Publications by authors named "Claire-Marie Dhaenens"

50 Publications

PRPH2 mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease.

Hum Mutat 2021 Dec 20;42(12):1521-1547. Epub 2021 Sep 20.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Mutations in PRPH2, encoding peripherin-2, are associated with the development of a wide variety of inherited retinal diseases (IRDs). To determine the causality of the many PRPH2 variants that have been discovered over the last decades, we surveyed all published PRPH2 variants up to July 2020, describing 720 index patients that in total carried 245 unique variants. In addition, we identified seven novel PRPH2 variants in eight additional index patients. The pathogenicity of all variants was determined using the ACMG guidelines. With this, 107 variants were classified as pathogenic, 92 as likely pathogenic, one as benign, and two as likely benign. The remaining 50 variants were classified as variants of uncertain significance. Interestingly, of the total 252 PRPH2 variants, more than half (n = 137) were missense variants. All variants were uploaded into the Leiden Open source Variation and ClinVar databases. Our study underscores the need for experimental assays for variants of unknown significance to improve pathogenicity classification, which would allow us to better understand genotype-phenotype correlations, and in the long-term, hopefully also support the development of therapeutic strategies for patients with PRPH2-associated IRD.
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http://dx.doi.org/10.1002/humu.24275DOI Listing
December 2021

Three cases of adult-onset Brown-Vialetto-Van Laere syndrome: Novel variants in SLC52A3 gene and MRI abnormalities.

Neuromuscul Disord 2021 08 26;31(8):752-755. Epub 2021 Jun 26.

Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France; Centre de référence des maladies neuromusculaires Nord Est Ile de France, Lille University Medical Centre, Lille, France; Neurology Department, Lille University Medical Center, Lille, France.

Brown-Vialetto-Van Laere syndrome is a rare, autosomal, recessive neurological condition caused by variants in the riboflavin transporter genes SLC52A2 and SLC52A3. Here, we report on three cases. Case 1 was a 35-year-old woman from a consanguineous family who presented with progressive deafness, subacute multiple cranial nerve impairments (III, VII, IX, XII), and MRI abnormalities (including as hypersignal from the cranial nerves). The patient was homozygous for a novel SLC52A3variant. Case 2 was the woman's brother, who presented similar symptoms. Case 3 was an 18-year-old woman experiencing progressive hearing loss, bilateral steppage gait and a cranial nerves impairment (VII and XII). MRI revealed hypersignal in the root nerves and cauda equina. A novel heterozygous variant in SLC52A3 was identified. A subacute history of polyradiculoneuropathy along with progressive deafness, cranial nerve impairment, and MRI abnormalities should raise suspicion for Brown-Vialetto-Van Laere syndrome.
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http://dx.doi.org/10.1016/j.nmd.2021.06.009DOI Listing
August 2021

Novel Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy.

Int J Mol Sci 2021 Jun 15;22(12). Epub 2021 Jun 15.

Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, 59045 Lille, France.

Variants of the gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct variants, which might explain the observed rod involvement. Our study highlights the role of in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in previously undetected by classical sequencing methods. In addition, variable phenotypes in -associated patients might be due to the presence of additional gene defects.
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http://dx.doi.org/10.3390/ijms22126410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232641PMC
June 2021

CNGB1-related rod-cone dystrophy: A mutation review and update.

Hum Mutat 2021 06 16;42(6):641-666. Epub 2021 May 16.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France.

Cyclic nucleotide-gated channel β1 (CNGB1) encodes the 240-kDa β subunit of the rod photoreceptor cyclic nucleotide-gated ion channel. Disease-causing sequence variants in CNGB1 lead to autosomal recessive rod-cone dystrophy/retinitis pigmentosa (RP). We herein present a comprehensive review and analysis of all previously reported CNGB1 sequence variants, and add 22 novel variants, thereby enlarging the spectrum to 84 variants in total, including 24 missense variants (two of which may also affect splicing), 21 nonsense, 19 splicing defects (7 at noncanonical positions), 10 small deletions, 1 small insertion, 1 small insertion-deletion, 7 small duplications, and 1 gross deletion. According to the American College of Medical Genetics and Genomics classification criteria, 59 variants were considered pathogenic or likely pathogenic and 25 were variants of uncertain significance. In addition, we provide further phenotypic data from 34 CNGB1-related RP cases, which, overall, are in line with previous findings suggesting that this form of RP has long-term retention of useful central vision despite the early onset of night blindness, which is valuable for patient counseling, but also has implications for it being considered a priority target for gene therapy trials.
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http://dx.doi.org/10.1002/humu.24205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218941PMC
June 2021

A ROD-CONE DYSTROPHY IS SYSTEMATICALLY ASSOCIATED TO THE RTN4IP1 RECESSIVE OPTIC ATROPHY.

Retina 2021 Aug;41(8):1771-1779

MitoLab Team, UMR CNRS 6015-INSERM U1083, Institut MitoVasc, Angers University and Hospital, Angers, France.

Purpose: RTN4IP1 biallelic mutations cause a recessive optic atrophy, sometimes associated to more severe neurological syndromes, but so far, no retinal phenotype has been reported in RTN4IP1 patients, justifying their reappraisal.

Methods: Seven patients from four families carrying biallelic RTN4IP1 variants were retrospectively reviewed, with emphasis on their age of onset, visual acuity, multimodal imaging including color and autofluorescence frames, spectral-domain optical coherence tomography with RNFL and macular analyses.

