Anthony T Moore

Great Ormond Street Hospital for Children NHS Foundation Trust, Londinium, England, United Kingdom

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Publications (189)1070.18 Total impact

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    Ophthalmology 04/2015; 122(4):e22. DOI:10.1016/j.ophtha.2014.08.041 · 6.17 Impact Factor
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    ABSTRACT: We have identified TUBGCP4 variants in individuals with autosomal-recessive microcephaly and chorioretinopathy. Whole-exome sequencing performed on one family with two affected siblings and independently on another family with one affected child revealed compound-heterozygous mutations in TUBGCP4. Subsequent Sanger sequencing was performed on a panel of individuals from 12 French families affected by microcephaly and ophthalmic manifestations, and one other individual was identified with compound-heterozygous mutations in TUBGCP4. One synonymous variant was common to all three families and was shown to induce exon skipping; the other mutations were frameshift mutations and a deletion. TUBGCP4 encodes γ-tubulin complex protein 4, a component belonging to the γ-tubulin ring complex (γ-TuRC) and known to regulate the nucleation and organization of microtubules. Functional analysis of individual fibroblasts disclosed reduced levels of the γ-TuRC, altered nucleation and organization of microtubules, abnormal nuclear shape, and aneuploidy. Moreover, zebrafish treated with morpholinos against tubgcp4 were found to have reduced head volume and eye developmental anomalies with chorioretinal dysplasia. In summary, the identification of TUBGCP4 mutations in individuals with microcephaly and a spectrum of anomalies in eye development, particularly photoreceptor anomalies, provides evidence of an important role for the γ-TuRC in brain and eye development. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 03/2015; DOI:10.1016/j.ajhg.2015.02.011 · 10.99 Impact Factor
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    ABSTRACT: To present a detailed clinical and molecular study of four patients from two consanguineous families with a similar childhood-onset retinal dystrophy resulting from novel homozygous nonsense mutations in RBP3. Four children with mutations in RBP3 encoding interphotoreceptor binding protein (IRBP) were ascertained by whole exome sequencing and subsequent direct Sanger sequencing. Detailed phenotyping was performed including full clinical evaluation, electroretinography, fundus photography, fundus autofluorescence (FAF) imaging and spectral domain optical coherence tomography (OCT). Results of ophthalmic examination, whole exome sequence analysis and Sanger sequence analysis. Two novel homozygous nonsense mutations (c.1530T>A ; p.Y510* and c.3454G>T ; p.E1152*) in RBP3 were identified in four patients from two families. All four patients had a similar, unusual retinal dystrophy characterized by childhood onset high myopia, generalized rod and cone dysfunction and an unremarkable fundus appearance. FAF imaging showed multiple paracentral foci of low autofluorescence in one patient and patchy increased FAF in the region of the vascular arcades in another. The OCT showed loss of outer retinal bands over peripheral macular areas in all 4 cases. This report is the first to describe the retinal dystrophy in children caused by homozygous nonsense RBP3 mutations highlighting the requirement for IRBP in normal eye development and visual function. Longitudinal study will reveal if the four children reported here will progress to a more typical retinitis pigmentosa phenotype previously described in adults with RBP3 mutations. RBP3 related disease should be considered in children with high myopia and retinal dystrophy, particularly when there are no significant fundus changes. Copyright © 2015 by Association for Research in Vision and Ophthalmology.
    Investigative Ophthalmology &amp Visual Science 03/2015; DOI:10.1167/iovs.15-16520 · 3.66 Impact Factor
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    ABSTRACT: Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration (‘retinal disease-specific’); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one ‘retinal disease-specific’ USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype-phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.
