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Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 253 records · Page 14Linked to original sources
PubMed1998

The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord and muscular atrophy. SMA is caused by alterations to the survival of motor neuron (SMN) gene, the function of which has hitherto been unclear. Here, we present immunoblot analyses showing that normal SMN protein expression undergoes a marked decay in the postnatal period compared with fetal development. Morphological and immunohistochemical analyses of the SMN protein in human fetal tissues showed a general distribution in the cytoplasm, except in muscle cells, where SMN protein was immunolocalized to large cytoplasmic dot-like structures and was tightly associated with membrane-free heavy sedimenting complexes. These cytoplasmic structures were similar in size to gem. The SMN protein was markedly deficient in tissues derived from type I SMA fetuses, including skeletal muscles and, as previously shown, spinal cord. While our data do not help decide whether SMA results from impaired SMN expression in spinal cord, skeletal muscle or both, they suggest a requirement for SMN protein during embryo-fetal development.

Animals↗
PubMed1998

Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease.

Hirschsprung disease (HSCR) is a frequent neurocristopathy characterized by the absence of submucosal and myenteric plexuses in a variable length of the gastrointestinal tract. Pedigrees and segregation analyses suggested the involvement of one or several dominant genes with low penetrance in HSCR. Considering that RET and glial cell line-derived neurotrophic factor (GDNF) mutations have been reported in the disease, we regarded the other RET ligand, neurturin (NTN), as an attractive candidate gene, especially as it shares large homologies with GDNF. Here, we report on the finding of a heterozygous missense NTN mutation in a large non-consanguineous family including four children affected with a severe aganglionosis phenotype extending up to the small intestine. Interestingly, it appears that the NTN mutation reported here is not sufficient to cause HSCR, and this multiplex family also segregates a RET mutation. This cascade of independent and additive genetic events fits well with the multigenic pattern of inheritance expected in HSCR, and further support the role of RET ligands in development of the enteric nervous system.

Amino Acid Sequence↗
PubMed1998

Wilms' tumor and gonadal dysgenesis in a child with the 2q37.1 deletion syndrome.

Here we report Wilms' tumor, gonadal dysgenesis and a bifid uterus in an 18-month-old female with a terminal deletion of the long arm of chromosome 2 [46,XX,del(2)(q37.1)]. Since Wilms' tumor has been previously reported in the 2q37 deletion syndrome, the present observation raises the question of whether a tumor susceptibility gene maps to chromosome 2q37 and suggests giving consideration to the possible occurrence of Wilms' tumor in the course of disease.

Abnormalities, Multiple↗
PubMed1998

Relation of genotype 22q11 deletion to phenotype of pulmonary vessels in tetralogy of Fallot and pulmonary atresia-ventricular septal defect.

OBJECTIVE: To compare the morphology of the pulmonary vessels in tetralogy of Fallot or pulmonary atresia-ventricular septal defect (PA-VSD) with (del22q) and without 22Q11 deletion (non-del22q). PATIENTS: 94 consecutive infants (54 with tetralogy of Fallot, 40 with PA-VSD) were studied using ultrasound and catheterisation. MOLECULAR INVESTIGATIONS: Identification of the 22q deletion was performed either by fluorescent in situ hybridisation or polymerisation chain reaction genotyping. RESULTS: 25 patients were del22q (16/40 (40%) PA-VSD v 9/54 (17%) tetralogy of Fallot; p < 0.02). Major aortopulmonary collateral arteries was more common in patients with PA-VSD-del22q (p < 0.03). Such collaterals were identified in 13 patients: 10 del22q and three non-del22q (p < 0.001). The size of the right and left pulmonary arteries expressed as a standard deviation (SD) difference of the normal range was -4.2 (quartiles -5.3 and -2.9) for PA-VSD del22q, and -2.6 (-3.1 and -1.8) for PA-VSD non-del22q (p = 0.02). The mean (SD) difference between the measured and theoretical Nakata index was -373 (94) for PA-VSD del22q v -245 (93) in PA-VSD non-del22q (p = 0.0002). In tetralogy of Fallot patients with and without del22q, the size of the pulmonary arteries was similar (p = 0.6). CONCLUSIONS: A "specific" phenotype could be defined in patients with deletion: PA-VSD, major aortopulmonary collateral arteries with complex loop morphology, and small central pulmonary arteries. Differences in the morphology of the pulmonary vessels may indicate a different timing of the faulty developmental pathway in patients with and without 22q11 deletion.

