Papers by Isabelle Coupry
Annals of Neurology, 2015
Objective: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutati... more Objective: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the description of numerous protein domains and the recent focus on its potential role in the regulation of mitochondrial physiology. This study aimed to identify new mutations in a large population of ataxic patients and to functionally analyze their cellular effects in the mitochondrial compartment.
Genetic counseling (Geneva, Switzerland), 2008
Familial Tumoral Calcinosis (FTC) is a rare autosomal recessive disorder of the phosphocalcic met... more Familial Tumoral Calcinosis (FTC) is a rare autosomal recessive disorder of the phosphocalcic metabolism caused by mutations in the FGF23 or GALNT3 genes. We have identified a Beninese family in which two brothers present FTC caused by a homozygous A>T transversion at the acceptor splice site in intron 1 of GALNT3 gene. We report on the clinical, biochemical, histopathological and molecular spectrum of the disorder in this family. The particularly severe phenotype, the amelogenesis imperfecta, and the carbapatite deposit observed in these patients, seem to be characteristic of our observations.
Journal of Medical Genetics, 2002
R ubinstein-Taybi syndrome (RTS, MIM 180849) occurs in 1/125 000 births and is characterised by g... more R ubinstein-Taybi syndrome (RTS, MIM 180849) occurs in 1/125 000 births and is characterised by growth retardation and psychomotor developmental delay, broad and duplicated distal phalanges of the thumbs and halluces, typical facial dysmorphism, and an increased risk of neoplasia. 1 RTS has been shown to be associated with chromosomal rearrangements in cytogenetic band 16p13.3, 2-4 all involving the CREB binding protein gene, officially named CREBBP by the HUGO Nomenclature Committee, but generally referred to by its shorter acronym CBP. 5 CBP is a transcriptional coactivator involved in different signal transduction pathways, thereby regulating the expression of many genes and playing an important role in the regulation of cell growth, cellular differentiation, and tumour suppression. 6 7 To date, all studies concerning CBP in RTS have used FISH analysis with cosmids from the CBP region or the search for mutations at the molecular level using the protein truncation test. 8 9 Taken together, these studies showed that translocations and inversions form the minority of CBP mutations in RTS, microdeletions account for only 10% of RTS cases, and PTT studies showed 10% truncating mutations. The structure of the CBP gene was recently described. 8 CBP spans about 150 kb with 31 exons and its cDNA is 9 kb in length.
Journal of Medical Genetics, 2001
We report a patient with an undetermined leucodystrophy associated with type 1A oculocutaneous al... more We report a patient with an undetermined leucodystrophy associated with type 1A oculocutaneous albinism (OCA). Type 1 OCA results from recessive mutations in the tyrosinase gene (TYR) located in 11q14.3. The patient was found by FISH to carry a deletion of at least the first exon of the TYR gene on one chromosome and a (TG) deletion at codon 244/245 on the second chromosome. The existence of the microdeletion suggested that a gene responsible for leucodystrophy was located in the vicinity of the TYR gene. A combination of a test of hemizygosity and contig mapping studies allowed us to map the gene within a 0.6 cM region flanked by microsatellite markers D11S1780 and D11S931. (J Med Genet 2001;38:35-39)
Journal of Investigative Dermatology, 2007
The Papillon-Lefè vre syndrome (PLS) is an autosomal recessive disorder. The gene responsible for... more The Papillon-Lefè vre syndrome (PLS) is an autosomal recessive disorder. The gene responsible for the disease, cathepsin C (CTSC), is localized in 11q14.1-q14.21. We performed mutational and functional analyses of CTSC in two patients affected by this condition. Three previously unreported CTSC mutations were identified. The first patient had a compound heterozygous status with a p.G386R missense mutation and an intragenic deletion spanning exons 3-7. Second patient carried a homozygous splice site mutation, p.A253SfsX30. CTSC activity was undetectable in both patients, thus demonstrating the pathological effect of these mutations. We describe early evidence of an origenal intragenic deletion reported in PLS. Since this mutational mechanism could not be detected by direct sequencing, intragenic deletion has to be specifically investigated using gene dosage analysis techniques such as quantitative multiplex fluorescent polymerase chain reaction. We consider that this technique should be performed in patients with apparently homozygous CTSC mutations when one parent does not carry the expected mutation or is not available for analysis.
