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X-Linked Idiopathic Infantile Nystagmus Associated with a Missense Mutation in FRMD7 Alan Shiels Washington University School of Medicine in St

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X-Linked Idiopathic Infantile Nystagmus Associated with a Missense Mutation in FRMD7 Alan Shiels Washington University School of Medicine in St Washington University School of Medicine Digital Commons@Becker Open Access Publications 2007 X-linked idiopathic infantile nystagmus associated with a missense mutation in FRMD7 Alan Shiels Washington University School of Medicine in St. Louis Thomas M. Bennett Washington University School of Medicine in St. Louis Jessica B. Prince Washington University School of Medicine in St. Louis Lawrence Tychsen Washington University School of Medicine in St. Louis Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Shiels, Alan; Bennett, Thomas M.; Prince, Jessica B.; and Tychsen, Lawrence, ,"X-linked idiopathic infantile nystagmus associated with a missense mutation in FRMD7." Molecular Vision.13,. 2233-2241. (2007). https://digitalcommons.wustl.edu/open_access_pubs/1787 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Molecular Vision 2007; 13:2233-41 <http://www.molvis.org/molvis/v13/a253/> ©2007 Molecular Vision Received 5 November 2007 | Accepted 26 November 2007 | Published 29 November 2007 X-linked idiopathic infantile nystagmus associated with a missense mutation in FRMD7 Alan Shiels, Thomas M. Bennett, Jessica B. Prince, Lawrence Tychsen Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO Purpose: 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. Methods: Eye movements were recorded using binocular infrared digital video-oculography. Genomic DNA was pre- pared from blood or buccal-cells, and linkage analysis was performed using short tandem repeat (STR) and single nucle- otide polymorphism (SNP) markers. Pedigree and haplotype data were managed using Cyrillic, and LOD scores calcu- lated using MLINK. Mutation profiling of PCR-amplified exons was performed by dye-terminator cycle-sequencing and analyzed by automated capillary electrophoresis. Results: Video-oculography of affected males recorded conjugate, horizontal, pendular nystagmus with increasing-ve- locity 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 [θ]=0) and DXS1047 (Z=3.87, θ=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. Conclusions: 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. Idiopathic infantile nystagmus (IIN), also referred to as forms may also present. Less often, IIN may exhibit predomi- congenital nystagmus (CN), congenital “motor” nystagmus nantly vertical or torsional (elliptical) waveforms. Beyond (CMN), idiopathic congenital nystagmus (ICN), or congeni- exclusion of sensory defect nystagmus and neurological nys- tal idiopathic nystagmus (CIN), is a genetically heterogeneous tagmus, IIN must also be carefully differentiated from certain form of developmental nystagmus that usually presents be- other forms of infantile nystagmus including, fusional malde- tween birth and 6 months of age with an estimated annual velopment nystagmus syndrome or latent fixation nystagmus, incidence of 1/20,000 [1]. IIN is a diagnosis of “primary” or spamus nutans syndrome, which is characterized by asymetric isolated nystagmus after exclusion of “secondary” nystagmus or unilateral nystagmus, and periodic alternating nystagmus, associated with patent neurological disease (e.g. glioma, cor- which resembles IIN except that the null-point shifts position tical visual impairment), or identifiable sensory visual defects in a regular cyclic pattern [2]. including, opacities of the cornea, lens and vitreous, foveal All three classical types of Mendelian inheritance have hypoplasia in albinism and aniridia, achromatopsia, retinal been reported for IIN (Table 1); however, X-linked inherit- dystrophies, and optic nerve hypoplasia. Classical IIN pre- ance is likely the most common form [3]. Two loci for autoso- sents as conjugate, horizontal oscillations of the eyes, in pri- mal dominant IIN have been identified on 6p12 (NYS2) [4,5] mary or eccentric gaze (i.e. uniplanar), often with a preferred and 7p11.2 (NYS3) [6,7] with tentative evidence from haplo- head turn or tilt that is associated with a fixed “null-point” type analysis for additional loci [8,9]. Indeed, a third locus for where the nystagmus intensity is dampened [2]. Other associ- autosomal donminant nystagmus (NYS4) has been mapped ated features are restricted to strabismus (esotropia), refrac- to 13q31-q33 [10,11]; however NYS4 involves tive error (astigmatism), and occasionally head nodding. Eye vestibulocerebellar dysfunction and is clinically distinct from movement recordings reveal that classical IIN is predominantly IIN. X-linked IIN has been associated with two physically a horizontal jerk waveform, with a “diagnostic” accelerating independent loci (both symbolized NYS1) that map to Xp11.4- velocity slow phase. However, pendular and triangular wave- p11.3 [8,12] and Xq26.3-q27.1 [13-18]. In addition, a locus for infantile periodic alternating nystagmus (NYS5), which Correspondence to: A. Shiels, Department of Ophthalmology and often accompanies albinism, has been assigned to chromo- Visual Sciences, Campus Box 8096, Washington University School some X [19]. Here we define an interval on Xq for IIN and of Medicine, 660 South Euclid Ave., St. Louis, MO, 63110; Phone: identify a mutation in the gene encoding a putative cytoskeletal (314) 362-1637; FAX: (314) 362-1646; email: protein referred to as four-point-one (4.1), ezrin, radixin, [email protected] 2233 Molecular Vision 2007; 13:2233-41 <http://www.molvis.org/molvis/v13/a253/> ©2007 Molecular Vision moesin (FERM) domain containing-7 (FRMD7), which was technology Information [NCBI]) were polymerase chain re- recently associated with XL-IIN [20-24]. action (PCR) amplified with M13-tailed primers [25] in the presence of an IRDye800 labeled M13-universal primer (Li- METHODS Cor, Lincoln, NE), and detected using a 4200 DNA analyzer Participants and ophthalmic exams: Ethical approval for this running Gene ImagIR software (Li-Cor) as described previ- study was obtained from the Washington University Human ously [26]. Single nucleotide polymorphism (SNP) markers Research Protection Office, and written informed consent was from the SNP database (dbSNP, NCBI), were PCR amplified provided by all participants prior to enrollment in accordance with M13-tailed primers designed from the flanking sequence with the tenets of the Declaration of Helsinki. Participants were (250-500 bp apart) using appropriate software (e.g. ascertained from the ophthalmic records at St. Louis Children’s PrimerQuest, idtdna.com), and scored by sequencing essen- Hospital. Blood samples were collected by venepuncture tially as described for mutation analysis below. Pedigree and (about 20 ml) or finger-stick (about 200 µl) into K2EDTA haploptype data were managed using Cyrillic (v.2.1) software vacutainer or microtainer tubes (BD Biosciences, San Jose, (FamilyGenetix Ltd., Reading, UK), and two-point LOD scores CA), respectively. Buccal-cell samples were self-collected into (Z) calculated using the MLINK sub-program from the LINK- 50 ml conical tubes (Falcon; BD Biosciences) after vigorous AGE (5.1) package of programs [27] assuming X-linked domi- rinsing (about 30 s) with Scope (about 20 ml) mouthwash nant inheritance with 45% penetrance in females. Marker al- (Procter & Gamble, Cincinnati, OH). lele frequencies were assumed to be equal, and a gene fre- Ophthalmologic examination included: best-corrected quency of 0.0001 was assumed for the disease locus. visual acuity in each eye (using optotypes at 33 cm and 6 m), Mutation analysis: Genomic sequence for FRMD7 was cycloplegic refraction, visual field testing, pupillary exami- obtained from the Entrez human genome browser (NCBI), and nation for isocoria and afferent defects, slit lamp examination gene-specific M13-tailed PCR primers were selected from the with retro-illumination, ocular motor examination for strabis- NCBI resequencing amplicon (RSA) probe database (NCBI). mus (cover testing), binocular sensorial testing of fusion and Genomic DNA (1 ng/µl, 10-50 µl reactions), was amplified stereopsis (Titmus and Randot tests), and dilated funduscopic (35-40 cycles) in a GeneAmp 9700 thermal cycler using examination of the optic nerves, maculae, and peripheral reti- AmpliTaq Gold Universal PCR Master Mix (Applied nae. Care was taken to verify absence of signs of ocular or Biosystems, Foster City, CA) and gene-specific primers (25 oculocutaneous albinism, e.g. iris transillumination defects,
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