Results: Seven patients from four RTN4IP1 families developed in their first decade of life a bilateral recessive optic atrophy with severe central visual loss, and primary nystagmus developed in 5 of 7 patients. Six patients were legally blind. In a second stage, the seven individuals developed a rod-cone dystrophy, sparing the macular zone and the far periphery. This retinal damage was identified by 55° field fundus autofluorescence frames and also by spectral-domain optical coherence tomography scans of the temporal part of the macular zone in five of the seven patients. Full-field electroretinography measurements disclosed reduced b-wave amplitude of the rod responses in all patients but two. Family 4 with the p.R103H and c.601A > T (p.K201*) truncating mutation had further combined neurological signs with cerebellar ataxia, seizures, and intellectual disability.

Conclusion: RTN4IP1 recessive optic atrophy is systematically associated to a rod-cone dystrophy, which suggests that both the retinal ganglion cells and the rods are affected as a result of a deficit in the mitochondrial respiratory chain. Thus, systematic widefield autofluorescence frames and temporal macular scans are recommended for the evaluation of patients with optic neuropathies.
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http://dx.doi.org/10.1097/IAE.0000000000003054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297537PMC
August 2021

Variable Presentation of Leber Hereditary Optic Neuropathy in Children of a Family Harboring a Rare m.13051G>A mtDNA Mutation.

J Neuroophthalmol 2020 12;40(4):569-571

Exploration de la Vision et Neuro-Ophtalmologie (VMS, CM, PD, SD-D), CHU de Lille, Lille, France; Université de Lille (VMS), Faculté de Médecine, Lille Cedex, France; Neurologie pédiatrique (J-MC), CHU de Lille, Lille, France; and Université de Lille (C-MD), Inserm UMRS 1172, CHU Lille, Biochemistry and Molecular Biology Department UF Génopathies, Lille, France.

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http://dx.doi.org/10.1097/WNO.0000000000001083DOI Listing
December 2020

Pathogenic variants in cause autosomal dominant and autosomal recessive retinitis pigmentosa.

J Med Genet 2021 08 17;58(8):570-578. Epub 2020 Aug 17.

Institute for Neurosciences of Montpellier, University of Montpellier, Montpellier, France

Background: Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.

Methods: Exome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen possible pathogenic role.

Results: Exome sequencing of a family with RP revealed a splice variant in . Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in . In addition, the clinical diagnosis of the retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of and its paralog in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments.

Conclusion: This study discusses a previously unreported association between monoallelic or biallelic variants and RP. Notably, similar observations have been reported for .
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http://dx.doi.org/10.1136/jmedgenet-2020-107150DOI Listing
August 2021

Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease.

JAMA Ophthalmol 2020 10;138(10):1035-1042

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

Importance: The mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management.

Objective: To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1.

Design, Setting, And Participants: Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020.

Main Outcomes And Measures: Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed.

Results: A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P = .02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P = .005).

Conclusions And Relevance: This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.2990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441467PMC
October 2020

Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.

Genet Med 2020 07 20;22(7):1235-1246. Epub 2020 Apr 20.

Bartiméus Diagnostic Center for Complex Visual Disorders, Zeist, The Netherlands.

Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands.

Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays.

Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband.

Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
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http://dx.doi.org/10.1038/s41436-020-0787-4DOI Listing
July 2020

Myotonic Dystrophy: an RNA Toxic Gain of Function Tauopathy?

Adv Exp Med Biol 2019 ;1184:207-216

University of Lille, INSERM, CHU-Lille, UMR-S 1172 - Alzheimer & Tauopathies, LabEx DISTALZ, Lille, France.

Myotonic dystrophies (DM) are rare inherited neuromuscular disorders linked to microsatellite unstable expansions in non-coding regions of ubiquitously expressed genes. The DMPK and ZNF9/CNBP genes which mutations are responsible for DM1 and DM2 respectively. DM are multisystemic disorders with brain affection and cognitive deficits. Brain lesions consisting of neurofibrillary tangles are often observed in DM1 and DM2 brain. Neurofibrillary tangles (NFT) made of aggregates of hyper and abnormally phosphorylated isoforms of Tau proteins are neuropathological lesions common to more than 20 neurological disorders globally referred to as Tauopathies. Although NFT are observed in DM1 and DM2 brain, the question of whether DM1 and DM2 are Tauopathies remains a matter of debate. In the present review, several pathophysiological processes including, missplicing, nucleocytoplasmic transport disruption, RAN translation which are common mechanisms implicated in neurodegenerative diseases will be described. Together, these processes including the missplicing of Tau are providing evidence that DM1 and DM2 are not solely muscular diseases but that their brain affection component share many similarities with Tauopathies and other neurodegenerative diseases. Understanding DM1 and DM2 pathophysiology is therefore valuable to more globally understand other neurodegenerative diseases such as Tauopathies but also frontotemporal lobar neurodegeneration and amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1007/978-981-32-9358-8_17DOI Listing
April 2020

Peripapillary Sparing With Near Infrared Autofluorescence Correlates With Electroretinographic Findings in Patients With Stargardt Disease.

Invest Ophthalmol Vis Sci 2019 12;60(15):4951-4957

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientfique, Institut de la Vision, Paris, France.

Purpose: To evaluate the correlation between the quantification of peripapillary sparing and electroretinogram (ERG) outcomes in autosomal recessive Stargardt disease (STGD1).

