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1.
Sylvain Hanein Mathilde Garcia Lucas Fares-Taie Valérie Serre Yves De Keyzer Thierry Delaveau Isabelle Perrault Nathalie Delphin Sylvie Gerber Alain Schmitt Jean-Marc Masse Arnold Munnich Josseline Kaplan Frédéric Devaux Jean-Michel Rozet 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Hereditary optic neuropathies (HONs) are a heterogeneous group of disorders that affect retinal ganglion cells (RGCs) and axons that form the optic nerve. Leber's Hereditary Optic Neuropathy and the autosomal dominant optic atrophy related to OPA1 mutations are the most common forms. Nonsyndromic autosomal recessive optic neuropathies are rare and their existence has been long debated. We recently identified the first gene responsible for these conditions, TMEM126A. This gene is highly expressed in retinal cellular compartments enriched in mitochondria and supposed to encode a mitochondrial transmembrane protein of unknown function.Methods
A specific polyclonal antibody targeting the TMEM126A protein has been generated. Quantitative fluorescent in situ hybridization, cellular fractionation, mitochondrial membrane association study, mitochondrial sub compartmentalization analysis by both proteolysis assays and transmission electron microscopy, and expression analysis of truncated TMEM126A constructs by immunofluorescence confocal microscopy were carried out.Results
TMEM126A mRNAs are strongly enriched in the vicinity of mitochondria and encode an inner mitochondrial membrane associated cristae protein. Moreover, the second transmembrane domain of TMEM126A is required for its mitochondrial localization.Conclusions
TMEM126A is a mitochondrial located mRNA (MLR) that may be translated in the mitochondrial surface and the protein is subsequently imported to the inner membrane. These data constitute the first step toward a better understanding of the mechanism of action of TMEM126A in RGCs and support the importance of mitochondrial dysfunction in the pathogenesis of HON.General significance
Local translation of nuclearly encoded mitochondrial mRNAs might be a mechanism for rapid onsite supply of mitochondrial membrane proteins. 相似文献2.
Isabelle Perrault Fadi?F. Hamdan Marlène Rio José-Mario Capo-Chichi Nathalie Boddaert Jean-Claude Décarie Bruno Maranda Rima Nabbout Michel Sylvain Anne Lortie Philippe?P. Roux Elsa Rossignol Xavier Gérard Giulia Barcia Patrick Berquin Arnold Munnich Guy?A. Rouleau Josseline Kaplan Jean-Michel Rozet Jacques?L. Michaud 《American journal of human genetics》2014,94(6):891-897
Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs∗48] and c.3709C>T [p.Arg1237∗]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328∗] and c.6232G>T [p.Glu2078∗]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes. 相似文献
3.
Mutation spectrum and splicing variants in the OPA1 gene 总被引:17,自引:0,他引:17
Cécile Delettre Jean-Michel Griffoin Josseline Kaplan Hélène Dollfus Birgit Lorenz Laurence Faivre Guy Lenaers Pascale Belenguer Christian P. Hamel 《Human genetics》2001,109(6):584-591
Optic atrophy type 1 (OPA1, MIM 165500) is a dominantly inherited optic neuropathy that features low visual acuity leading in many cases to legal blindness. We have recently shown, with others, that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein, underlie the dominant form of optic atrophy. Here we report that OPA1 has eight mRNA isoforms as a result of the alternative splicing of exon 4 and two novel exons named 4b and 5b. In addition, we screened a cohort of 19 unrelated patients with dominant optic atrophy by direct sequencing of the 30 OPA1 exons (including exons 4b and 5b) and found mutations in 17 (89%) of them of which 8 were novel. A majority of these mutations were truncative (65%) and located in exons 8 to 28, but a number of them were amino acid changes predominantly found in the GTPase domain (exons 8 to 15). We hypothesize that at least two modifications of OPA1 may lead to dominant optic atrophy, that is alteration in GTPase activity and loss of the last seven C-terminal amino acids that putatively interact with other proteins. 相似文献
4.
I. Perrault Sophie Châtelin Vanessa Nancy Jean-Michel Rozet Sylvie Gerber Imad Ghazi Eric Souied Jean-Louis Dufier Arnold Munnich Jean de Gunzburg Josseline Kaplan 《Human genetics》1998,102(3):322-326
Leber’s congenital amaurosis (LCA) is the earliest and most severe of all inherited retinal dystrophies. Recently, we mapped
an LCA gene to chromosome 17p13.1 (LCA1) and ascribed the disease to mutations of the retinal guanylate cyclase (ret GC) gene
in a subset of families of North African ancestry. Owing to the genetic heterogeneity of LCA and considering that LCA1 results
from an impaired production of cGMP in the retina (with permanent closure of cGMP-gated cation channels), we hypothesized
that the activation of the cGMP phosphodiesterase (PDE) could trigger the disease by lowering the intracellular cGMP level
in the retina. The rod and cone cGMP-PDE inhibitory subunits were regarded therefore as candidate genes in LCA. Here, we report
the exclusion of five rod and cone cGMP-PDE subunits in LCA families unlinked to chromosome 17p13.
Received: 7 April 1997 / Accepted: 3 November 1997 相似文献
5.
