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M-P Moizard,
N Ronce, S Blesson,
E Bieth,
L Burglen,
C Mignot,
I Mortemousque,
N Marmin,
B Dessay,
C Danesino,
F Feillet,
P Castelnau,
A Toutain,
C Moraine,
M Raynaud
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ABSTRACT: Moizard M-P, Ronce N, Blesson S, Bieth E, Burglen L, Mignot C, Mortemousque I, Marmin N, Dessay B, Danesino C, Feillet F, Castelnau P, Toutain A, Moraine C, Raynaud M. Twenty-five novel mutations including duplications in the ATP7A gene. Menkes disease (MD) and occipital horn syndrome (OHS) are allelic X-linked recessive copper deficiency disorders resulting from ATP7A gene mutations. MD is a severe condition leading to progressive neurological degeneration and death in early childhood, whereas OHS has a milder phenotype with mainly connective tissue abnormalities. Until now, molecular analyses have revealed only deletions and point mutations in both diseases. This study reports new molecular data in a series of 40 patients referred for either MD or OHS. We describe 23 point mutations (9 missense mutations, 7 splice site variants, 4 nonsense mutations, and 3 small insertions or deletions) and 7 intragenic deletions. Of these, 18 point mutations and 3 deletions are novel. Furthermore, our finding of four whole exon duplications enlarges the mutation spectrum in the ATP7A gene. ATP7A alterations were found in 85% of cases. Of these alterations, two thirds were point mutations and the remaining one third consisted of large rearrangements. We found that 66.6% of point mutations resulted in impaired ATP7A transcript splicing, a phenomenon more frequent than expected. This finding enabled us to confirm the pathogenic role of ATP7A mutations, particularly in missense and splice site variants.
Clinical Genetics 05/2010; · 3.13 Impact Factor
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F Laumonnier,
C Shoubridge,
C Antar,
L S Nguyen,
H Van Esch,
T Kleefstra,
S Briault,
J P Fryns,
B Hamel,
J Chelly,
H H Ropers,
N Ronce, S Blesson,
C Moraine,
J Gécz,
M Raynaud
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ABSTRACT: Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.
Molecular psychiatry 03/2009; 15(7):767-76. · 15.05 Impact Factor
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ABSTRACT: The mucopolysaccharidoses (MPS) form a group of heterogeneous hereditary lysosomal storage diseases, distinguished by facial dysmorphy in gargoyle-like facies. The enzymatic deficiency involves the degradation of glycosaminoglycans, whose accumulation manifests in severe general and ophthalmologic problems.
We report the cases of two 18-month-old girls consulting for corneal clouding and photophobia. The diagnosis was made based on the facial dysmorphy, then biologically corroborated: Scheie's syndrome (MPS type I-S) and Hurler's syndrome (MPS type I-H). The corneal clouding was isolated or associated with bilateral disc swelling. Enzyme replacement therapy was instituted in both cases while waiting for bone marrow transplantation, with a better prognosis in the first case because of the type of MPS and the less severe neurological involvement.
The accumulation of glycosaminoglycans in ocular tissues can involve stromal opacities, glaucoma, retinopathy, and optic nerve swelling. Whereas the ophthalmological involvement is often secondary, it can lead the ophthalmologist to the diagnosis of MPS. The early diagnosis of MPS, before the onset of neurological signs, is vital, since treatment can stop disease progression.
Better knowledge of the clinical signs of MPS on the part of the ophthalmologists could improve the prognosis of these patients.
Journal francais d'ophtalmologie 03/2007; 30(2):165-9. · 0.51 Impact Factor
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Journal of Medical Genetics 05/2004; 41(4):e47. · 6.36 Impact Factor
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ABSTRACT: A study was conducted to explain the mechanism of an unusual discrepancy between short- and long-term culture examination methods of chorionic villus sampling (CVS).
In a 29-year-old Caucasian woman, transabdominal CVS was carried out at 12 weeks of gestation. Non-mosaic karyotype 46,XX,i(21q) was found on long-term CVS culture but number and morphology of chromosomes were normal on short-term culture, amniocyte culture, hygroma colli fluid and fetal fibroblast.
Chromosomal aberration probably appeared after the trophoblast cell line differentiation, four days after fertilization, by means of a 21 centromere misdivision and formation of a i(21q) with secondary positive selection of the 46,XX,i(21q) cell line and loss of the 46,XX in the fetus.
The restricted number of cases with this type of discrepancy limits the possibility of drawing generalised conclusions. In case of discrepancy, we recommend confirmation by amniocentesis or by fetal blood combined with sonographic examination to provide a more definitive diagnosis.
Prenatal Diagnosis 11/2002; 22(10):856-8. · 2.11 Impact Factor
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ABSTRACT: IntroductionLes mucopolysaccharidoses (MPS) forment un groupe de maladies de surcharge lysosomales héréditaires hétérogènes, caractérisées par un faciès en « gargouille ».Le déficit enzymatique concerne le catabolisme des glycosaminoglycanes, dont l’accumulation entraîne des troubles généraux et ophtalmologiques graves.Cas cliniquesNous rapportons les cas de 2 fillettes âgées de 18 mois, consultant pour cornées troubles et photophobie. Le diagnostic a été évoqué devant leur dysmorphie faciale puis confirmé biologiquement. Il s’agissait d’une maladie de Scheie (MPS type I-S) et d’une maladie de Hurler (MPS type I-H). Les opacités cornéennes étaient isolées ou associées à un œdème papillaire bilatéral. Une enzymothérapie a été instaurée dans les 2 cas dans l’attente d’une allogreffe de moelle, avec un meilleur pronostic dans le premier cas compte tenu du type de MPS et de l’atteinte neurologique moins avancée.DiscussionL’accumulation des glycosaminoglycanes, présents sous diverses formes dans les tissus oculaires, peut entraîner des opacités stromales, un glaucome secondaire, une rétinopathie de type pigmentaire, et/ou un œdème papillaire. Alors que l’atteinte ophtalmologique est souvent au second plan, elle peut cependant amener l’ophtalmologiste au diagnostic de MPS.ConclusionLa précocité du diagnostic des MPS, avant la constitution des déficits neurologiques, est devenue primordiale, puisque le traitement peut en stopper l’évolution. Ainsi, une meilleure connaissance du tableau clinique par les ophtalmologistes pourrait en améliorer le pronostic.BackgroundThe mucopolysaccharidoses (MPS) form a group of heterogeneous hereditary lysosomal storage diseases, distinguished by facial dysmorphy in gargoyle-like facies. The enzymatic deficiency involves the degradation of glycosaminoglycans, whose accumulation manifests in severe general and ophthalmologic problems.Cases reportWe report the cases of two 18-month-old girls consulting for corneal clouding and photophobia. The diagnosis was made based on the facial dysmorphy, then biologically corroborated: Scheie's syndrome (MPS type I-S) and Hurler's syndrome (MPS type I-H). The corneal clouding was isolated or associated with bilateral disc swelling. Enzyme replacement therapy was instituted in both cases while waiting for bone marrow transplantation, with a better prognosis in the first case because of the type of MPS and the less severe neurological involvement.DiscussionThe accumulation of glycosaminoglycans in ocular tissues can involve stromal opacities, glaucoma, retinopathy, and optic nerve swelling. Whereas the ophthalmological involvement is often secondary, it can lead the ophthalmologist to the diagnosis of MPS. The early diagnosis of MPS, before the onset of neurological signs, is vital, since treatment can stop disease progression.ConclusionBetter knowledge of the clinical signs of MPS on the part of the ophthalmologists could improve the prognosis of these patients.
Journal Français d'Ophtalmologie.