Methods: Near infrared fundus autofluorescence (NIR-FAF) images of 101 eyes of 101 patients were retrospectively reviewed. Peripapillary sparing was assessed both qualitatively and quantitatively. The area of spared tissue (AST) was calculated in a 1-mm-wide ring around the optic disc after binarization of the 55° NIR-FAF. These measurements were correlated with the presence of normal ERG (group I), abnormal photopic responses (group II), or abnormal photopic and scotopic responses (group III).

Results: AST showed significant correlations with ERG groups (R = -0.802, P < 0.001). While qualitative assessment of peripapillary sparing (i.e., present or not) also showed a significant correlation with ERG groups (R = -0.435, P < 0.001), it was weaker than by AST quantification. The ordinal regression analysis showed that the increase in AST was associated with a decrease in the odds of belonging to ERG groups II and III, with an odds ratio of 0.82 (95% confidence interval [CI] 0.78-0.87), P < 0.001.

Conclusions: The AST around the optic disc in eyes with STGD1 correlates with the impairment of photoreceptors as shown in the ERG. If replicated in future longitudinal studies, the quantification of peripapillary sparing may prove to be a useful parameter for evaluating the visual prognosis of these eyes.
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http://dx.doi.org/10.1167/iovs.19-27100DOI Listing
December 2019

Prevalence of Deep-Intronic Variants and Related Phenotype in An Unsolved "One-Hit" Cohort with Stargardt Disease.

Int J Mol Sci 2019 Oct 11;20(20). Epub 2019 Oct 11.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France.

We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of . Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic analysis and correlation with the genotype was performed in case a known intronic pathogenic variant was identified. All other variants found on the analyzed sequences were queried for minor allele frequency and possible pathogenicity by in silico predictions. The second mutated allele was found in 14 (20%) subjects. The three known deep-intronic variants found were c.5196+1137G>A in intron 36 (6 subjects), c.4539+2064C>T in intron 30 (4 subjects) and c.4253+43G>A in intron 28 (4 subjects). Even though the phenotype depends on the compound effect of the biallelic variants, a genotype-phenotype correlation suggests that the c.5196+1137G>A was mostly associated with a mild phenotype and the c.4539+2064C>T with a more severe one. A variable effect was instead associated with the variant c.4253+43G>A. In addition, two novel variants, c.768+508A>G and c.859-245_859-243delinsTGA never associated with Stargardt disease before, were identified and a possible splice defect was predicted in silico. Our study calls for a larger cohort analysis including targeted locus sequencing and 3D protein modeling to better understand phenotype-genotype correlations associated with deep-intronic changes and patients' selection for clinical trials.
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http://dx.doi.org/10.3390/ijms20205053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829239PMC
October 2019

Severe retinitis pigmentosa with posterior staphyloma in a family with c.886C>A p.(Lys296Glu) mutation.

Ophthalmic Genet 2019 08 22;40(4):365-368. Epub 2019 Aug 22.

Biochemistry and Molecular Biology Department - UF Génopathies, Univ Lille , Lille , France.

: Posterior pole staphylomata (PSS) is an outward bulging of ocular wall, rarely reported in association with inherited retinal degenerations. : We report a large French family of Jewish ancestry with a peculiar form of dominant retinitis pigmentosa (RP) and posterior pole staphyloma (PPS). Eight members were clinically and genetically examined. : All affected members complained of night blindness from early childhood and their ERGs were extinguished in the first decade of life. Seven out of eight presented PPS on fundus examination and SD-OCT. The youngest patient did not present PPS at 11 months of age, but the signs of posterior pole bowing became evident at age 8 years. There was no association between the presence of PPS and refraction. Patients with PPS were either hyperopic or myopic, but all have a high with-the-rule astigmatism. A myopic shift was observed for all of them at follow-up. In this family, the disease segregated with the c.886A>G mutation in gene. : A PPS development was observed in initially non-myopic patients of a family with unusually severe dominant RP. The PPS concerned only the area with relatively preserved outer retinal layers (outer nuclear layer and ellipsoid zone). How the outer retina could guide choroid and scleral remodelling remains unclear.
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http://dx.doi.org/10.1080/13816810.2019.1655771DOI Listing
August 2019

Cost-effective molecular inversion probe-based ABCA4 sequencing reveals deep-intronic variants in Stargardt disease.

Hum Mutat 2019 10 18;40(10):1749-1759. Epub 2019 Jun 18.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: Stargardt disease (STGD1) is caused by biallelic mutations in ABCA4, but many patients are genetically unsolved due to insensitive mutation-scanning methods. We aimed to develop a cost-effective sequencing method for ABCA4 exons and regions carrying known causal deep-intronic variants.

Methods: Fifty exons and 12 regions containing 14 deep-intronic variants of ABCA4 were sequenced using double-tiled single molecule Molecular Inversion Probe (smMIP)-based next-generation sequencing. DNAs of 16 STGD1 cases carrying 29 ABCA4 alleles and of four healthy persons were sequenced using 483 smMIPs. Thereafter, DNAs of 411 STGD1 cases with one or no ABCA4 variant were sequenced. The effect of novel noncoding variants on splicing was analyzed using in vitro splice assays.