Aorta↗
PubMed1998

Structure and refinement of the physical mapping of the gamma- glutamylcysteine ligase regulatory subunit (GLCLR) gene to chromosome 1p22.1 within the critically deleted region of human malignant mesothelioma.

Glutathione is a ubiquitous antioxidant in mammalian tissues. The first step of its synthesis is catalyzed by the glutamate-cysteine ligase (GLCL) which consists of a heavy, catalytic subunit and a light, regulatory subunit (GLCLR). Previous genetic analyses have revealed frequent losses of chromosome 1p22-->p21 in human malignant mesothelioma and the shortest region of overlapping deletions has been narrowed between the two loci D1S435 and D1S236. An expressed sequence tag of the GLCLR gene was found within a YAC contig encompassing the same interval aoffwas therefore considered as a good candidate gene for predisposition to human mesothelioma. We report here the characterization of the genomic structure of the GLCLR gene and the refine its physical mapping to chromosome 1p22.1.

Base Sequence↗
PubMed1998

[Angiomatous and cerulodermic macules: early cutaneous signs of neurofibromatosis type I].

BACKGROUND: Diagnosis of neurofibromatosis type I (NF-1) relies on the NIH consensus conference criteria. However, because of delayed penetrance, they are of limited value in infancy or early childhood. Less frequent signs, namely blue-red and fusco-ceruleus macules, may be clues for diagnosis. CASE REPORTS: We report on two children, aged 2 1/2 and 5, in whom these cutaneous findings were present early in childhood. In addition, they had sufficient criteria for NF1. DISCUSSION: These cutaneous signs, although infrequently reported, are present early in life. Hence they may be useful clues for diagnosis of NF-1 in childhood.

Cafe-au-Lait Spots↗
PubMed1998

[From monogenic to polygenic: model of Hirschsprung disease].

Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene, the endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB and EDN3 missense mutations have been reported in isolated HSCR patients. Some of these results were obtained after the identification of mouse genes whose natural or site-directed mutations resulted in megacolon and coat color spotting. There is also conclusive evidence for the involvement of other independent loci in HSCR. In particular, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate genes for HSCR. The dissection of the genetic etiology of HSCR disease may then provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin. Finally, the study of the molecular bases of HSCR is also a step towards the understanding of developmental genetics of the enteric nervous system giving support to the role of the tyrosine kinase and endothelin-signaling pathways in the development of neural crest-derived enteric neurons in human.

Animals↗
PubMed1997

Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human.

Krebs cycle disorders constitute a group of rare human diseases which present an amazing complexity considering our current knowledge on the Krebs cycle function and biogenesis. Acting as a turntable of cell metabolism, it is ubiquitously distributed in the organism and its enzyme components encoded by supposedly typical house-keeping genes. However, the investigation of patients presenting specific defects of Krebs cycle enzymes, resulting from deleterious mutations of the considered genes, leads to reconsider this simple envision by revealing organ-specific impairments, mostly affecting neuromuscular system. This often leaves aside organs the metabolism of which strongly depends on mitochondrial energy metabolism as well, such as heart, kidney or liver. Additionally, in some patients, a complex pattern of tissue-specific enzyme defect was also observed. The lack of functional additional copies of Krebs cycle genes suggests that the complex expression pattern should be ascribed to tissue-specific regulations of transcriptional and/or translational activities, together with a variable cell adaptability to Krebs cycle functional defects.

