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Biomedical subjects

C Petit

Publications and source records attributed to C Petit.

At least 73 records · Page 4Linked to original sources
PubMed2000

A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C.

Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)1. Six different USH1 loci have been reported. So far, only MYO7A (USH1B), encoding myosin VIIA, has been identified as a gene whose mutation causes the disease. Here, we report a gene underlying USH1C (MIM 276904), a USH1 subtype described in a population of Acadian descendants from Louisiana and in a Lebanese family. We identified this gene (USH1C), encoding a PDZ-domain-containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas. In patients we found a splice-site mutation, a frameshift mutation and the expansion of an intronic variable number of tandem repeat (VNTR). We showed that, in the mouse inner ear, only the sensory hair cells express harmonin. The inner ear Ush1c transcripts predicted several harmonin isoforms, some containing an additional coiled-coil domain and a proline- and serine-rich region. As several of these transcripts were absent from the eye, we propose that USH1C also underlies the DFNB18 form of isolated deafness.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus.

About 60% of congenital hearing impairment cases in developed countries are due to genetic defects. Data on the molecular basis of hereditary hearing reflects vast genetic heterogeneity. There are >400 disorders in which hearing impairment is one of the characteristic traits of a syndrome. Linkage studies have identified more than 40 human chromosomal loci associated with non-syndromic hearing loss. So far, 16 of these 40 non-syndromic hearing impairment genes have been identified. We have studied the molecular basis of hearing impairment in four Druze families from the same village in Northern Galilee. The Druze are a small, isolated population in the Middle East practising endogamous marriage. Thus it was expected that a single mutation would account for hearing impairments in all these families. Our results show that at least four different genes are involved. Hearing impairment was caused in one family by a novel mutation in the recently identified OTOF (the DFNB9 gene), by a novel Pendred syndrome mutation (Thr193Ile) in another family, and by a GJB2 mutation (35delG also known as 30delG) in the third family. In the fourth family linkage was excluded from all known hearing impairments loci (recessive and dominant) as well as from markers covering chromosomes 11-22, pointing therefore to the existence of another non-syndromic recessive hearing loss (NSRD) locus on chromosomes 1-10.

Carrier Proteins↗
PubMed2000

The karyophilic properties of human immunodeficiency virus type 1 integrase are not required for nuclear import of proviral DNA.

Integrase (IN) is a key component of the preintegration nucleoprotein complex (PIC), which transports the retroviral genome from the cytoplasm to the nucleus of newly infected cells. Retroviral IN proteins have intrinsic karyophilic properties, which for human immunodeficiency virus type 1 (HIV-1) are currently attributed to regions that display sequence homology to previously characterized nuclear localization signals. We asked here whether the karyophilic properties of HIV-1 IN are involved in the nuclear import of PIC. We mutated three conserved basic regions in the C-terminal domain of IN and analyzed the effects of mutations on subcellular localization of the protein, viral particle composition, IN dimerization within virions, and infectivity. Alteration of two sequences caused the loss of nuclear accumulation of IN and drastically reduced the capacity of the protein to multimerize. Mutation of the most C-terminal sequence had no effect on the subcellular localization and dimerization of IN. Nevertheless, conservation of all three sequences was required for viral infectivity. Despite the perturbation of IN subcellular localization, all mutant viruses displayed normal reverse transcription and nuclear transport of PICs in newly infected cells. The replicative defect was instead at the level of integration, for which all mutants were markedly affected in vivo. Besides reinforcing the association between dimerization of IN and nuclear accumulation of the enzyme, our data demonstrate that subcellular localization of IN alone cannot predict the fate of the PICs.

Amino Acid Sequence↗
PubMed2000

Kallmann syndrome.

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Chromosome Mapping↗
PubMed2000

DFNA3.

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Chromosome Mapping↗
PubMed2000

DFNB9 and DFNB12.

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Chromosome Mapping↗
PubMed2000

NO-Mediated aromatic nitration during decomposition of phenolic S-nitrosothiols in non-aqueous aerobic medium.

Five novel S-nitrosothiol compounds (6-10) derived from L-cysteine were generated in solution and their decomposition rate was followed by UV spectroscopy. In acetonitrile, compounds 9 and 10 were the most stable of this series with a half-life of 24 h. The final organic decomposition products of the five S-nitrosothiols were also analysed. Derivatives 8, 9, and 10, possessing a phenolic hydroxyl group, afforded an unexpected decomposition pathway, with nitration of aromatic ring occurring in non-aqueous media. A mechanism involving a phenoxy radical seems to be implicated.

Aerobiosis↗
PubMed2000

Use of PRINS for preconception screening of polar bodies for common aneuploidies.

It has been shown that preconceptional screening for oocyte aneuploidies could help increase the pregnancy rate after in vitro fertilization (IVF), particularly in cases of advanced maternal age. The FISH (fluorescent in situ hybridization) technique is usually used to examine the first polar body (I-PB) for oocyte screening and so avoid fertilizing and transferring embryos from aneuploid oocytes. We have tested the feasibility of using another technique, the primed in situ (PRINS) reaction for this purpose. PRINS is a rapid, inexpensive method of labelling chromosomes. Chromosomes were labelled by in situ annealing with chromosome-specific oligonucleotide primers, followed by primer extension with labelled nucleotides using Taq DNA polymerase. A total of 183 PRINS reactions were performed with primers for chromosomes 13, 16, 18, 21 or X on 63 I-PBs removed from oocytes that failed to become fertilized during IVF. Each I-PB underwent three successive double-labelling reactions and intense signals were obtained in less than 40 min. Our data suggest that PRINS may be a useful alternative or a complement to FISH for detecting the main aneuploidies in all oocytes obtained after follicular puncture.