Results: Thirty-four ABCA4 variants previously identified in 16 STGD1 cases were reliably identified. In 155/411 probands (38%), two causal variants were identified. We identified 11 deep-intronic variants present in 62 alleles. Two known and two new noncanonical splice site variants showed splice defects, and one novel deep-intronic variant (c.4539+2065C>G) resulted in a 170-nt mRNA pseudoexon insertion (p.[Arg1514Lysfs*35,=]).

Conclusions: smMIPs-based sequence analysis of coding and selected noncoding regions of ABCA4 enabled cost-effective mutation detection in STGD1 cases in previously unsolved cases.
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http://dx.doi.org/10.1002/humu.23787DOI Listing
October 2019

Systematic thyroid screening in myotonic dystrophy: link between thyroid volume and insulin resistance.

Orphanet J Rare Dis 2019 02 13;14(1):42. Epub 2019 Feb 13.

CHU Lille, Endocrinology, Diabetology and Metabolism, F-59000, Lille, France.

Background: Myotonic dystrophy (DM1), a neuromuscular disease related to DMPK gene mutations, is associated to endocrine disorders and cancer. A routine endocrine work-up, including thyroid ultrasound (US), was conducted in 115 genetically-proven DM1 patients in a neuromuscular reference center. The aim of this study was to determine the prevalence and the causes of US thyroid abnormalities in DM1.

Results: In the whole population (age 45.1 ± 12.2 years, 61.7% female), palpable nodules or goiters were present in 29.2%. The percentage of US goiter (thyroid volume > 18 mL) and US nodules were, respectively, 38.3 and 60.9%. Sixteen of the 115 patients had a thyroidectomy, after 22 fine-needle aspiration cytology guided by thyroid imaging reporting and data system (TIRADS) classification. Six micro- (1/6 pT3) and 3 macro-papillary thyroid carcinoma (PTCs) (2/3 intermediate risk) were diagnosed (7.9% of 115). Thyroid US led to the diagnosis of 4 multifocal and 2 unifocal (including 1 macro-PTC) non-palpable PTCs. Ultrasound thyroid volume was positively correlated to body mass index (BMI) (p = 0.015) and parity (p = 0.036), and was inversely correlated to TSH (p < 0.001) and vitamin D levels (p = 0.023). The BMI, the frequencies of glucose intolerance and PTC were significantly higher in UsGoiter versus non-UsGoiter groups.

Conclusion: In this systematically screened DM1 cohort, the frequency of UsGoiter, mainly associated to BMI, was about 40%, US nodules 60%, thyroidectomies 13-14%, and PTCs 8%, two-thirds of them being micro-PTCs with good prognosis. Therefore, a systematic screening remains debatable. A targeted US screening in case of clinical abnormality or high BMI seems more appropriate.
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http://dx.doi.org/10.1186/s13023-019-1019-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375124PMC
February 2019

Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy.

Hum Mutat 2019 05 14;40(5):578-587. Epub 2019 Feb 14.

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

The autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) disease locus has been mapped to chromosome 6q14-16.2 that overlaps the North Carolina macular dystrophy (NCMD) locus MCDR1. NCMD is a nonprogressive developmental macular dystrophy, in which variants upstream of PRDM13 have been implicated. Whole genome sequencing was performed to interrogate structural variants (SVs) and single nucleotide variants (SNVs) in eight individuals, six affected individuals from two families with PBCRA, and two individuals from an additional family with a related developmental macular dystrophy. A SNV (chr6:100,046,804T>C), located 7.8 kb upstream of the PRDM13 gene, was shared by all PBCRA-affected individuals in the disease locus. Haplotype analysis suggested that the variant arose independently in the two families. The two affected individuals from Family 3 were screened for rare variants in the PBCRA and NCMD loci. This revealed a de novo variant in the proband, 21 bp from the first SNV (chr6:100,046,783A>C). This study expands the noncoding variant spectrum upstream of PRDM13 and suggests altered spatio-temporal expression of PRDM13 as a candidate disease mechanism in the phenotypically distinct but related conditions, NCMD and PBCRA.
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http://dx.doi.org/10.1002/humu.23715DOI Listing
May 2019

Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides.

Genet Med 2019 08 15;21(8):1751-1760. Epub 2019 Jan 15.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability.

Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.

Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.

Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.
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http://dx.doi.org/10.1038/s41436-018-0414-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752325PMC
August 2019

Expanding the Mutation Spectrum in : Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort.

Int J Mol Sci 2018 Jul 27;19(8). Epub 2018 Jul 27.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France.

Here we report novel mutations in with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment ( = 0.002) and an earlier age of onset ( = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of underlying Stargardt disease.
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http://dx.doi.org/10.3390/ijms19082196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121640PMC
July 2018

Phenotypic Characteristics of a French Cohort of Patients with X-Linked Retinoschisis.

Ophthalmology 2018 10 5;125(10):1587-1596. Epub 2018 May 5.

Centre de Maladies Rares "Dystrophies Rétiniennes d'Origine Génétique," DHU Sight Restore INSERM-DHOS CIC 1423, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France; INSERM, CNRS, Institut de la Vision, Sorbonne Université, Paris, France. Electronic address:

Purpose: To analyze the retinal structure in patients with X-linked retinoschisis (XLRS) using spectral-domain OCT and to correlate the morphologic findings with visual acuity, electroretinographic results, and patient age.

Design: Retrospective, observational study.

Participants: Data from 52 consecutive male patients with molecularly confirmed XLRS were collected retrospectively.

