title: Abnormal retinal development associated with FRMD7 mutations.
abstract: Idiopathic infantile nystagmus (IIN) is a genetically heterogeneous disorder, often associated with FRMD7 mutations. As the appearance of the retina is reported to be normal based on conventional fundus photography, IIN is postulated to arise from abnormal cortical development. To determine whether the afferent visual system is involved in FRMD7 mutations, we performed in situ hybridization studies in human embryonic and fetal stages (35 days post-ovulation to 9 weeks post-conception). We show a dynamic retinal expression pattern of FRMD7 during development. We observe expression within the outer neuroblastic layer, then in the inner neuroblastic layer and at 9 weeks post-conception a bilaminar expression pattern. Expression was also noted within the developing optic stalk and optic disk. We identified a large cohort of IIN patients (n = 100), and performed sequence analysis which revealed 45 patients with FRMD7 mutations. Patients with FRMD7 mutations underwent detailed retinal imaging studies using ultrahigh-resolution optical coherence tomography. The tomograms were compared with a control cohort (n = 60). The foveal pit was significantly shallower in FRMD7 patients (P < 0.0001). The optic nerve head morphology was abnormal with significantly decreased optic disk area, retinal nerve fiber layer thickness, cup area and cup depth in FRMD7 patients (P < 0.0001). This study shows for the first time that abnormal afferent system development is associated with FRMD7 mutations and could be an important etiological factor in the development of nystagmus.
authors.affiliation: Ophthalmology Group, School of Medicine, University of Leicester, RKCSB, PO Box 65, Leicester LE2 7LX, UK mgt14@le.ac.uk ig15@le.ac.uk.
authors.forename: Mervyn G
authors.initials: MG
authors.lastname: Thomas
authors.affiliation: MRC-Wellcome Trust Human Developmental Biology Resource (Newcastle), Institute of Human Genetics, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Moira
authors.initials: M
authors.lastname: Crosier
authors.affiliation: MRC-Wellcome Trust Human Developmental Biology Resource (Newcastle), Institute of Human Genetics, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindsay
authors.affiliation: Ophthalmology Group, School of Medicine, University of Leicester, RKCSB, PO Box 65, Leicester LE2 7LX, UK.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Biological Sciences, Developmental Neurobiology Laboratory, Nara Women's University, Nara 630-8506, Japan.
authors.forename: Masasuke
authors.initials: M
authors.lastname: Araki
authors.affiliation: Department of Ophthalmology and Centre for Medical Genetics, Ghent University and Ghent University Hospital, Ghent 9000, Belgium.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Ophthalmology Group, School of Medicine, University of Leicester, RKCSB, PO Box 65, Leicester LE2 7LX, UK.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: McLean
authors.affiliation: Ophthalmology Group, School of Medicine, University of Leicester, RKCSB, PO Box 65, Leicester LE2 7LX, UK.
authors.forename: Viral
authors.initials: V
authors.lastname: Sheth
authors.affiliation: Ophthalmology Group, School of Medicine, University of Leicester, RKCSB, PO Box 65, Leicester LE2 7LX, UK.
authors.forename: Gail
authors.initials: G
authors.lastname: Maconachie
authors.affiliation: Ophthalmology Group, School of Medicine, University of Leicester, RKCSB, PO Box 65, Leicester LE2 7LX, UK Department of Ophthalmology, Nottingham University Hospital NHS Trust, Nottingham, UK.
authors.forename: Shery
authors.initials: S
authors.lastname: Thomas
authors.affiliation: UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: Ophthalmology Group, School of Medicine, University of Leicester, RKCSB, PO Box 65, Leicester LE2 7LX, UK mgt14@le.ac.uk ig15@le.ac.uk.
authors.forename: Irene
authors.initials: I
authors.lastname: Gottlob
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D020417:Nystagmus, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009898:Optic Disk / Q000378:metabolism / Q000473:pathology; D012160:Retina / Q000378:metabolism / Q000473:pathology; D041623:Tomography, Optical Coherence
chemical_list: D003598:Cytoskeletal Proteins; C516168:FRMD7 protein, human; D008565:Membrane Proteins