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

Abstract

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.

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

“…Mutations of FRMD7 are the major etiological contributor of ICN (1)(2)(3)(4)(5). A previous study by the current authors demonstrated that FRMD7 interacts with RhoGDI, whereby it specifically activates the Rac1 signalling involved in neuronal development.…”

“…There are currently no effective treatments for ICN and patients experience a significant decrease in their quality of life over time. To date, >40 mutations of FRMD7 have been detected worldwide in people from various ethnic backgrounds (1)(2)(3)(4)(5)(7)(8)(9). A previous study by the current authors identified two novel missense mutations (c.781C>G and c.886G>C) and a truncated mutation (c.1003C>T) of human FRMD7 in three X-linked ICN pedigrees (3).…”

“…It has been demonstrated that mutations in the FERM domain containing protein 7 (FRMD7) gene is one of the major causes of X-linked idiopathic congenital nystagmus (ICN) (1)(2)(3)(4)(5). ICN is an oculomotor disorder arising from a primary defect in the regions related to ocular motor control.…”

Lysosomal storage disease in the brain: mutations of the β-mannosidase gene identified in autosomal dominant nystagmus

“…2 The most common cause of congenital nystagmus seems to be mutations of the X-linked FRMD7 gene (NYS1), which also have been detected by us and others in China. 4 Mutations in the GPR143 gene have been found to be responsible for another X-linked ocular albinism and nystagmus (NYS6). Moreover, at least six susceptibility loci have been mapped from 1996 to 2014, including NYS2 (6p12; OMIM 164100), NYS3 (7p11; OMIM 608345), NYS4 (13q; OMIM 193003), NYS5 (Xp11.4; OMIM 300589), NYS7 (1q31-q32; OMIM 614826), and one additional locus in the X chromosome identified by a recent study.…”

“…6 Identification of disease-causing mutations will provide a basis for determining the molecular pathogenesis of the disease and for the development of effective therapies. To identify potential genetic etiology for these ocular disorders in our hereditary disease program, 4 we applied whole-exome sequencing (WES) and bioinformatics to recently recruited patients with nystagmus. In this study we report both the identification of heterozygous mutations in the MANBA gene in patients with infantile nystagmus and the molecular association of nystagmus with lysosomal storage disease (LSDs).…”