Methods: Complete clinical evaluation included best-corrected visual acuity, full-field electroretinography, fundus photography, spectral-domain OCT, and fundus autofluorescence. Spectral-domain OCT images were analyzed to determine full thickness of the retina and tomographic structural changes.

Main Outcome Measures: Relationships between age, OCT, and visual acuity were assessed.

Results: One hundred four eyes of 52 patients were included. The mean age at inclusion was 24±15 years (range, 3-57 years). The best-corrected visual acuity ranged from no light perception to 0.1 logarithm of the minimum angle of resolution (mean, 0.6±0.38 logarithm of the minimum angle of resolution). Macular schisis was found in 88% of eyes and macular atrophy was found in 11% of eyes, whereas peripheral schisis was present in 30% of eyes. A spoke-wheel pattern of high and low intensity was the most frequently observed fundus autofluorescence abnormality (51/94 eyes [54%]). The b-to-a amplitude ratio on bright-flash dark-adapted electroretinography was reduced significantly in 45 of 64 eyes (70%). Spectral-domain OCT was available for 97 eyes and showed foveoschisis in 76 of 97 eyes (78%), parafoveal schisis in 10 of 97 eyes (10%), and foveal atrophy in 11 of 97 eyes (11%). Mean central macular thickness (CMT) was of 373.6±140 μm. Cystoid changes were localized mainly in the inner nuclear layer (85/97 eyes [88%]). Qualitative defects in photoreceptor structures were found in most eyes (79/97 eyes [81%]), and the most frequent abnormality was an interruption of the photoreceptor cell outer segment tips (79/79 eyes [100%]). Older age correlated well with lower CMT (correlation coefficient [CC], -0.44; P < 0.001) and with lower photoreceptor outer segment (PROS) length (CC, -0.42; P < 0.001). Lower visual acuity correlated strongly with lower PROS length (CC, -0.53; P < 0.001).

Conclusions: This study underlined the wide variety of clinical features of XLRS. It highlighted the correlation between visual acuity, patient age, and OCT features, emphasizing the relevance of the latter as potential outcome measure in clinical trials.
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http://dx.doi.org/10.1016/j.ophtha.2018.03.057DOI Listing
October 2018

Alternative promoter usage generates novel shorter MAPT mRNA transcripts in Alzheimer's disease and progressive supranuclear palsy brains.

Sci Rep 2017 10 3;7(1):12589. Epub 2017 Oct 3.

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France.

Alternative promoter usage is an important mechanism for transcriptome diversity and the regulation of gene expression. Indeed, this alternative usage may influence tissue/subcellular specificity, protein translation and function of the proteins. The existence of an alternative promoter for MAPT gene was considered for a long time to explain differential tissue specificity and differential response to transcription and growth factors between mRNA transcripts. The alternative promoter usage could explain partly the different tau proteins expression patterns observed in tauopathies. Here, we report on our discovery of a functional alternative promoter for MAPT, located upstream of the gene's second exon (exon 1). By analyzing genome databases and brain tissue from control individuals and patients with Alzheimer's disease or progressive supranuclear palsy, we identified novel shorter transcripts derived from this alternative promoter. These transcripts are increased in patients' brain tissue as assessed by 5'RACE-PCR and qPCR. We suggest that these new MAPT isoforms can be translated into normal or amino-terminal-truncated tau proteins. We further suggest that activation of MAPT's alternative promoter under pathological conditions leads to the production of truncated proteins, changes in protein localization and function, and thus neurodegeneration.
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http://dx.doi.org/10.1038/s41598-017-12955-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626709PMC
October 2017

Test-Retest Variability of Functional and Structural Parameters in Patients with Stargardt Disease Participating in the SAR422459 Gene Therapy Trial.

Transl Vis Sci Technol 2016 Oct 1;5(5):10. Epub 2016 Oct 1.

Oregon Health & Science University, Casey Eye Institute, Portland, OR, USA.

Purpose: The goal of this analysis was to determine the test-retest variability of functional and structural measures from a cohort of patients with advanced forms of Stargardt Disease (STGD) participating in the SAR422459 (NCT01367444) gene therapy clinical trial.

Methods: Twenty-two participants, aged 24 to 66, diagnosed with advanced forms of STGD, with at least one pathogenic mutation on each chromosome participating in the SAR422459 (NCT01367444) gene therapy clinical trial, were screened over three visits within 3 weeks or less. Functional visual evaluations included: best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score, semiautomated kinetic perimetry (SKP) using isopters I4e, III4e, and V4e, hill of vision (HOV) calculated from static visual fields (SVF) by using a 184n point centrally condensed grid with the stimulus size V test target. Retinal structural changes such as central macular thickness and macular volume were assessed by spectral-domain optical coherence tomography (SD-OCT). Repeatability coefficients (RC) and 95% confidential intervals (CI) were calculated for each parameter using a hierarchical mixed-effects model and bootstrapping.

Results: Criteria for statistically significant changes for various parameters were found to be the following: BCVA letter score (8 letters), SKP isopters I4e, III4e, and V4e (3478.85; 2488.02 and 2622.46 deg, respectively), SVF full volume HOV (V 14.62 dB-sr), central macular thickness, and macular volume (4.27 μm and 0.15 mm, respectively).

Conclusions: This analysis provides important information necessary to determine if significant changes are occurring in structural and functional assessments commonly used to measure disease progression in this cohort of patients with STGD. Moreover, this information is useful for future trials assessing safety and efficacy of treatments in STGD.