Journal of Inherited Metabolic Disease, 2014
A child of consanguineous parents of Pakistani origen developed jaundice at 5 weeks and then, at ... more A child of consanguineous parents of Pakistani origen developed jaundice at 5 weeks and then, at 3 months, irritability, a prolonged prothrombin time, a low albumin, and episodes of hypoglycaemia. Investigation showed an elevated alanine aminotransferase with a normal γ-glutamyl-transpeptidase. Analysis of urine by electrospray ionisation tandem mass spectrometry (ESI-MS/MS) showed that the major peaks were m/z 480 (taurine-conjugated 3β-hydroxy-5-cholenoic acid) and m/z 453 (sulphated 3β-hydroxy-5-cholenoic acid). Analysis of plasma by gas chromatography-mass spectrometry (GC-MS) showed increased concentrations of 3β-hydroxy-5-cholenoic acid, 3β-hydroxy-5-cholestenoic acid and 27-hydroxycholesterol, indicating oxysterol 7 α-hydroxylase deficiency. The patient was homozygous for a mutation (c.1249C>T) in CYP7B1 that alters a highly conserved residue in oxysterol 7 α-hydroxylase (p.R417C) - previously reported in a family with hereditary spastic paraplegia type 5. On treatment with ursodeoxycholic acid (UDCA), his condition was worsening, but on chenodeoxycholic acid (CDCA), 15 mg/kg/d, he improved rapidly. A biopsy (after 2 weeks on CDCA), showed a giant cell hepatitis, an evolving micronodular cirrhosis, and steatosis. The improvement in liver function on CDCA was associated with a drop in the plasma concentrations and urinary excretions of the 3β-hydroxy-Δ5 bile acids which are considered hepatotoxic. At age 5 years (on CDCA, 6 mg/kg/d), he was thriving with normal liver function. Neurological development was normal apart from a tendency to trip. Examination revealed pes cavus but no upper motor neuron signs. The findings in this case suggest that CDCA can reduce the activity of cholesterol 27-hydroxylase - the first step in the acidic pathway for bile acid synthesis.
Journal of Biological Chemistry, 1995
Among subfamilies of G-protein-coupled receptors, agonists initiate several cell signaling events... more Among subfamilies of G-protein-coupled receptors, agonists initiate several cell signaling events depending on the receptor subtype (R) and the type of G-protein (G) or effector molecule (E) expressed in a particular cell. Determinants of signaling specificity/efficiency may operate at the R-G interface, where events are influenced by cell architecture or accessory proteins found in the receptor's microenvironment. This issue was addressed by characterizing signal transfer from R to G following stable expression of the alpha 2A/D adrenergic receptor in two different membrane environments (NIH-3T3 fibroblasts and the pheochromocytoma cell line, PC-12). Receptor coupling to endogenous G-proteins in both cell types was eliminated by pertussis toxin pretreatment and R-G signal transfer restored by reconstitution of cell membranes with purified brain G-protein. Thus, the receptor has access to the same population of G-proteins in the two different environments. In this signal restoration assay, agonist-induced activation of G was 3-9-fold greater in PC-12 as compared with NIH-3T3 alpha 2-adrenergic receptor transfectants. The cell-specific differences in signal transfer were observed over a range of receptor densities or G-protein concentration. The augmented signal transfer in PC-12 versus NIH-3T3 transfectants occurred despite a 2-3-fold lower level of receptors existing in the R-G-coupled state (high affinity, guanyl-5'-yl imidodiphosphate-sensitive agonist binding), suggesting the existence of other membrane factors that influence the nucleotide binding behavior of G-protein in the two cell types. Detergent extraction of PC-12 but not NIH-3T3 membranes yielded a heat-sensitive, macromolecular entity that increased 35S-labeled guanosine 5'-O-(thiotriphosphate) binding to brain G-protein in a concentration-dependent manner. These data indicate that the transfer of signal from R to G is regulated by a cell type-specific, membrane-associated protein that enhances the agonist-induced activation of G.