    European journal of human genetics: EJHG 02/2015; DOI:10.1038/ejhg.2014.283 · 4.23 Impact Factor
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    ABSTRACT: Oliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy. Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
  • Acta ophthalmologica 12/2014; DOI:10.1111/aos.12592 · 2.51 Impact Factor
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    ABSTRACT: Mutations in Prominin-1 (Prom1) gene are known to cause retinitis pigmentosa and Stargardt disease, both of which are associated with progressive photoreceptor cell death. There are no effective therapies for either disorder. The aim of this study was to investigate the mechanism of the retinal degeneration in Prom1-deficient mouse models. We constructed Prom1 knockout mice with two distinct genetic backgrounds of C57BL/6 and C57BL/6xCBA/NSlc, and investigated the photoreceptor degeneration by means of histology and functional tests. In addition, we examined the effect of light on the Prom1-/- retina by rearing the mice in the normal light/dark cycle and completely dark conditions. Finally, we investigated if the retinoic-acid derivative Fenretinide slowed the pace of retinal degeneration in these mouse models. The Prom1-/- knockout mice with both backgrounds developed photoreceptor degeneration after eye opening, but the CB57/BL6 background mice developed photoreceptor cell degeneration much faster than the C57BL/6xCBA/NSlc mice, demonstrating genetic background dependency. Interestingly, our histological and functional examination showed that the photoreceptor cell degeneration of Prom1 knockout mice was light dependent, and was almost completely inhibited when the mutant mice were kept in the dark. The Prom1 knockout retina showed strong downregulation of expression of the visual cycle components, Rdh12 and Abca4. Furthermore, administration of Fenretinide, which lowers the level of the toxic lipofuscin, slowed the degeneration of photoreceptor cells. These findings improve our understanding of the mechanism of cell death in Prominin1 related disease and provide evidence that fenretinide may be worth studying in human disease. Copyright © 2014 by Association for Research in Vision and Ophthalmology.
    Investigative Ophthalmology &amp Visual Science 11/2014; 56(1). DOI:10.1167/iovs.14-15479 · 3.66 Impact Factor
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    ABSTRACT: Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous inherited degenerative retinopathies caused by abnormalities of photoreceptors or retinal pigment epithelium in the retina leading to progressive sight loss. Rhodopsin is the prototypical G-protein-coupled receptor located in the vertebrate retina and responsible for dim light vision. Here, novel M39R and N55K variants were identified as causing an intriguing sector phenotype of RP in affected patients, with selective degeneration in the inferior retina. In order to gain insights into the molecular aspects associated with this sector RP phenotype, whose molecular mechanism remains elusive, the mutations were constructed by site-directed mutagenesis, expressed in heterologous systems and studied by biochemical, spectroscopic and functional assays. M39R and N55K opsins had variable degrees of chromophore regeneration when compared to WT opsin, but showed no gross structural misfolding or altered trafficking. M39R showed a faster rate for transducin activation than WT rhodopsin with a faster metarhodopsinII decay, whereas N55K presented a reduced activation rate and an altered photobleaching pattern. N55K also showed an altered retinal release from the opsin binding pocket upon light exposure, affecting its optimal functional response. Our data suggest that these sector RP mutations cause different protein phenotypes which may be related to their different clinical progression. Overall, these findings illuminate the molecular mechanisms of sector RP associated with rhodopsin mutations.
    Journal of Biological Chemistry 10/2014; 289(52). DOI:10.1074/jbc.M114.609958 · 4.60 Impact Factor
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    ABSTRACT: Purpose To describe the clinical and molecular characteristics of patients with childhood-onset Stargardt disease (STGD). Design Retrospective case series. Participants Forty-two patients who were diagnosed with STGD in childhood at a single institution between January 2001 and January 2012. Methods A detailed history and a comprehensive ophthalmic examination were undertaken, including color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and pattern and full-field electroretinograms. The entire coding region and splice sites of ABCA4 were screened using a next-generation, sequencing-based strategy. The molecular genetic findings of childhood-onset STGD patients were compared with those of adult-onset patients. Main Outcome Measures Clinical, imaging, electrophysiologic, and molecular genetic findings. Results The median ages of onset and the median age at baseline examination were 8.5 (range, 3–16) and 12.0 years (range, 7-16), respectively. The median baseline logarithm of the minimum angle of resolution visual acuity was 0.74. At baseline, 26 of 39 patients (67%) with available photographs had macular atrophy with macular/peripheral flecks; 11 (28%) had macular atrophy without flecks; 1 (2.5%) had numerous flecks without macular atrophy; and 1 (2.5%) had a normal fundus appearance. Flecks were not identified at baseline in 12 patients (31%). SD-OCT detected foveal outer retinal disruption in all 21 patients with available images. Electrophysiologic assessment demonstrated retinal dysfunction confined to the macula in 9 patients (36%), macular and generalized cone dysfunction in 1 subject (4%), and macular and generalized cone and rod dysfunction in 15 individuals (60%). At least 1 disease-causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; ≥2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD. Conclusions Childhood-onset STGD is associated with severe visual loss, early morphologic changes, and often generalized retinal dysfunction, despite often having less severe fundus abnormalities on examination. One third of children do not have flecks at presentation. The relatively high proportion of deleterious ABCA4 variants supports the hypothesis that earlier onset disease is often owing to more severe variants in ABCA4 than those found in adult-onset disease.