Clinico‐molecular analysis of eleven patients with Hermansky–Pudlak type 5 syndrome,a mild form of HPS
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Vincent Michaud Eulalie Lasseaux Claudio Plaisant Alain Verloes Yaumara Perdomo‐Trujillo Christian Hamel Nursel H. Elcioglu Bart Leroy Josseline Kaplan Pierre‐Simon Jouk Didier Lacombe Patricia Fergelot Fanny Morice‐Picard Benoit Arveiler 《Pigment cell & melanoma research》2017,30(6):563-570
Hermansky–Pudlak syndrome (HPS), first described in 1959, is a rare form of syndromic oculocutaneous albinism associated with bleeding diathesis and in some cases pulmonary fibrosis and granulomatous colitis. All 10 HPS types are caused by defects in vesicle trafficking of lysosome‐related organelles (LRO) proteins. The HPS5 protein associates with HPS3 and HPS6 to form the biogenesis of lysosome‐related organelles complex‐2 (BLOC‐2). Here, we report the clinical and genetic data of 11 patients with HPS‐5 analyzed in our laboratory. We report 11 new pathogenic variants. The 11 patients present with ocular features that are typical for albinism, with mild hypopigmentation, and with no other major complication, apart from a tendency to bleed. HPS‐5 therefore appears as a mild form of HPS, which is often clinically undistinguishable from mild oculocutaneous or ocular forms of albinism. Molecular analysis is therefore required to establish the diagnosis of this mild HPS form, which has consequences in terms of prognosis and of clinical management of the patients. 相似文献
6.
A. Toutain Nathalie Ronce Benoît Dessay Laura Robb Christine Francannet Martine Le Merrer Marie-Louise Briard Josseline Kaplan Claude Moraine 《Human genetics》1997,99(2):256-261
Nance-Horan syndrome (NHS) is an X-linked disease characterized by severe congenital cataract with microcornea, distinctive
dental findings, evocative facial features and mental impairment in some cases. Previous linkage studies have placed the NHS
gene in a large region from DXS143 (Xp22.31) to DXS451 (Xp22.13). To refine this localization further, we have performed linkage
analysis in four families. As the maximum expected Lod score is reached in each family for several markers in the Xp22.31–p22.13
region and linkage to the rest of the X chromosome can be excluded, our study shows that NHS is a genetically homogeneous
condition. An overall maximum two-point Lod score of 9.36 (θ = 0.00) is obtained with two closely linked markers taken together,
DXS207 and DXS1053 in Xp22.2. Recombinant haplotypes indicate that the NHS gene lies between DXS85 and DXS1226. Multipoint
analysis yields a maximum Lod score of 9.45 with the support interval spanning a 15-cM region that includes DXS16 and DXS1229/365.
The deletion map of the Xp22.3–Xp21.3 region suggests that the phenotypic variability of NHS is not related to gross rearrangement
of sequences of varying size but rather to allelic mutations in a single gene, presumably located proximal to DXS16 and distal
to DXS1226. Comparison with the map position of the mouse Xcat mutation supports the location of the NHS gene between the GRPR and PDHA1 genes in Xp22.2.
Received: 14 June 1996 / Revised: 10 October 1996 相似文献
7.
Noradrenaline potently antagonizes the effects of N-methyl-D-aspartate (NMDA) (80 microM) on cyclic GMP production in immature rat cerebellar slices in vitro (IC50 = 0.6 microM). The effect is stereospecific (D-noradrenaline, IC50 = 100 microM), and also observed with adrenaline (IC50 = 0.5 microM) and isoprenaline (IC50 = 1.2 microM). The alpha 1-adrenoceptor agonists methoxamine or phenylephrine or the mixed alpha 1/alpha 2 agonists oxymetazoline or xylometazoline (100 microM) do not block the effects of NMDA, but the alpha 2-adrenoceptor agonist clonidine is weakly active (IC50 = 200 microM). Salbutamol and terbutaline were also inactive except at high concentrations (300 microM), as were a number of other catechol and phenylethylamine derivatives. The antagonistic effects of noradrenaline on the NMDA response were insensitive to phentolamine, atenolol, or propranolol (up to 100 microM), but were blocked by the alpha 2 antagonist idazoxan (1-10 microM). The Na+,K+-ATPase inhibitor ouabain (0.1-10 microM) markedly potentiates the effects of NMDA in this model, and also antagonizes and reverses the ability of noradrenaline (10 microM) to block the effects of NMDA. The results suggest that noradrenaline and Na+,K+-ATPase activity have potent modulatory effects on the NMDA response. 相似文献
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10.
Perrault I Hanein S Gerber S Barbet F Ducroq D Dollfus H Hamel C Dufier JL Munnich A Kaplan J Rozet JM 《American journal of human genetics》2004,75(4):639-646
Leber congenital amaurosis (LCA), the most early-onset and severe form of all inherited retinal dystrophies, is responsible for congenital blindness. Ten LCA genes have been mapped, and seven of these have been identified. Because some of these genes are involved in the visual cycle, we regarded the retinal pigment epithelium and photoreceptor-specific retinal dehydrogenase (RDH) genes as candidate genes in LCA. Studying a series of 110 unrelated patients with LCA, we found mutations in the photoreceptor-specific RDH12 gene in a significant subset of patients (4.1%). Interestingly, all patients harboring RDH12 mutations had a severe yet progressive rod-cone dystrophy with severe macular atrophy but no or mild hyperopia. 相似文献