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S Vuillaumier-Barrot,
C Bouchet-Seraphin,
M Chelbi,
A Eude-Caye,
E Charluteau,
C Besson,
S Quentin,
L Devisme, C Le Bizec,
P Landrieu,
A Goldenberg,
K Maincent,
P Loget,
O Boute,
B Gilbert-Dussardier,
F Encha-Razavi,
M Gonzales,
B Grandchamp,
N Seta
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ABSTRACT: Dystroglycanopathies are a heterogeneous group of muscular dystrophies with autosomal recessive inheritance characterized by abnormal glycosylation of alpha-dystroglycan. The most severe phenotypes are Walker-Warburg Syndrome (WWS) and muscle-eye-brain disease (MEB) presenting with lissencephaly type II (LIS II) and in which muscular dystrophy is associated with mental retardation and eye abnormalities. To date, six distinct genes, POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE and recently in one case DPM3, have been shown to be involved in dystroglycanopathies. Genomic sequencing alone is still frequently used for diagnosis purpose, not allowing detection of intragenic rearrangements at the heterozygous state contrarily to RNA analysis, quantitative PCR and CGH array analysis. These latter methods enabled us to identify four new intragenic rearrangements in the LARGE gene in three fetuses with WWS, born to two unrelated families: deletion of exons 9-10 and duplication of introns 1-4 for the first family and deletion of exons 4 and 7 for the second one; and a deletion of the last six exons of the POMGNT1 gene in two unrelated MEB patients. Genomic dosage studies using emerging tools such as CGH array should be included in routine molecular analysis of dystroglycanopathies, not only for the screening of the LARGE gene in which this kind of mutation seems to be more frequent than point mutations, but also for the other involved genes, especially in severe clinical cases.
Neuromuscular Disorders 07/2011; 21(11):782-90. · 2.80 Impact Factor
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ABSTRACT: Alternating hemiplegia of childhood (AHC) is a rare neuropediatric disorder classically characterized by episodes of hemiplegia developing in the first months of life, various non-epileptic paroxysmal events and global neurological impairment. If the etiology is unresolved, the disorder is highly suspected to be monogenic with DE NOVO autosomal dominant mutations. A missense mutation in the SLC2A1 gene encoding the facilitative glucose transporter-1 (GLUT1) was recently described in a child fulfilling the existing criteria for the diagnosis of AHC, with the exception of age at onset, thus suggesting a clinical overlap between AHC and GLUT1 deficiency syndrome due to SLC2A1 mutations. We have studied a cohort of 23 patients to investigate whether patients with classical AHC harbor SLC2A1 mutations. Automated Sanger sequencing and MLPA analyses failed to detect any SLC2A1 mutations in the 23 patients analyzed, thus excluding mutations of this gene as a frequent cause of classical AHC.
Neuropediatrics 12/2010; 41(6):267-9. · 0.94 Impact Factor
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T Dupré,
S Vuillaumier-Barrot,
I Chantret,
H S Yayé, C Le Bizec,
A Afenjar,
C Altuzarra,
C Barnérias,
L Burglen,
P de Lonlay,
F Feillet,
S Napuri,
N Seta,
S E H Moore
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ABSTRACT: In type I congenital disorders of glycosylation (CDG I), proteins necessary for the biosynthesis of the lipid-linked oligosaccharide (LLO) required for protein N-glycosylation are defective. A deficiency in guanosine diphosphate-mannose: GlcNAc(2)-PP-dolichol mannosyltransferase-1 (MT-1) causes CDG Ik (OMIM 608540), and only five patients, with severe multisystemic clinical presentations, have been described with this disease. Objective To characterise genetic, biochemical and clinical data in five new CDG Ik cases and compare these findings with those of the five previously described patients. Methods LLO biosynthesis was examined in skin biopsy fibroblasts, mannosyltransferases were assayed in microsomes prepared from these cells, and ALG1-encoding MT-1 was sequenced at the DNA and complementary DNA levels. Clinical data for the five new patients were collated.
Cells from five patients with non-typed CDG I revealed accumulations of GlcNAc(2)-PP-dolichol, the second intermediate in the biosynthesis of LLO. Assay of MT-1, -2 and -3, the first three mannosyltransferases required for extension of this intermediate, demonstrated only MT-1 to be deficient. DNA sequencing of ALG1 revealed nine different mutations, seven of which have not been previously reported. Clinical presentations are severe, with dysmorphias, CNS involvement and ocular disturbances being prevalent.