    Ophthalmology 10/2014; 122(2). DOI:10.1016/j.ophtha.2014.08.012 · 6.17 Impact Factor
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    ABSTRACT: Purpose: Gene therapy trials for inherited photoreceptor disorders are planned. Anatomical metrics to select the best candidates and outcomes are needed. Adaptive optics (AO) imaging enables visualization of photoreceptor structure, though analytical tools are lacking. Here we present criteria to assess residual photoreceptor integrity in achromatopsia (ACHM). Methods: Two AOSLOs, at the Medical College of Wisconsin and Moorfields Eye Hospital, were used to image the photoreceptor mosaic of eleven subjects with ACHM and seven age-matched controls. Images were obtained, processed and montaged using previously described methods. Cone density and reflectivity were quantified to assess residual cone photoreceptor structure. Results: All subjects with ACHM had reduced numbers of cone photoreceptors, albeit to a variable degree. In addition, the relative cone reflectivity varied greatly. Interestingly, subjects with GNAT2-associated ACHM had the greatest number of residual cones and the reflectivity of those cones was significantly greater than that of the cones in the subjects with CNGA3/B3-associated ACHM. Conclusions: We present cone reflectivity as a metric that can be used to characterize cone structure in ACHM. This method may be applicable to subjects with other cone disorders. In ACHM, we hypothesize that cone numerousity (and/or density) combined with cone reflectivity could be used to gauge the therapeutic potential. As gene replacement would not add cones, reflectivity could be a more powerful AO-metric for monitoring the cellular response to treatment and could provide a more immediate indicator of efficacy than behavioral measures, which may take longer to change.
    Investigative Ophthalmology &amp Visual Science 10/2014; DOI:10.1167/iovs.14-14225 · 3.66 Impact Factor
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    ABSTRACT: Purpose: To present a detailed phenotypic and molecular study of a series of 18 patients from 11 families with retinal dystrophies consequent on mutations in the cone-rod homeobox (CRX) gene and to report a novel phenotype. Methods: Families were ascertained from a tertiary clinic in the UK and enrolled in to retinal dystrophy studies investigating the phenotype and molecular basis of inherited retinal disease. Eleven patients were ascertained from the study cohorts and a further 7 from investigation of affected relatives. Detailed phenotyping included electrodiagnostic testing and retinal imaging. Bi-directional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 reported patients and segregation confirmed in available relatives. Results: Based on clinical characteristics and electrophysiology, 4 patients had Leber congenital amaurosis (LCA), 2 rod cone dystrophy (RCD), 5 cone rod dystrophy (CORD), 1 cone dystrophy (COD) and 6 macular dystrophy with different phenotypes observed within 4 of the 11 families. The macular dystrophy patients presented between 35-50 years old and had visual acuities at last review ranging from 0.2 to 1.5 logMAR (20/32 to 20/630 Snellen). All 18 patients were heterozygous for a mutation in CRX with 7 novel mutations identified. There was no evident association between age of onset and position or type of CRX mutation. De novo mutations were confirmed in 3 patients. Conclusions: Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult onset, macular dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies.
    Investigative Ophthalmology &amp Visual Science 09/2014; 55(10). DOI:10.1167/iovs.14-14715 · 3.66 Impact Factor
  • Edited by Puech Bernard; De Laey Jean-Jacques; Holder Graham, 09/2014; Springer, 2014. eBook ISBN 978-3-540-69466-3.., ISBN: 978-3-540-69466-3.
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    ABSTRACT: Purpose: To describe the dark-adaptation (DA) functions in subjects with molecularly proven achromatopsia (ACHM) using refined testing conditions with a view to guiding assessment in forthcoming gene therapy trials. Methods: The DA functions of 9 subjects with ACHM were measured and compared to those of normal observers. The size and retinal location of the stimuli used to measure DA sensitivities were varied in four distinct testing condition sets, and the effect of altering these parameters assessed. Results: In three of the four testing condition sets, achromats had significantly higher mean final thresholds than normal observers, whereas in the fourth condition set they did not. A larger, more central stimulus revealed the greatest difference between the final DA thresholds of achromat and normal subjects, and also demonstrated the slowest rate of recovery amongst the achromat group. Conclusions: In this, the largest study of DA functions in molecularly proven ACHM to date, we have identified optimal testing conditions that accentuate the relative difference between achromats and normal observers. These findings can help optimize DA testing in future trials, as well as help resolve the dichotomy in the literature regarding the normality or otherwise of DA functions in ACHM. Furthermore, the shorter testing time and less intense adaptation light used in these experiments may prove advantageous for more readily and reliably probing scotopic function in retinal disease, and be particularly valuable in the frequent post-therapeutic assessments required in the context of the marked photophobia in ACHM.
