Showing papers by "Jean-Louis Mandel published in 1999"

Friedreich's ataxia: Point mutations and clinical presentation of compound heterozygotes

Abstract: Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.

A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation.

Abstract: Karine Merienne; Sylvie Jacquot; Solange Pannetier; Maria Zeniou; Agnes Bankier; Jozef Gecz; Jean-louis Mandel; John Mulley; Paolo Sassone-corsi; Andre Hanauer

A Novel RNA-binding Nuclear Protein That Interacts With the Fragile X Mental Retardation (FMR1) Protein

Abstract: Silenced expression of the FMR1 gene is responsible for the fragile X syndrome. The FMR1 gene codes for an RNA binding protein (FMRP), which can shuttle between the nucleus and the cytoplasm and is found associated to polysomes in the cytoplasm. By two-hybrid assay in yeast, we identified a novel protein interacting with FMRP: nuclear EMRP interacting protein (NUFIP). NUFIP mRNA expression is strikingly similar to that of the FMR1 gene in neurones of cortex, hippocampus and cerebellum. At the subcellular level, NUFIP colocalizes with nuclear isoforms of FMRP in a dot-like pattern. NUFIP presents a C2H2 zinc finger motif and a nuclear localization signal, but has no homology to known proteins and shows RNA binding activity in vitro. NUFIP does not interact with the FMRP homologues encoded by the FXR1 and FXR2 genes. Thus, these results indicate a specific nuclear role for FMRP.

Identification of novel mutations in the MTM1 gene causing severe and mild forms of X-linked myotubular myopathy.

Abstract: X-linked myotubular myopathy (XLMTM) is a congenital muscular disease characterized by severe hypotonia and generalized muscle weakness, leading in most cases to early postnatal death. The gene responsible for the disease, MTM1, encodes a dual specificity phosphatase, named myotubularin, which is highly conserved throughout evolution. To date, 139 MTM1 mutations in independent patients have been reported, corresponding to 93 different mutations. In this report we describe the identification of 21 mutations (14 novel) in XLMTM patients. Seventeen mutations are associated with a severe phenotype in males, with death occurring mainly before the first year of life. However, four mutations-three missense (R241C, I225T, and novel mutation P179S) and one single-amino acid deletion (G294del)-were found in patients with a much milder phenotype. These patients, while having a severe hypotonia at birth, are still alive at the age of 4, 7, 13, and 15 years, respectively, and display mild to moderate muscle weakness.

Polyglutamine-containing proteins in schizophrenia.

Abstract: Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamine-expanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab 1C2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia.

Properties of polyglutamine expansion in vitro and in a cellular model for Huntington's disease.

Abstract: Eight neurodegenerative diseases have been shown to be caused by the expansion of a polyglutamine stretch in specific target proteins that lead to a gain in toxic property. Most of these diseases have some features in common. A pathological threshold of 35-40 glutamine residues is observed in five of the diseases. The mutated proteins (or a polyglutamine-containing subfragment) form ubiquitinated aggregates in neurons of patients or mouse models, in most cases within the nucleus. We summarize the properties of a monoclonal antibody that recognizes specifically, in a Western blot, polyglutamine stretches longer than 35 glutamine residues with an affinity that increases with polyglutamine length. This indicates that the pathological threshold observed in five diseases corresponds to a conformational change creating a pathological epitope, most probably involved in the aggregation property of the carrier protein. We also show that a fragment of a normal protein carrying 38 glutamine residues is able to aggregate into regular fibrils in vitro. Finally, we present a cellular model in which the induced expression of a mutated full-length huntingtin protein leads to the formation of nuclear inclusions that share many characteristics with those observed in patients: those inclusions are ubiquitinated and contain only an N-terminal fragment of huntingtin. This model should thus be useful in studying a processing step that is likely to be important in the pathogenicity of mutated huntingtin.

In utero fetal muscle biopsy: a precious aid for the prenatal diagnosis of Duchenne muscular dystrophy.

Abstract: Prenatal diagnosis for Duchenne muscular dystrophy can usually be performed using DNA analysis. This approach would be impossible when there is only one prior affected male and no identifiable gene deletion. Therefore, in utero fetal thigh muscle biopsy with direct examination of muscle by dystrophin analysis may provide the only means of prenatal diagnosis. We report such a case in which fetal muscle biopsy was able to exclude Duchenne muscular dystrophy. A detailed literature review of the topic is provided.

Variation on a trinucleotide theme

Abstract: Four of the spinocerebellar ataxias (SCAs) are due to CAG triplet repeats; now SCA8 is found to be the exception to the rule.