spinal motor neuron subtypes
and modulate the length of neurite branching in developing
cortical neurons, respectively [15-17]. Recently, Pu et al.
 reported that expression of FRMD7 in the fetal brain was
mainly detected in the brainstem, which is associated with
ocular motor control. Betts-Henderson et al.  found
FRMD7 may play a role in multiple aspects of neuronal
FRMD7 contains FERM-N, FERM-M, FERM-C, and FA
structural domains in the NH2-terminus with conserved
domains concentrated at the B41 and FERM-C domains
(Figure 3). The B41 domain is located from residue 1 to 192,
and the FERM-C domain is located from residue 186 to 279.
Approximately 44 mutations causing congenital nystagmus
have been reported in FRMD7, including 23 missense
mutations, 8 splicing site mutations, 1 synonymous mutation,
4 nonsense mutations, 6 frame-shift mutations, and 2 deletions
[1,4-14]. These mutations are mainly located in the FERM
domain in FRMD7.
TABLE 1. PRIMERS USED TO AMPLIFY THE EXONS OF FRMD7.
Product length (bp)
Figure 1. Pedigree of the Chinese family
with ICN. The squares and circles
respectively. The shaded symbols
signify the affected individuals, the
dotted circles represent female carriers,
a diagonal line symbol indicates a
deceased family member, and the arrow
indicates the proband.
Molecular Vision 2011; 17:2765-2768 <http://www.molvis.org/molvis/v17/a299>© 2011 Molecular Vision
We are reporting the third frame-shift mutation in
Chinese people. The presence of the mutation in all patients
and carriers, and its absence in unaffected individuals and the
100 unrelated controls, support that the identified mutation
causes the pathogenesis of ICN. The mutation identified in
this study was found in the 12th exon, resulting in a truncated
FRMD7 with FERM domain, while the COOH-terminus of
FRMD7 protein was deleted. In the Pu et al.  study, a
nonsense mutation type (COOH-terminally truncated protein)
exhibited a different subcellular localization pattern from the
wild type, which suggests that the COOH-terminus of
FRMD7 may play a key role in the subcellular localization of
Conclusion: Our results expand the spectrum of
FRMD7 mutations causing ICN and also confirm the role of
FRMD7 in the pathogenesis of ICN. Direct sequencing of
FRMD7 can be used as a method in gene diagnosis of
idiopathic congenital nystagmus.
We are grateful to the patients and their family members for
their cooperation in this study. This study was supported by
the National Natural Science Foundation (No. 30950007).
The study was approved by the Ethics Committee of the
Peking University 3rd Hospital and conformed to the
Declaration of Helsinki. Great thanks for the comments from
Mark Tso, Professor, Wilmer Eye Institute, Johns Hopkins
University. Many thanks should also be given to Tina-Marie
(email@example.com), for her editorial assistance.
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Articles are provided courtesy of Emory University and the Zhongshan Ophthalmic Center, Sun Yat-sen University, P.R. China.
The print version of this article was created on 19 October 2011. This reflects all typographical corrections and errata to the
article through that date. Details of any changes may be found in the online version of the article.