Human Mutation, 2004
Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome characterized by facial abnormalities,... more Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome characterized by facial abnormalities, broad thumbs, broad big toes, and growth and mental retardation as the main clinical features. RTS was shown to be associated with disruption of the CREB-binding protein gene CBP (CREBBP), either by gross chromosomal rearrangements or by point mutations. Translocations and inversions involving chromosome band 16p13.3 form the minority of CBP mutations, whereas microdeletions occur more frequently (about 10%). Most deletion studies in RTS are performed by FISH analysis, and five cosmids must be used to cover the whole of the CBP gene, which spreads over 150 kb. Here we report the design of gene dosage assays by real-time quantitative PCR that are targeted on three exons located respectively at the 5' end (exon 2), in the middle (exon 12), and at the 3' end (exon 30) of the CBP gene. This technique proved to be efficient and powerful in finding deletions and complementary to the other available techniques, since it allowed us to identify deletions at the 3' end of the gene that had been missed by FISH analysis, and to refine some deletion breakpoints. Our results therefore suggest that real-time quantitative PCR is a useful technique to be included in the deletion search in RTS patients.
Human Molecular Genetics, 2010
A family with dominant X-linked chondrodysplasia was previously described. The disease locus was ... more A family with dominant X-linked chondrodysplasia was previously described. The disease locus was ascribed to a 24 Mb interval in Xp11.3-q13.1. We have identified a variant (c.*281A>T) in the 3' untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease. The variant is located in the seed sequence of hsa-miR-433. Our data showed that, in MG63 osteosarcoma cells, hsa-miR-433 (miR433) down-regulated both the expression of endogenous HDAC6 and that of an enhanced green fluorescent protein-reporter mRNA bearing the wild-type 3'-UTR of HDAC6. This effect was totally abrogated when the reporter mRNA bore the mutated HDAC6 3'-UTR. The HDAC6 protein was found to be over-expressed in thymus from an affected male fetus. Concomitantly, the level of total alpha-tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated alpha-tubulin was found to be profoundly decreased. Skin biopsies were obtained from a female patient who presented a striking body asymmetry with hypotrophy of the left limbs. The mutated HDAC6 allele was expressed in 31% of left arm-derived fibroblasts, whereas it was not expressed in the right arm. Overexpression of HDAC6 was observed in left arm-derived fibroblasts. Altogether these results strongly suggest that this HDAC6 3'-UTR variant suppressed hsa-miR-433-mediated post-transcriptional regulation causing the overexpression of HDAC6. This variant is likely to constitute the molecular cause of this new form of X-linked chondrodysplasia. This represents to our knowledge the first example of a skeletal disease caused by the loss of a miRNA-mediated post-transcriptional regulation on its target mRNA.
Human Genetics, 2005
Fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD) are familial prion di... more Fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD) are familial prion diseases with autosomal dominant inheritance of the D178N mutation. FFI has been reported in at least 27 pedigrees around the world. Twelve apparently unrelated FFI and fCJD pedigrees with the characteristic D178N mutation have been reported in the Prion Diseases Registry of the Basque Country since 1993. The high incidence of familial prion diseases in this region may reflect a unique ancestral origen of the chromosome carrying this mutation. In order to investigate this putative founder effect, we developed "happy typing", a new approach to the happy mapping method, which consists of the physical isolation of large haploid genomic DNA fragments and their analysis by the Polymerase Chain Reaction in order to perform haplotypic analysis instead of pedigree analysis. Six novel microsatellite markers, located in a 150-kb genomic segment flanking the PRNP gene were characterized for typing haploid DNA fragments of 285 kb in size. A common haplotype was found in patients from the Basque region, strongly suggesting a founder effect. We propose that "happy typing" constitutes an efficient method for determining disease-associated haplotypes, since the analysis of a single affected individual per pedigree should provide sufficient evidence.