Adolescent↗
PubMed1997

The consequences of a mild respiratory chain deficiency on substrate competitive oxidation in human mitochondria.

The competition between the respiratory substrates to gain access simultaneously to the respiratory chain depends on the dehydrogenase activity, the mitochondrial ubiquinone pool, and the oxidizing activity of the cytochrome segment. By studying the co-oxidation of NADH and succinate by control human liver homogenates, we found that a change in the balance between respiratory chain complex activities may affect significantly the ability of the mitochondria to oxidize one or the other substrate. Accordingly, in the particular case of a patient presenting with a partial complex I and IV deficiency, we observed a strongly reduced ability to oxidize NADH in the presence of succinate. It therefore appeared that even a slight imbalance between respiratory chain enzyme activities may result in a full blockade of a given substrate oxidation.

Cytochrome-c Oxidase Deficiency↗
PubMed1997

Sequence and structure of the human OXA1L gene and its upstream elements.

The genes encoding proteins involved in respiratory chain assembly represent candidate genes for nuclearly-encoded multiple respiratory chain deficiency. Using the long PCR amplification procedure, we have characterized the organization and complete sequence of OXA1L, a gene involved in the assembly of several complexes of the mitochondrial respiratory chain. The OXA1L gene (5 kb) is composed of 10 exons and 9 introns and contains a 24 N-terminal amino-acid stretch is characteristic of a mitochondrial presequence. The screening of OXA1L mutation in patients with multiple respiratory chain deficiency is now feasible.

Amino Acid Sequence↗
PubMed1997

Prezygotic origin of the isochromosome 12p in Pallister-Killian syndrome.

Pallister-Killian syndrome is a rare disorder comprising multiple congenital anomalies, streaks of hypo(hyper)pigmentation, seizures, profound mental retardation, and the presence of an extra metacentric chromosome i(12)(p10), usually limited to skin fibroblasts. The mechanism and parental origin of the extra chromosome i(12)(p10) are unknown. Here, we present a girl with Pallister-Killian syndrome and the i(12)(p10) in 50% of cultured skin fibroblasts. Using microsatellite DNA markers of chromosome 12p, we detected 3 alleles--including 2 different alleles of maternal origin--in cultured skin fibroblasts, suggesting that the tetrasomy 12p is the result of a prezygotic event, with a nondisjunction event during maternal meiosis.

Abnormalities, Multiple↗
PubMed1997

cDNA isolation, expression, and chromosomal localization of the mouse survival motor neuron gene (Smn).

Spinal muscular atrophy (SMA) is a frequent autosomal recessive disease in human characterized by degeneration of motor neurons of the spinal cord. The genomic region containing the defective gene (5q13) is particularly unstable and prone to large-scale deletions whose characterization led to the identification of the survival motor neuron (SMN) gene, the SMA determining gene encoding a hitherto unknown protein. As an initial step toward the generation of a murine model for SMA, we identified and characterized a full-length murine Smn cDNA. The coding sequence of the mouse Smn gene was found to be 82% identical, at the amino acid level, with the human SMN coding sequence. The Smn locus was mapped to the segment of mouse chromosome 13 exhibiting conservation of synteny with human chromosome 5q11-q23, which contains the SMN gene. However, no evidence for a duplication of the Smn gene was found in the mouse, suggesting that the duplication reported in human is a recent evolutionary event.

Amino Acid Sequence↗
PubMed1997

Microsatellite DNA markers detects 95% of chromosome 22q11 deletions.