    Investigative Ophthalmology &amp Visual Science 08/2014; 55(10). DOI:10.1167/iovs.14-14910 · 3.66 Impact Factor
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    ABSTRACT: Purpose: To longitudinally characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical gene therapy trials. Methods: 38 molecularly confirmed ACHM subjects underwent serial assessments, including spectral domain optical coherence tomography (SD-OCT), microperimetry, and fundus autofluorescence (FAF). Foveal structure on SD-OCT was graded and compared for evidence of progression, along with serial measurements of foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness. FAF patterns were characterized and compared over time. Results: Mean follow-up was 19.5 months (age range at baseline: 6-52 years). Only 2 of 37 subjects (5%) demonstrated change in serial foveal SD-OCT scans. There was no statistically significant change over time in FTRT (p=0.83), ONL thickness (p=0.27), hyporeflective zone (HRZ) diameter (p=0.42), visual acuity (p=0.89), contrast sensitivity (p=0.22), mean retinal sensitivity (p=0.84), and fixation stability (p=0.58). Three distinct FAF patterns were observed (n=30): central increased FAF (n=4), normal FAF (n=11), and well-demarcated reduced FAF (n=15); with the latter group displaying a slow increase in the area of reduced FAF of 0.03 mm2 over 19.3 months (p=0.002). Conclusions: Previously published cross-sectional studies have described conflicting findings with respect to the age-dependency of progression. This study, which constitutes the largest and longest prospective longitudinal study of ACHM to date, suggests that although ACHM may be progressive, any such progression is slow and subtle in most patients, and does not correlate with age or genotype. We also describe the first serial assessment of FAF, which is highly variable between individuals, even of similar age and genotype.
    Investigative Ophthalmology &amp Visual Science 08/2014; 55(9). DOI:10.1167/iovs.14-14937 · 3.66 Impact Factor
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    ABSTRACT: Mutations in the OPN1LW (L-) and OPN1MW (M-) cone opsin genes underlie a spectrum of cone photoreceptor defects from stationary loss of colour vision to progressive retinal degeneration. Genotypes of 22 families with a range of cone disorders were grouped into three classes: deletions of the Locus Control Region (LCR); missense mutation (p.Cys203Arg) in an L-/M- hybrid gene; and exon 3 single nucleotide polymorphism (SNP) interchange haplotypes in an otherwise normal gene array. Moderate to high myopia was observed in all mutation categories. Individuals with LCR deletions or p.Cys203Arg mutations were more likely to have nystagmus and poor vision, with disease progression in some p.Cys203Arg patients. Three disease-associated exon 3 SNP haplotypes encoding LIAVA, LVAVA or MIAVA, were identified in our cohort. These patients were less likely to have nystagmus but more likely to show progression, with all patients over the age of 40 having marked macular abnormalities. Previously, the haplotype LIAVA has been shown to result in exon 3 skipping. Here we show that haplotypes LVAVA and MIAVA also result in aberrant splicing, with a residual low level of correctly spliced cone opsin. The OPN1LW/OPN1MW:c.532A>G SNP, common to all three disease-associated haplotypes, appears to be principally responsible for this mutational mechanism.This article is protected by copyright. All rights reserved
    Human Mutation 08/2014; 35(11). DOI:10.1002/humu.22679 · 5.05 Impact Factor
  • Journal of American Association for Pediatric Ophthalmology and Strabismus 08/2014; 18(4):e24. DOI:10.1016/j.jaapos.2014.07.077 · 1.14 Impact Factor
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    ABSTRACT: Enhanced S-cone syndrome (ESCS) forms part of the differential diagnosis of night blindness in childhood.