Translational Relevance: Determination of variability of functional and structural measures in participants with advanced stages of the STGD is necessary to assess efficacy and safety in treatment trials involving STGD patients.
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http://dx.doi.org/10.1167/tvst.5.5.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054761PMC
October 2016

The MAPT gene is differentially methylated in the progressive supranuclear palsy brain.

Mov Disord 2016 12 6;31(12):1883-1890. Epub 2016 Oct 6.

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease causing parkinsonian symptoms. Altered DNA methylation of the microtubule-associated protein tau gene correlates with the expression changes in Alzheimer's disease and Parkinson's disease brains. However, few studies examine the sequences beyond the constitutive promoter.

Objectives: Because activating different microtubule-associated protein tau gene control regions via methylation might regulate the differential tau expression constituting the specific signatures of individual tauopathies, we compared methylation of a candidate promoter, intron 0.

Methods: We assessed DNA methylation in the brains of patients with different tauopathies (35 Alzheimer's disease, 10 corticobasal degeneration, and 18 PSP) and 19 controls by intron 0 pyrosequencing. We also evaluated methylation in an independent cohort of 11 PSP cases and 12 controls. Frontal (affected by tau pathology) and occipital (unaffected) cortices were analyzed.

Results: In the initial samples, one CpG island site in intron 0 (CpG1) showed significant hypomethylation in PSP-affected frontal cortices when compared with controls (P = .022). Such hypomethylation was observed in replicate samples, but not in occipital cortices or other tauopathies. PSP and control samples (combining the initial and replicate samples) remained significantly different after adjustment for potential confounding factors (age, H1/H1 diplotype; P = .0005). PSP-affected tissues exhibited microtubule-associated protein tau RNA hyperexpression when compared with controls (P = .004), although no correlation with CpG1 methylation was observed.

Conclusions: This exploratory study suggests that regions other than the constitutive promoter may be involved in microtubule-associated protein tau gene regulation in tauopathies and that intron 0 hypomethylation may be a specific epigenetic signature of PSP. These preliminary findings require confirmation. © 2016 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26820DOI Listing
December 2016

A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene.

Sci Rep 2016 09 7;6:32544. Epub 2016 Sep 7.

Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.

To revisit the autosomal dominant Sorsby fundus dystrophy (SFD) as a syndromic condition including late-onset pulmonary disease. We report clinical and imaging data of ten affected individuals from 2 unrelated families with SFD and carrying heterozygous TIMP3 mutations (c.572A > G, p.Y191C, exon 5, in family 1 and c.113C > G, p.S38C, exon 1, in family 2). In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma. In the preceding generation, the mother died of pulmonary emphysema and she was blind after the age of 50. Her two great-grandsons (<20 years), had abnormal Bruch Membrane thickness, a sign of eye disease. In family 2, eye and lung diseases were also associated in two generations, both occurred later, and lung disease was moderate (bronchiectasis). This is the first report of a syndromic SFD in line with the mouse model uncovering the role of TIMP3 in human lung morphogenesis and functions. The TIMP3 gene should be screened in familial pulmonary diseases with bronchiectasis, associated with a medical history of visual loss. In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations.
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http://dx.doi.org/10.1038/srep32544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013278PMC
September 2016

A NOVEL P.ASP304GLY MUTATION IN BEST1 GENE ASSOCIATED WITH ATYPICAL BEST VITELLIFORM MACULAR DYSTROPHY PHENOTYPE AND HIGH INTRAFAMILIAL VARIABILITY.

Retina 2016 Sep;36(9):1733-40

*Eye Clinic, University of Cagliari, Cagliari, Italy; †CHRU Lille, Biochemistry and Molecular Biology Department, UF Génopathies, Lille, France; Lille University, Faculté de Médecine, Lille, France; ‡Department of Ophthalmology, IRCCS Ospedale San Raffaele, University Vita-Salute San Raffaele, Milan, Italy; §Department of Ophthalmology, Centre Hospitalier Intercommunal de Creteil, University Paris Est Creteil, Creteil, France; and ¶CRB, Centre de Ressources Biologique, Centre Hospitalier Intercommunal de Creteil, University Paris Est Creteil, Creteil, France.

Purpose: To report the atypical phenotypic characteristics of patients with a novel p.Asp304Gly mutation in BEST1.

Methods: Affected individuals underwent a complete ophthalmic examination, including best-corrected visual acuity, fundus autofluorescence, spectral domain optical coherence tomography, and electrophysiologic testing. All individuals were screened for mutations in the BEST1 gene.

Results: Five patients of the same Italian family were clinically examined. All patients complained of decreased vision as the initial symptom. Best-corrected visual acuity ranged from 20/800 to 20/32. On fundus examination, all patients showed atypical Best vitelliform macular dystrophy phenotype with multifocal macular and extramacular involvement. The spectral domain optical coherence tomography characteristics of central macular and extramacular lesions varied in each patient and included "giant" choroidal excavation, extensive flat macular elevation with hyporeflective subretinal material accumulation surrounded by hyperautofluorescent spots/annulus, and extensive hypoautofluorescent extramacular atrophic areas. Electrooculogram was always abnormal with Arden ratio lower than 1.55, whereas electroretinogram was normal in the two younger patients and abnormal (low amplitude) in the three older patients. Genetic analysis revealed a novel missense mutation in BEST1, substituting aspartate for glycine at amino acid 304.