5 patients with CDG Ik are described, and their identification reveals that in France, this disease and CDG Ib (mannose phosphate isomerase deficiency: OMIM 602579) are the most frequently diagnosed CDG I after CDG Ia (phosphomannomutase 2 deficiency: OMIM 601785) and substantiate previous observations indicating that this disease presents at the severe end of the CDG I clinical spectrum.
Journal of Medical Genetics 11/2010; 47(11):729-35. · 6.36 Impact Factor
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C Bouchet,
S Vuillaumier-Barrot,
M Gonzales,
S Boukari, C Le Bizec,
C Fallet,
A-L Delezoide,
H Moirot,
A Laquerriere,
F Encha-Razavi,
G Durand,
N Seta
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ABSTRACT: Walker Warburg syndrome (WWS) is the most severe of a group of multiple congenital disorders known as lissencephaly type II ( LIS Type II) associated with congenital muscular dystrophy and eye abnormalities. The POMT1 gene is the most frequently affected found in 20% of patients with WWS. We describe five fetuses with WWS in three non-related families carrying a same mutation in the POMT1 gene. All fetuses presented with tetra ventricular hydrocephaly, and arachnoidal neuroglial ectopia and cortical dysplasia characteristic of LIS type II. We performed sequencing of the POMT1 gene on fetal DNA. The five fetuses were found to share an insertion of an inversed Alu repeated DNA element within exon 3 of the POMT1 gene, all at the heterozygous state except one at the homozygous state. This mutation was associated with a common transition c.2203 C > T (p.Arg735Cys) in exon 20 on the same allele and similar intragenic haplotype, suggesting that the three families could be related or indicating a possible founder effect in France. Insertions of Alu sequences, which are rarely found in coding regions, have occasionally been reported to cause other genetic diseases. However, this is the first report of a retrotransposon insertion in the POMT1 gene associated with WWS.
Molecular Genetics and Metabolism 01/2007; 90(1):93-6. · 3.19 Impact Factor
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Journal of Medical Genetics 12/2002; 39(11):849-51. · 6.36 Impact Factor
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ABSTRACT: A T911C (F304S) substitution in the ALG6 gene involved in congenital disorder of glycosylation type Ic (OMIM 603147) has been described. However, whether the F304S substitution is a common polymorphism or a causal mutation remains unclear. We screened for the T911C substitution in the ALG6 gene in 54 unrelated healthy French individuals. We developed a restriction fragment length polymorphism assay with a mutagenic primer introducing a diagnostic DdeI restriction site. We found 23 heterozygotes (42.6%) and 3 homozygous individuals (5.5%). This result indicates that T911C is a common polymorphism with an allele frequency of 27% in a French population and not a causal mutation of congenital disorder of glycosylation type Ic.
Journal of Human Genetics 02/2001; 46(9):547-8. · 2.57 Impact Factor
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ABSTRACT: A previous multicentric study set up by the Société française de biologie clinique has emphasized the usefulness of a standardized procedure for the determination by high performance liquid chromatography of alpha-tocopherol in serum or plasma. In our study, we have tested every step of the different published procedures: internal standard adduct, lipoprotein denaturation and vitamin extraction. Reproducibility of results was improved by the use of tocol as an internal standard when compared to retinol or alpha-tocopherol acetates. Lipoprotein denaturation was more efficient with ethanol addition than with methanol and when the ethanol/water ratio was > or = 0.7. Use of n-hexane or n-heptane gave the same recovery of alpha-tocopherol. When organic solvent/water ratio was > or = 1, n-hexane enabled to efficiently extract, in a one-step procedure, the alpha-tocopherol from both normo and hyperlipidemic sera. Performances of the selected procedure were: detection limit: 0.5 microM--linear range: 750 microM--within run coefficient of variation: 2.03%--day to day: 4.76%. Finally, this pluricentric study allows us to propose an optimised procedure for the determination of alpha-tocopherol in serum or plasma.
Annales de biologie clinique 02/1995; 53(6):343-52. · 0.34 Impact Factor