    Jama Ophthalmology 07/2014; DOI:10.1001/jamaophthalmol.2014.2343 · 3.83 Impact Factor
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    ABSTRACT: IMPORTANCE We describe novel ocular phenotypic features caused by mutations in ADAMTS18. The exact role of ADAMTS18 in ocular disease is unclear, and our work further contributes to the understanding of this gene and its protein. OBJECTIVE To expand the phenotypic characterization in patients with homozygous mutations in ADAMTS18 and report novel mutational data. DESIGN, SETTING, AND PARTICIPANTS A case series with genetic investigations was conducted at tertiary referral clinical and university settings. Three families participated. MAIN OUTCOME MEASURES Phenotype and genotype description of 3 families. RESULTS Four affected patients from 3 families with an unusual ocular phenotype had full ophthalmic and systemic examination. A single affected individual in the first family had bilateral microcornea, ectopic pupils, and cone-rod dystrophy. In a second family, 2 brothers showed bilateral microcornea, childhood cataract, ectopia lentis, rhegmatogenous retinal detachment, and cone-rod dystrophy. In the third family, a single affected individual had the same features as those in family 2, without ectopia lentis. Causative mutations were sought using homozygosity mapping, Sanger sequencing, and massively parallel sequencing of the whole exome. Novel homozygous mutations in ADAMTS18 were identified, consisting of c.1067T>A [p.L356*] in the first proband, c.2159G>C [p.C720S] in the 2 affected brothers, and c.1952G>A [p.R651Q] in the third proband. All 3 mutations are predicted to be pathogenic. CONCLUSIONS AND RELEVANCE Mutations in ADAMTS18 are associated with ocular developmental abnormalities including microcornea, ectopia lentis, and early onset of cone-rod dystrophy. This report provides further evidence that ADAMTS18 plays a key role in ocular development. Physicians should consider screening ADAMTS18 in patients with microcornea and cone-rod dystrophy.
    Jama Ophthalmology 05/2014; DOI:10.1001/jamaophthalmol.2014.940 · 3.83 Impact Factor
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    ABSTRACT: In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with "cone-first" retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumed loss-of-function variants: c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs(∗)2];[Glu529Valfs(∗)2], and c.[401delT(;)3354G>A], p.[Leu134Argfs(∗)45(;)Trp1118(∗)]. We then inspected previously collected exome sequence data from individuals with related phenotypes and found two siblings with homozygous nonsense variant c.1627G>T (p.Glu543(∗)) in TTLL5. Subsequently, we tested a panel of 55 probands with retinal dystrophy for TTLL5 mutations; one proband had a homozygous missense change (c.1627G>A [p.Glu543Lys]). The retinal phenotype was highly similar in three of four families; the sibling pair had a more severe, early-onset disease. In human and murine retinae, TTLL5 localized to the centrioles at the base of the connecting cilium. TTLL5 has been previously reported to be essential for the correct function of sperm flagella in mice and play a role in polyglutamylation of primary cilia in vitro. Notably, genes involved in the polyglutamylation and deglutamylation of tubulin have been associated with photoreceptor degeneration in mice. The electrophysiological and fundus autofluorescence imaging presented here should facilitate the molecular diagnosis in further families.
    The American Journal of Human Genetics 05/2014; 94(5):760-9. DOI:10.1016/j.ajhg.2014.04.003 · 10.99 Impact Factor
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    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 hybridisation studies in human embryonic and foetal 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 bi-laminar expression pattern. Expression was also noted within the developing optic stalk and optic disc.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 ultra-high resolution optical coherence tomography. The tomograms were compared to 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 disc area, retinal nerve fibre 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 aetiological factor in the development of nystagmus.
    Human Molecular Genetics 03/2014; 23(15). DOI:10.1093/hmg/ddu122 · 6.68 Impact Factor

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5k Citations
1,070.18 Total Impact Points


  • 2014–2015
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Clinical and Academic Department of Ophthalmology (CADO)
      Londinium, England, United Kingdom
  • 2001–2015
    • University College London
      • Institute of Ophthalmology
      Londinium, England, United Kingdom
  • 2009–2014
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
    • City University London
      Londinium, England, United Kingdom
  • 1997–2014
    • Moorfields Eye Hospital NHS Foundation Trust
      • Department of Medical Retina
      Londinium, England, United Kingdom
  • 2013
    • Keio University
      • Department of Ophthalmology
      Edo, Tōkyō, Japan
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
    • Central Manchester University Hospitals NHS Foundation Trust
      Manchester, England, United Kingdom
  • 2006–2013
    • University of Cambridge
      • Department of Medical Genetics
      Cambridge, England, United Kingdom
  • 2011
    • UK Department of Health
      Londinium, England, United Kingdom
  • 2002
    • University of Leeds
      Leeds, England, United Kingdom
  • 2000
    • London Research Institute
      Londinium, England, United Kingdom
  • 1995
    • Ninewells Hospital
      Dundee, Scotland, United Kingdom
  • 1994
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
  • 1993
    • Memorial University of Newfoundland
      Saint John's, Newfoundland and Labrador, Canada