Conclusion: We describe the atypical phenotype and high intrafamilial variability associated with a new mutation in the BEST1 gene in an Italian family affected with Best vitelliform macular dystrophy. Clinicians should consider screening the BEST1 gene even in the absence of the typical phenotype and in case of high intrafamilial variability.
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http://dx.doi.org/10.1097/IAE.0000000000000966DOI Listing
September 2016

A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium.

Hum Mol Genet 2016 Mar 6;25(5):916-26. Epub 2016 Jan 6.

National Center in Genetic of Sensory Diseases, Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier Hospital, Montpellier, France.

Inherited retinal dystrophies are clinically and genetically heterogeneous with significant number of cases remaining genetically unresolved. We studied a large family from the West Indies islands with a peculiar retinal disease, the Martinique crinkled retinal pigment epitheliopathy that begins around the age of 30 with retinal pigment epithelium (RPE) and Bruch's membrane changes resembling a dry desert land and ends with a retinitis pigmentosa. Whole-exome sequencing identified a heterozygous c.518T>C (p.Leu173Pro) mutation in MAPKAPK3 that segregates with the disease in 14 affected and 28 unaffected siblings from three generations. This unknown variant is predicted to be damaging by bioinformatic predictive tools and the mutated protein to be non-functional by crystal structure analysis. MAPKAPK3 is a serine/threonine protein kinase of the p38 signaling pathway that is activated by a variety of stress stimuli and is implicated in cellular responses and gene regulation. In contrast to other tissues, MAPKAPK3 is highly expressed in the RPE, suggesting a crucial role for retinal physiology. Expression of the mutated allele in HEK cells revealed a mislocalization of the protein in the cytoplasm, leading to cytoskeleton alteration and cytodieresis inhibition. In Mapkapk3-/- mice, Bruch's membrane is irregular with both abnormal thickened and thinned portions. In conclusion, we identified the first pathogenic mutation in MAPKAPK3 associated with a retinal disease. These findings shed new lights on Bruch's membrane/RPE pathophysiology and will open studies of this signaling pathway in diseases with RPE and Bruch's membrane alterations, such as age-related macular degeneration.
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http://dx.doi.org/10.1093/hmg/ddv624DOI Listing
March 2016

Distinctive Patterns of Transthyretin Amyloid in Salivary Tissue: A Clinicopathologic Study of 92 Patients With Amyloid-containing Minor Salivary Gland Biopsies.

Am J Surg Pathol 2015 Aug;39(8):1035-44

Departments of *Pathology †Internal Medicine ‡Biochemistry and Molecular Biology, UF Génopathies §Nephrology ∥Neurology ¶Cardiology #Hematology, CHRU de Lille, Regional Competence Center for Systemic Amyloidosis, and University Lille Nord de France, F-59000, Lille **Laboratoire de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, CHU Paris Sud, Université Paris Sud, Le Kremlin Bicêtre ††Laboratoire de Biochimie et Génétique Moléculaire, Faculté de Médecine Paris, Université Paris Descartes, Sorbonne Paris Cité, Assistance Publique - Hôpitaux de Paris, Groupe Hospitalier Cochin-Hôtel Dieu; INSERM, Centre de Recherche des Cordeliers, URMS 872, équipe 17 ‡‡Pathology Department, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Sorbonne Universités, UPMC Paris 6, Paris, France, F-75020.

Accurate typing of amyloidosis is still a major issue for pathologists and clinicians. Besides clinical data and immunohistochemistry, the histologic distribution of amyloid could represent a useful tool to prevent typing errors, such as the misdiagnosis of hereditary and senile amyloidosis as light chain-related amyloidosis (AL). Minor salivary gland biopsy (MSGB) is a widely performed procedure for amyloidosis diagnosis and typing. In the largest clinicopathologic series of amyloid-containing MSGB specimens to date, we investigated for the first time whether amyloidosis subtypes can be distinguished according to their pattern of salivary amyloid deposition. The histologic distribution and semiquantification of amyloid within salivary tissue were thoroughly reassessed for each case using Congo red-fluorescence. Clinical data were retrospectively collected. The cohort included 92 patients with amyloid-containing minor salivary gland biopsies. The type of amyloidosis was AL in 51 patients (55.4%), non-V30M mutant ATTR in 10 (10.9%), V30M mutant ATTR in 8 (8.7%), serum amyloid A-derived amyloidosis (AA) in 6 (6.5%), wild-type ATTR in 4 (4.3%), gelsolin in 3 (3.3%), and unclassified in 10 (10.9%). Amyloid was more abundant in AL and AA compared with ATTR amyloidosis, because of more extensive basement membranes and vascular deposits. Conversely, non-V30M mutant ATTR and wt-ATTR were strongly associated with peculiar amyloid nodules located in close contact with salivary excretory ducts, with a specificity of 91.7%. In conclusion, our study suggests for the first time that MSGB, in addition to its high sensitivity for amyloidosis diagnosis, is a simple and effective tool for the recognition of ATTR amyloidosis.
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http://dx.doi.org/10.1097/PAS.0000000000000430DOI Listing
August 2015

High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in france and characterization of biochemical and clinical features.

Am J Ophthalmol 2015 Feb 5;159(2):302-14. Epub 2014 Nov 5.

Institut National de la Santé et de la Recherche Médicale, U1051, Institute for Neurosciences of Montpellier, Montpellier, France; University of Montpellier 1, Montpellier, France; University of Montpellier 2, Montpellier, France; CHRU, Genetics of Sensory Diseases, Montpellier, France.