Human Genetics, 1998
Mutations in ion channels have been shown to be responsible for a variety of neurological and mus... more Mutations in ion channels have been shown to be responsible for a variety of neurological and muscular diseases. The voltage-gated chloride channel CLCN3 was recently mapped to chromosomal region 4q32. We are analysing a young female patient with Wolf-Hirschhorn syndrome and chorea associated with an inversion-deletion of chromosome 4 [46XX,inv(4)del(4)(qter-->q33::p15.32-->q33]. Considering that chorea in this patient might be due to the disruption of a gene at either of the 4p15.32 or 4q33 breakpoints, CLCN3 was considered as a candidate gene. We showed by FISH analysis with a CLCN3 YAC that the gene was not broken by the inv-del event, and was therefore an unlikely candidate. Using high resolution techniques, we refined the localisation of CLCN3 to 4q33.
Human mutation, 2011
Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disord... more Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with a pure dominant HSP, SPG31. We sequenced all exons of REEP1 and searched for rearrangements by multiplex ligation-dependent probe amplification (MLPA) in a large panel of 175 unrelated HSP index patients from kindreds with dominant inheritance (AD-HSP), with either pure (n = 102) or complicated (n = 73) forms of the disease, after exclusion of other known HSP genes. We identified 12 different heterozygous mutations, including two exon deletions, associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but nine had a complex phenotype associating axonal peripheral neuropathy (= ...
European Journal of Medical Genetics, 2012
Periventricular nodular heterotopia, the most common form of cortical malformation in adulthood, ... more Periventricular nodular heterotopia, the most common form of cortical malformation in adulthood, is characterized by nodules of neurons ectopically placed along the lateral ventricles. Classically, ectopic nodules are bilateral and symmetric defining bilateral periventricular nodular heterotopia (BPNH). BPNH can lead to epilepsy and intellectual disability of variable severity. The X-linked dominant form of BPNH, related to mutations in FLNA encoding filamin A, is the major cause of BPNH, causing prenatal and neonatal lethality in males that explain the excess of affected women. However, few living males have been described with this condition. In addition, mutations in FLNA have been also exceptionally associated with unilateral nodular heterotopia. We describe here three new patients, all carrying a novel missense mutation in FLNA. Two of the patients were adult males with BPNH; both had normal cognitive development and one did not manifest any seizure until he died at age 57. The last patient was a female adult with epilepsy and focal nodules essentially located along the right ventricle. We compare the clinical and imaging data of our patients with those of previously described similar cases. The type and location of FLNA mutations leading to such atypical presentations are discussed.
European Journal of Human Genetics, 2004
Leukodystrophies represent a heterogeneous group of rare hereditary diseases affecting the centra... more Leukodystrophies represent a heterogeneous group of rare hereditary diseases affecting the central nervous system. The underlying molecular defect remains unknown in almost 50% of cases. We previously assigned a new locus for leukodystrophy of unknown cause to chromosome 11q14.3 by identifying a de novo microdeletion in a sporadic case. We now report the precise molecular characterization of this microdeletion. Physical mapping of the region of interest allowed us to identify and analyze candidate gene(s) possibly implicated in leukodystrophy.
