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Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 289 records · Page 16Linked to original sources
PubMed1997

The gene encoding p44, a subunit of the transcription factor TFIIH, is involved in large-scale deletions associated with Werdnig-Hoffmann disease.

Mutations of the survival motor neurone gene (SMN) are associated with spinal muscular atrophy (SMA), a frequent lethal autosomal recessive disorder. In spite of this, no phenotype-genotype correlation was observed, since the SMN gene is lacking in the majority of patients affected with either the severe form (type I) or the milder forms (types II and III). Here, we show that the gene encoding p44, a subunit of the basal transcription factor TFIIH, is duplicated in the SMA region and that the p44 gene products (p44t and p44c) differ by three amino acid changes. Gene analysis of a total of 94 unrelated SMA patients revealed that the p44t gene is involved in large-scale deletions associated with Werdnig-Hoffmann disease (type I). The TFIIH polypeptide composition as well as transcription and DNA repair activities are normal in patients lacking the p44t gene on both mutant chromosomes, suggesting that the p44t gene is not critical for the development of SMA.

Centromere↗
PubMed1997

[Positive diagnosis of Leber's hereditary optic neuropathy using molecular genetics].

INTRODUCTION: Leber's hereditary optic neuropathy (LHON) is a bilateral optic atrophy, more common in males than in females. No specific clinical feature or biologic test exists to evidence LHON. We report here the case of a man affected with a nonfamilial bilateral optic atrophy, whose diagnostic remained uncertain for 17 years. PATIENT AND METHODS: This patient was hospitalized at the age of 27 in order to establish diagnosis. He had an ophthalmologic examination once a year. He was also affected with chronic renal failure. Detection of the G to A mutation at position 11778 of the DNA was assessed by restriction enzyme digestion of amplified genomic DNA. RESULTS: The 11778 mitochondrial DNA mutation was evidenced, in homoplasmic condition in white blood cells. DISCUSSION: Molecular biology allows to substantiate the diagnosis of LHON and is relatively easy and cheap. Assessment of mitochondrial DNA provides a useful diagnostic tool for nonfamilial or atypical cases of LHON.

Adult↗
PubMed1997

Nicotinamide adenine dinucleotides permeate through mitochondrial membranes in human Epstein-Barr virus-transformed lymphocytes.

Human cultured cells are widely used for the investigation of respiratory chain disorders. Oxidative properties are generally investigated by means of polarographic studies carried out on detergent-permeabilized cells. By studying the oxidative properties of Epstein- Barr virus-transformed B lymphocytes, we found that the respiration was significantly decreased after 3-4 days of cell culture. Simultaneously, we observed decreased NAD(+)-dependent oxidations (malate, glutamate, pyruvate) that became dependent upon the addition of exogenous NAD+. The effect of NAD+ was shown to be related to an influx of catalytic amount of NAD+ into the mitochondrial matrix. A full ability to oxidize NAD(+)-dependent substrates was restored less than 2 h after a change of the culture medium. These observations suggested: (a) the occurrence of fluxes of catalytic amounts of NAD+ through the mitochondrial inner membrane in human cells; (b) an early control of mitochondrial metabolism by matrix NAD+ content in cells grown under limiting growth conditions; (c) the possible confusion between complex I deficiency and a decrease content of matrix NAD+ when using human cultured cells.

B-Lymphocytes↗
PubMed1997

[Mutations of the endothelin-3 gene in isolated and syndromic forms of Hirschsprung disease].

AIMS AND METHODS: Hirschsprung's disease is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been identified in Hirschsprung's disease, namely the RET proto-oncogene, the Glial cell line-Derived Neurotrophic Factor and the endothelin B receptor. A total of 174 probands with isolated Hirschsprung's disease (59 familial, 117 sporadic cases), and 4 patients with associated Waardenburg's syndrome and Hirschsprung's disease (1 familial, 3 sporadic cases) were screened for mutations in the coding sequence of the endothelin 3 gene. The coding sequence of the endothelin 3 gene was analyzed for point mutations, using a combination of SSCP analysis and direct DNA sequencing. RESULTS: Two heterozygous mutations (A17T and A224T) were identified in two patients with isolated Hirschsprung's disease. Two homozygous truncations mutations (E55X and GC262->T) were identified in patients with the Waardenburg's syndrome/Hirschsprung's disease association. CONCLUSION: The present data give further support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also suggest that either recessive and weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.

Endothelin-3↗
PubMed1996

Craniofacial anomalies and malformations in respiratory chain deficiency.

We report on facial anomalies including round face, high forehead, flat philtrum, apparently low-set ears, and short neck in 4 unrelated patients with mitochondrial respiratory enzyme deficiency. Pre- and postnatal growth retardation with microcephaly, brachydactyly, and hypoplasia of distal and middle phalanges was present in all 4 cases. The diagnosis of respiratory chain deficiency was confirmed by enzymatic and molecular studies. The combination of facial anomalies, prenatal growth failure, and malformations is suggestive of antenatal expression of the disease, and raises the question of the part that respiratory chain deficiencies play in human malformations.

Abnormalities, Multiple↗
PubMed1996

Exclusion of allelism of Noonan syndrome and neurofibromatosis-type 1 in a large family with Noonan syndrome-neurofibromatosis association.