Cono-truncal cardiac malformations account for some 50% of congenital heart defects in newborn infants. Recently, hemizygosity for chromosome 22q11.2 was reported in patients with the DiGeorge/Velo-cardio-facial syndromes (DGS/VCFS) and causally related disorders. We have explored the potential use of microsatellite DNA markers for rapid detection of 22q11 deletions in 19 newborn infants referred for cono-truncal heart malformations with associated DGS/VCFS anomalies. A failure of parental inheritance was documented in 84.2% of cases (16/19). PCR-based genotyping using microsatellite DNA markers located within the commonly deleted region allowed us either to confirm or reject a 22q11 microdeletion in 94.3% of cases (18/19) within 24 hours. This test is now currently performed in the infants referred to us for a cono-truncal heart malformation as a first intention screening for 22q11 microdeletion.

Alleles↗
PubMed1997

RET in human development and oncogenesis.

Hirschsprung disease and the multiple endocrine neoplasia type 2 syndromes are hereditary disorders related to the abnormal migration, proliferation or survival of neural crest cells and their derivatives. Hirschsprung disease is a frequent disorder of the enteric nervous system, resulting in intestinal obstruction. The multiple endocrine neoplasia type 2 syndromes predispose to cancers of neural crest derivatives. Both diseases are associated with heterozygous mutations in the RET proto-oncogene. RET encodes a transmembrane receptor tyrosine kinase expressed in neural crest lineages and whose ligand, glial-cell-line-derived neurotrophic factor, has been very recently identified. In vitro expression studies demonstrate that while Hirschsprung disease mutations result in loss of function of the mutant RET tyrosine kinase, multiple endocrine neoplasia type 2 mutations lead to its constitutive activation. Thus, the two 'faces' of RET, gain of function and loss of function, each lead to a different syndrome, respectively: multiple endocrine neoplasia type 2, a cancer syndrome, or Hirschsprung disease, a developmental defect.

Animals↗
PubMed1997

An extension of the admixture test for the study of genetic heterogeneity in hereditary multiple exostoses.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the presence of multiple cartilage-capped exostoses in the juxta-epiphyseal regions of the long bones. EXT is heterogeneous with at least three different locations currently having been identified on chromosomes 8, 11 and 19. We have tested a series of 29 EXT families for possible linkage to the three disease loci and estimated the probability of linkage of the disease to each locus in our series, by using an extension of the admixture test, which makes modelling of heterogeneous monogenic disease feasible. The maximum likelihood was obtained for proportions of 44%, 28% and 28% of families being linked to chromosome 8, 11 and 19, respectively. The a posteriori probability of linkage of the disease to EXT1, EXT2 and EXT3 was greater than 80% for 8/29, 5/29 and 3/29 families, respectively, and did not give evidence of a fourth locus for the disease. The present approach can be generalized to the investigation of genetic heterogeneity in other monogenic diseases, as it simultaneously estimates the location of each disease gene and the proportion of families linked to each locus.

Chromosomes, Human, Pair 11↗
PubMed1997

No mitochondrial cytochrome oxidase (COX) gene mutations in 18 cases of COX deficiency.

Cytochrome c oxidase (COX) deficiency causes a variety of neuromuscular and non-neuromuscular disorders in childhood and adulthood and can theoretically undergo either a nuclear or a mitochondrial (mt) mode of inheritance, making genetic counseling in COX deficiency particularly hazardous. In an attempt to determine the respective roles of mtDNA and nuclear DNA mutations in COX deficiency, we sequenced the three mitochondrially encoded COX subunits (COXI-III) in a series of 18 patients with isolated COX deficiency, especially as COXI-III code for the catalytic site of the enzyme. We failed to detect any deleterious mutations in this series. Moreover, no mtDNA deletion was observed and sequencing of the flanking tRNA genes involved in the maturation of the COX transcripts failed to detect deleterious mutations as well. The present study supports the view that the disease-causing mutations do not lie in the mt genome but, rather, in the nuclear genes encoding either the COX subunits or the proteins involved in assembly of the complex and suggests a recurrent risk of 25% rather than other modes of inheritance in COX deficiencies.

Cell Nucleus↗