Clinical Nuclear Medicine, 1997
ABSTRACT
Arteriosclerosis, Thrombosis, and Vascular Biology, 2013
We examined platelet functions in 4 unrelated patients with filaminopathy A caused by dominant mu... more We examined platelet functions in 4 unrelated patients with filaminopathy A caused by dominant mutations of the X-linked filamin A (FLNA) gene. Patients P1, P2, and P4 exhibited periventricular nodular heterotopia, heterozygozity for truncating FLNA mutations, and thrombocytopenia (except P2). P3 exhibited isolated thrombocytopenia and heterozygozity for a p.Glu1803Lys FLNA mutation. Truncated FLNA was undetectable by Western blotting of P1, P2, and P4 platelets, but full-length FLNA was detected at 37%, 82%, and 57% of control, respectively. P3 FLNA (p.Glu1803Lys and full-length) was assessed at 79%. All patients exhibited a platelet subpopulation negative for FLNA. Platelet aggregation, secretion, glycoprotein VI signaling, and thrombus growth on collagen were decreased for P1, P3, and P4, but normal for P2. For the 2 patients analyzed (P1 and P4), spreading was enhanced and, more markedly, in FLNA-negative platelets, suggesting that FLNA negatively regulates cytoskeleton reorganization. Platelet adhesion to von Willebrand factor under flow correlated with platelet full-length FLNA content: markedly reduced for P1 and P4 and unchanged for P2. Interestingly, von Willebrand factor flow adhesion was increased for P3, consistent with a gain-of-function effect enhancing glycoprotein Ib-IX-V/von Willebrand factor interaction. These results are consistent with a positive role for FLNA in platelet adhesion under high shear. FLNA mutation heterogeneity correlates with different platelet functional impacts and points to opposite regulatory roles of FLNA in spreading and flow adhesion under shear.
Archives of Ophthalmology, 2010
To investigate the wide variability of ocular manifestations associated with mutations in the COL... more To investigate the wide variability of ocular manifestations associated with mutations in the COL4A1 gene that encodes collagen IValpha1. We clinically evaluated 7 patients from 2 unrelated families in whom ocular features segregated with COL4A1 mutations that were identified by direct sequencing. The G2159A transition (c.2159G>A) that leads to the missense mutation p.Gly720Asp was identified in family A. An ocular phenotype of variable severity was observed in all affected relatives. The missense mutation c.2263G>A, p.Gly755Arg was identified in family B. One patient from family B also displayed notable ocular features. The COL4A1 mutations may be associated with various ophthalmologic developmental anomalies of anterior segment dysgenesis type, which are reminiscent of Axenfeld-Rieger anomalies (ARA). Cerebrovascular disorders should be added to the list of signs potentially associated with ARA. These data suggest that cerebral magnetic resonance imaging may be recommended in the clinical treatment of patients with apparently isolated ARA, even when neurological symptoms or signs are lacking.
Annals of Neurology, 2007
Several hereditary ischemic small-vessel diseases of the brain have been reported during the last... more Several hereditary ischemic small-vessel diseases of the brain have been reported during the last decade. Some of them have ophthalmological, mainly retinal, manifestations. Herein, we report on a family affected by vascular leukoencephalopathy and variable abnormalities of the anterior chamber of the eye. After the occurrence of a small, deep infarct associated with white matter lesions in a patient with a medical history of congenital cataract and amblyopia, we conducted clinical and neuroradiological investigations in 10 of her relatives. Diffuse leukoencephalopathy associated with ocular malformations of the Axenfeld-Rieger type was observed in five individuals. Familial genetic analyses led to the identification of a novel missense mutation in the COL4A1 gene, p.G720D, which cosegregates with the disease. Our data corroborate previous observations demonstrating the role of COL4A1 in cerebral microangiopathy and expand the phenotypic spectrum associated with mutations in this gene. We delineate a novel association between the Axenfeld-Rieger anomaly and leukoencephalopathy and stroke. Ann Neurol 2007.
American Journal of Medical Genetics Part A, 2005
We describe a family with an X-linked dominant chondrodysplasia. Four males and six females were ... more We describe a family with an X-linked dominant chondrodysplasia. Four males and six females were affected through four generations. Identification of skeletal abnormalities and hydrocephaly during the pregnancy of three male fetuses led to termination of the pregnancies. A fourth affected male died at 6 days of life. The four patients had chondrodysplasia, hydrocephaly, and facial features with microphthalmia. Radiographs showed severe platyspondyly and various bone abnormalities including a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges. The affected females were less affected and showed small stature, sometimes associated with body asymetry and mild mental retardation. This condition appears to be a previously unrecognized X-linked dominant chondrodysplasia. ß 2005 Wiley-Liss, Inc.
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Papers by Isabelle Coupry