A large four-generation family with Noonan syndrome (NS) and neurofibromatosis-type 1 (NF1) was studied for clinical association between the two diseases and for linkage analysis with polymorphic DNA markers of the NF1 region in 17q11.2. Nonrandom segregation between NS and NF1 phenotypes was observed. Neurofibromatosis was tightly linked to NF1 markers, whereas Noonan syndrome was found not be allelic to NF1. These results suggest that two mutations at two independent but closely linked loci are the cause of neurofibromatosis-Noonan syndrome (NF-NS) association in this family.

Alleles↗
PubMed1996

[Advances in genetics: what benefits children?].

The advent of genetic therapy has raised great hopes, but it is clear that for children and their parents, the primary benefit from recent progress is in the possibility of positive diagnosis and presymptomatic diagnosis allowing more adapted management. For the family, genetic counselling allows well informed family planning and birth of healthy children. For the child to be born, continuing progress in genotypic diagnosis often leads to very delicate questions during the antenatal period, especially since certain diagnoses are still difficult and prognosis less than sure. The wide range of tools in molecular genetics may provide the answer in many situations. The rapid development of genetic tools in developed countries should now raise the question of their use in developing countries. This point might have a particular impact in research on genetic factors and sensibility to frequent infectious diseases such as tuberculosis or malaria. In this case, the aim is not diagnosis but the discovery of genes regulating susceptibility which could lead to pharmaceutical developments. This is undoubtedly a long term objective, but should not be overlooked.

Age Factors↗
PubMed1996

Survival motor neuron gene deletion in the arthrogryposis multiplex congenita-spinal muscular atrophy association.

The survival motor neuron (SMN) gene was lacking in 6/12 patients with arthrogryposis multiplex congenita (AMC) associated with spinal muscular atrophy (SMA). Neither point mutation in the SMN gene nor evidence for linkage to chromosome 5q13 were found in the other patients. Hitherto, arthrogryposis was regarded as an exclusion criterion in SMA. Our data strongly suggest that AMC of neurogenic origin is genetically heterogeneous, with a subgroup being allelic to SMA. Absence or interruption of the SMN gene in the AMC-SMA association will make the diagnosis easier and genetic counselling will now become feasible.

Arthrogryposis↗
PubMed1996

Fluxes of nicotinamide adenine dinucleotides through mitochondrial membranes in human cultured cells.

We report on the loss of mitochondrial nicotinamide adenine dinucleotides in human cultured cells along with cell culture and acidification of the culture medium. This was established both by the direct measurement of the decrease in the mitochondrial NAD content and by the alteration of the oxidative properties of the mitochondria. In situ, this loss could be reversed in less than 2 h by changing the culture medium or by readjusting the pH of the medium at physiological pH values. By studying the oxidative properties of intact, but NAD-depleted, mitochondria in digitonin-permeabilized cells, we found that a rapid influx of NAD could replenish the mitochondrial NAD pool. This allowed the restoration of an active NAD+-dependent substrate oxidation. Depletion of mitochondrial NAD in cells grown under quiescent conditions was further confirmed by fluorimetric measurement of mitochondrial NAD, as was the influx of NAD+ into the mitochondrial matrix. These data constitute the first evidence of rapid fluxes of NAD through mitochondrial membranes in animal cells. They also point to the possible confusion between a loss of mitochondrial NAD and a defect of respiratory chain complex I in the context of screening procedures for respiratory chain disorder in human.

B-Lymphocytes↗
PubMed1996

Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism.

The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases, our series seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder.

Achondroplasia↗
PubMed1996

Structure and organization of the human survival motor neurone (SMN) gene.

Spinal muscular atrophies (SMA) are characterized by degeneration of the anterior horn cells of the spinal cord and represent the second most common fatal autosomal-recessive disorder after cystic fibrosis. We have previously identified the survival motor neurone gene (SMN), a SMA-determining gene in the 5q13 region encoding a hitherto unknown protein. In this report, we describe the organization and structure of SMN. The gene is approximately equal to 20 kb in length and consists of nine exons. Sequence data of the 5' end of the gene show that the dinucleotide repeat C272 is close to several putative binding sites for transcription factors, which will help to characterize the regulation of the SMN and CBCD541 gene expression. The availability of the human SMN and its highly homologous counterpart (CBCD541) gene structures and exon-intron boundaries will hopefully speed up the characterization of SMN gene mutations in SMA.

Amino Acid Sequence↗
PubMed1996

Biochemical investigations and immunoblot analyses of two unrelated patients with an isolated deficiency in complex II of the mitochondrial respiratory chain.

Mitochondrial respiratory chain defects involving complex II are comparatively rare. We report the biochemical findings in two unrelated patients who both have an isolated complex II deficiency (40-50% of control values). Western blot analysis of mitochondrial fractions showed different findings between the two patients. In one patient there was a decrease in the levels of both the Fp and Ip subunits whereas in the other patient the levels of all immunoreactive complex II subunits were normal. This is the first time that an isolated deficiency of complex II activity associated with normal levels of protein subunits, using subunit specific antisera, has been described.

Blotting, Western↗