Adult↗
PubMed2000

[Contribution of human genetics to the understanding of sensory systems].

As in the other animal species, human senses are adapted to their environment. The energy of photonic, mechanical, thermic or chemical, stimulus is perceived by sensory cells, either dispersed or packed in a sensory end organ. Fifteen years ago, our knowledge of the molecular bases of the function of the various modes of sensory perception was rudimentary with the noticeable exception of that of the phototransduction cascade. Since then, several causative genes for human sensory defects have been isolated. We will examine the outcome of this research in fundamental and medical terms, and bring up the vast yet unexplored fields of the sensory perception. Human genetics should contribute to enlighten the molecular aspects of the latter.

Genetics, Medical↗
PubMed1999

Oxidation sensitivity may be a useful tool for the detection of the hematotoxic potential of newly developed molecules: application to antipsychotic drugs.

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various hematological disorders, e.g., agranulocytosis. Using five experimental conditions, we tested the oxidative potential of compounds with and without a history of hematological side effects, e.g., agranulocytosis and aplastic anemia. A statistical analysis was undertaken for each experimental condition and a multivariate analysis combining all results was performed. Two peroxidase-induced free radical models did not successfully discriminate between drugs with and without a history of causing hematologic problems (<70%). The lipid peroxidation system provided even less satisfactory discrimination, with only 56.25% correct classification. However, an 87.5% correct classification was obtained when using the oxidation potentials of these drugs determined at pH 4.7 and at pH 7.4. A multivariate analysis taking into account the five variables provided 87.5% success in classification. The two clusters were better discriminated in terms of a "distance coefficient." In a second analysis, the putative antipsychotic pyridobenzodiazepine analogues (JL5, JL8, JL18, and JL25) were classified in the cluster of toxic compounds, while the oxa- and thiazepine analogues (JL2, JL3, and JL13) were classified as nontoxic compounds. On the other hand, a few metabolites of clozapine and fluperlapine were classified in the toxic compound group. The procedure described herein is, to our knowledge, the first which classifies molecules of different structures as well as different pharmacological profiles according to their hematotoxic potential. Such a procedure could be used to predict drug-induced hematological side effects.

Agranulocytosis↗
PubMed1999

Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling.

BACKGROUND: DFNB1, the locus of an autosomal recessive form of deafness due to mutations in the connexin-26 gene (CX26 or GJB2) is one of the most frequent hereditary defects in human beings. To date, no clinical characterisation of the DFNB1 inner-ear defects has been reported, which precludes the provision of prognostic information and genetic counselling. METHODS: We enrolled, in a prospective study, 140 children from 104 families affected by sensorineural deafness with various degrees of hearing loss. The children either belonged to a family affected by autosomal recessive deafness (DFNB family) or represented sporadic cases. We searched for mutations in the 5' non-coding exon and in the coding region of CX26. Audiometric and radiological features were investigated and compared in deaf children with and without CX26 mutations. FINDINGS: CX26 mutations were present in 43 (49%) of the 88 families with cases of prelingual deafness versus none of the 16 families with postlingual forms of deafness (p<0.01). The inner-ear defects of 54 prelingually deaf children with biallelic CX26 mutations were compared with the defects in 57 prelingually deaf children without CX26 mutations. DFNB1 deafness varied from mild to profound, associated with sloping or flat audiometric curves and a radiologically normal inner ear. Hearing loss was not progressive in 11 of 16 cases tested, and variations in the severity of deafness between siblings were common. INTERPRETATION: The characteristic audiometric and radiological features of DFNB1 should be the reference used to guide the investigation, by CX26 molecular diagnostic tests, of deaf children with a compatible phenotype. Prognostic information can now be given to families: the hearing loss in DFNB1 deafness is non-progressive in most cases, at least up to young adulthood. An important element for genetic counselling is that the severity of hearing loss due to DFNB1 is extremely variable and cannot be predicted, even within families.

Case-Control Studies↗
PubMed1999

KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness.

Potassium channels regulate electrical signaling and the ionic composition of biological fluids. Mutations in the three known genes of the KCNQ branch of the K+ channel gene family underlie inherited cardiac arrhythmias (in some cases associated with deafness) and neonatal epilepsy. We have now cloned KCNQ4, a novel member of this branch. It maps to the DFNA2 locus for a form of nonsyndromic dominant deafness. In the cochlea, it is expressed in sensory outer hair cells. A mutation in this gene in a DFNA2 pedigree changes a residue in the KCNQ4 pore region. It abolishes the potassium currents of wild-type KCNQ4 on which it exerts a strong dominant-negative effect. Whereas mutations in KCNQ1 cause deafness by affecting endolymph secretion, the mechanism leading to KCNQ4-related hearing loss is intrinsic to outer hair cells.

Amino Acid Sequence↗
PubMed1999

Characterization of otoconin-95, the major protein of murine otoconia, provides insights into the formation of these inner ear biominerals.

During the course of a study aimed at identifying inner ear-specific transcripts, a 1,906-bp murine cDNA predicted to encode a secreted 469-aa protein with two domains of homology with the secreted phospholipases A2 was isolated. This transcript is specifically expressed in the inner ear from embryonic day 9.5. The encoded 95-kDa glycoprotein is the major protein of the utricular and saccular otoconia and thus was named otoconin-95. By immunohistofluorescence, otoconin-95 also was detected in the cupulae of the semicircular canals and in previously undescribed transient granular structures of the cochlea. Otoconin-95 was found to be synthesized by various nonsensory cell types, but not by the supporting cells of the sensory epithelia, which produce the otoconial precursor vesicles. In addition, multiple isoforms generated by differential splicing were observed in different combinations during development. Based on the present results, we propose a model for the formation of the otoconia.

Alternative Splicing↗