X-linked idiopathic infantile nystagmus associated with missense mutation in FRMD7

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Molecular vision (Impact Factor: 1.99). 11/2007; 13(252-55):2233-41.
Source: PubMed


Infantile nystagmus is a clinically and genetically heterogeneous eye movement disorder. Here we map and identify the genetic mutation underlying X-linked idiopathic infantile nystagmus (XL-IIN) segregating in two Caucasian-American families.
Eye movements were recorded using binocular infrared digital video-oculography. Genomic DNA was prepared from blood or buccal-cells, and linkage analysis was performed using short tandem repeat (STR) and single nucleotide polymorphism (SNP) markers. Pedigree and haplotype data were managed using Cyrillic, and LOD scores calculated using MLINK. Mutation profiling of PCR-amplified exons was performed by dye-terminator cycle-sequencing and analyzed by automated capillary electrophoresis.
Video-oculography of affected males recorded conjugate, horizontal, pendular nystagmus with increasing-velocity waveforms in primary gaze converting to jerk nystagmus in eccentric gaze. Linkage analysis detected significantly positive two-point LOD scores (Z) at markers DXS8078 (Z=4.82, recombination fraction [theta]=0) and DXS1047 (Z=3.87, theta=0). Haplotyping indicated that the IIN locus mapped to the physical interval DXS8057-(11.59 Mb)-rs6528335 on Xq25-q26. Sequencing of positional-candidate genes detected a c.425T>G transversion in exon-6 of the gene for FERM domain containing-7 (FRMD7) that cosegregated with affected and carrier status. In addition, the same change was found to cosegregate with IIN in a genetically unrelated family but was not detected in 192 control individuals.
The c.425T>G change is predicted to result in the missense substitution of the phylogenetically conserved leucine at codon 142 for an arginine (p.L142R), and supports a causative role for FRMD7 mutations in the pathogenesis of XL-IIN.

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    • "The FERM domain-containing protein 7 (FRMD7) at Xq26–Xq27 has been identified as responsible for X-linked ICN (5,6). Two novel missense mutations of the FRMD7 gene in the Chinese population have been reported (7), and to date, >40 mutations have been identified (8,9). A previous study indicated that FRMD7 may play an important role in neurite outgrowth, and downregulation of FRMD7 results in a strong reduction of the neurite length (10). "
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    ABSTRACT: 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.
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    ABSTRACT: 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.
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