Purpose: To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report 6 novel mutations, to characterize the biochemical features of a recurrent novel mutation, and to study the clinical features of adRP patients.

Design: Retrospective clinical and molecular genetic study.

Methods: Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot.

Results: We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1-0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families.

Conclusions: The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0%-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases, which could be underdiagnosed.
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http://dx.doi.org/10.1016/j.ajo.2014.10.033DOI Listing
February 2015

Frequency and clinical pattern of vitelliform macular dystrophy caused by mutations of interphotoreceptor matrix IMPG1 and IMPG2 genes.

Ophthalmology 2014 Dec 29;121(12):2406-14. Epub 2014 Jul 29.

Centre de Référence Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, Montpellier, France; Montpellier University, Montpellier, France; Institute for Neurosciences, INSERM, Montpellier, France.

Purpose: To assess the frequency of and to characterize the clinical spectrum and optical coherence tomography findings of vitelliform macular dystrophy linked to IMPG1 and IMPG2, 2 new causal genes expressed in the interphotoreceptor matrix.

Design: Retrospective epidemiologic, clinical, electrophysiologic, and molecular genetic study.

Participants: The database of a national referral center specialized in genetic sensory diseases was screened for patients with a macular vitelliform dystrophy without identified mutation or small deletion or large rearrangement in BEST1 and PRPH2 genes. Forty-nine families were included.

Methods: Clinical, imaging, and electro-oculogram findings were reviewed. Mutation screening of IMPG1 and IMPG2 genes were performed systematically.

Main Outcome Measures: Frequency, inheritance, and clinical pattern of vitelliform dystrophy associated with IMPG1 and IMPG2 mutations were characterized.

Results: IMPG1 was the causal gene in 3 families (IMPG1 1-3, 11 patients) and IMPG2 in a fourth family (2 patients). With an autosomal dominant transmission, families 1 and 2 had the c.713T→G (p.Leu238Arg) mutation in IMPG1 and family 4 had the c.3230G→T (p.Cys1077Phe) mutation in IMPG2. Patients with IMPG1 or IMPG2 mutations had a late onset and moderate visual impairment (mean visual acuity, 20/40; mean age of onset, 42 years), even in the sporadic case of family 3 with a presumed recessive transmission (age at onset, 38 years; mean visual acuity, 20/50). Drusen-like lesions adjacent to the vitelliform deposits were observed in 9 of 13 patients. The vitelliform material was above the retinal pigment epithelium (RPE) at any stage of the macular dystrophy, and this epithelium was well preserved and maintained its classical reflectivity on spectral-domain optical coherence tomography (SD-OCT). Electro-oculogram results were normal or borderline in 9 cases.

Conclusions: IMPG1 and IMPG2 are new causal genes in 8% of families negative for BEST1 and PRPH2 mutations. These genes should be screened in adult-onset vitelliform dystrophy with (1) moderate visual impairment, (2) drusen-like lesions, (3) normal reflectivity of the RPE line on SD-OCT, and (4) vitelliform deposits located between ellipsoid and interdigitation lines on SD-OCT. These clinical characteristics are not observed in the classical forms of BEST1 or PRPH2 vitelliform dystrophies.
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http://dx.doi.org/10.1016/j.ophtha.2014.06.028DOI Listing
December 2014

Brain pathology in myotonic dystrophy: when tauopathy meets spliceopathy and RNAopathy.

Front Mol Neurosci 2014 Jan 9;6:57. Epub 2014 Jan 9.

Alzheimer and Tauopathies, Faculty of Medicine, Jean-Pierre Aubert Research Centre, Institute of Predictive Medicine and Therapeutic Research, Inserm, UMR 837 Lille, France ; University of Lille Nord de France, UDSL Lille, France.

Myotonic dystrophy (DM) of type 1 and 2 (DM1 and DM2) are inherited autosomal dominant diseases caused by dynamic and unstable expanded microsatellite sequences (CTG and CCTG, respectively) in the non-coding regions of the genes DMPK and ZNF9, respectively. These mutations result in the intranuclear accumulation of mutated transcripts and the mis-splicing of numerous transcripts. This so-called RNA gain of toxic function is the main feature of an emerging group of pathologies known as RNAopathies. Interestingly, in addition to these RNA inclusions, called foci, the presence of neurofibrillary tangles (NFT) in patient brains also distinguishes DM as a tauopathy. Tauopathies are a group of nearly 30 neurodegenerative diseases that are characterized by intraneuronal protein aggregates of the microtubule-associated protein Tau (MAPT) in patient brains. Furthermore, a number of neurodegenerative diseases involve the dysregulation of splicing regulating factors and have been characterized as spliceopathies. Thus, myotonic dystrophies are pathologies resulting from the interplay among RNAopathy, spliceopathy, and tauopathy. This review will describe how these processes contribute to neurodegeneration. We will first focus on the tauopathy associated with DM1, including clinical symptoms, brain histology, and molecular mechanisms. We will also discuss the features of DM1 that are shared by other tauopathies and, consequently, might participate in the development of a tauopathy. Moreover, we will discuss the determinants common to both RNAopathies and spliceopathies that could interfere with tau-related neurodegeneration.
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http://dx.doi.org/10.3389/fnmol.2013.00057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885824PMC
January 2014
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