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Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 127 records · Page 7Linked to original sources
PubMed2001

Genotype-phenotype correlation in hereditary multiple exostoses.

Hereditary multiple exostoses (HME) is a genetically heterogeneous autosomal dominant disorder characterised by the development of bony protuberances mainly located on the long bones. Three HME loci have been mapped to chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3). The EXT1 and EXT2 genes encode glycosyltransferases involved in biosynthesis of heparan sulphate proteoglycans. Here we report on a clinical survey and mutation analysis of 42 HME French families and show that EXT1 and EXT2 accounted for more than 90% of HME cases in our series. Among them, 27/42 cases were accounted for by EXT1 (64%, four nonsense, 19 frameshift, three missense, and one splice site mutations) and 9/42 cases were accounted for by EXT2 (21%, four nonsense, two frameshift, two missense, and one splice site mutation). Overall, 31/36 mutations were expected to cause loss of protein function (86%). The most severe forms of the disease and malignant transformation of exostoses to chondrosarcomas were associated with EXT1 mutations. These findings provide the first genotype-phenotype correlation in HME and will, it is hoped, facilitate the clinical management of these patients.

Age of Onset↗
PubMed2001

beta(1)-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a clinically recognisable contiguous gene syndrome ascribed to interstitial deletions of chromosome 17p11.2. Patients have a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Serum melatonin levels and day-night behaviour were studied in nine SMS children (aged 4 to 17 years) given acebutolol, a selective beta(1)-adrenergic antagonist (10 mg/kg early in the morning). Cardiac examination, serum melatonin, motor activity recordings, and sleep diaries were monitored before and after drug administration. The present study shows that a single morning dose of acebutolol suppressed the inappropriate secretion of melatonin in SMS. A significant improvement of inappropriate behaviour with increased concentration, delayed sleep onset, increased hours of sleep, and delayed waking were also noted. These results suggest that beta(1)-adrenergic antagonists help to manage hyperactivity, enhance cognitive performance, and reduce sleep disorders in SMS.

Acebutolol↗
PubMed2001

Complete abolition of the retinal-specific guanylyl cyclase (retGC-1) catalytic ability consistently leads to leber congenital amaurosis (LCA).

PURPOSE: Leber congenital amaurosis (LCA) is the earliest and the most severe form of all inherited retinal dystrophies. In 1996, the current investigators ascribed the disease in families linked to the LCA1 locus on chromosome 17p13.1 to mutations in the photoreceptor-specific guanylyl cyclase (retGC-1) gene. So far, 22 different mutations, of which 11 are missense mutations, have been identified in 25 unrelated families. This is a report of the functional analyses of nine of the missense mutations. METHODS: cDNA constructs were generated that contained the retGC-1 missense mutations identified in patients related to the LCA1 locus. Mutants were expressed in COS7 cells and assayed for their ability to hydrolyze guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). RESULTS: All mutations lying in the catalytic domain showed a complete abolition of cyclase activity. In contrast, only one mutation lying in the extracellular domain also resulted in a severely reduced catalytic activity, whereas the others showed completely normal activity. CONCLUSIONS: More than half the mutations identified in patients related to the LCA1 locus are truncating mutations expected to result in a total abolition of retGC-1 activity. Concerning missense mutations, half of them lying in the catalytic domain of the protein also result in the complete inability of the mutant cyclases to hydrolyze GTP into cGMP in vitro. In contrast, missense mutations lying in the extracellular domain, except one affecting the initiation codon, showed normal catalytic activity of retGC-1. Nevertheless, considering that all patients related to the LCA1 locus displayed the same phenotype, it can be assumed that all missense mutations would have the same dramatic consequences on protein activity in vivo as truncation mutations.

Animals↗
PubMed2000

Clinical variability and genetic homogeneity of the camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is an autosomal recessive condition characterized by the association of congenital or early onset camptodactyly and noninflammatory arthropathy with synovial hyperplasia. Progressive coxa vara deformity and/or noninflammatory pericardial or pleural effusions have been observed in some patients. Recently, the disease gene has been assigned to human chromosome region 1q25-q31, and truncating mutations have been identified in the megakaryocyte stimulating factor gene. Studying 12 patients from 8 unrelated families, we emphasized hip and spine involvement, particularly in the course of the disease as shown in a 58-year-old patient. Despite clinical variability, linkage studies support genetic homogeneity of the disease.

Adolescent↗
PubMed2000

Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy.

Cytochrome c oxidase (COX) catalyzes both electron transfer from cytochrome c to molecular oxygen and the concomitant vectorial proton pumping across the inner mitochondrial membrane. Studying a large family with multiple cases of neonatal ketoacidotic comas and isolated COX deficiency, we have mapped the disease locus to chromosome 17p13.1, in a region encompassing two candidate genes involved in COX assembly-namely, SCO1 and COX10. Mutation screening revealed compound heterozygosity for SCO1 gene mutations in the patients. The mutated allele, inherited from the father, harbored a 2-bp frameshift deletion (DeltaGA; nt 363-364) resulting in both a premature stop codon and a highly unstable mRNA. The maternally inherited mutation (C520T) changed a highly conserved proline into a leucine in the protein (P174L). This proline, adjacent to the CxxxC copper-binding domain of SCO1, is likely to play a crucial role in the tridimentional structure of the domain. Interestingly, the clinical presentation of SCO1-deficient patients markedly differs from that of patients harboring mutations in other COX assembly and/or maturation genes.

Age of Onset↗
PubMed2000

A gene for pyridoxine-dependent epilepsy maps to chromosome 5q31.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder characterized by generalized seizures in the first hours of life and responding only to pyridoxine hydrochloride. The pathogenesis of PDE is unknown, but an alteration in the binding of pyridoxal 5-phosphate to glutamic acid decarboxylase (GAD) has been postulated in patients with PDE. Results are reported for genetic linkage analyses in four families with consanguineous parents and in one family with nonconsanguineous parents. The GAD1 (2q31) and GAD2 genes (10p23) were tested and excluded. A genomewide search was subsequently performed, using microsatellite markers at an average distance of 10 cM, and the search revealed linkage of the disease-causing gene to markers on chromosome 5q31.2-q31.3 (maximum LOD score [Z(max)] 8.43 at recombination fraction [theta] 0 and Zmax=7.58 at straight theta=0 at loci D5S2017 and D5S1972, respectively). A recombination event, between loci D5S638 and D5S463, in one family defined the distal boundary, and a second recombination event between loci D5S2011 and D5S2017 in another family defined the proximal boundary of the genetic interval encompassing the PDE gene (5.1 cM). Ongoing studies may lead to the identification of the disease-causing gene.

Chromosome Mapping↗
PubMed2000

Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency.

BACKGROUND: The respiratory-chain deficiencies are a broad group of largely untreatable diseases. Among them, coenzyme Q10 (ubiquinone) deficiency constitutes a subclass that deserves early and accurate diagnosis. METHODS: We assessed respiratory-chain function in two siblings with severe encephalomyopathy and renal failure. We used high-performance liquid chromatography analyses, combined with radiolabelling experiments, to quantify cellular coenzyme Q10 content. Clinical follow-up and detailed biochemical investigations of respiratory chain activity were carried out over the 3 years of oral quinone administration. FINDINGS: Deficiency of coenzyme Q10-dependent respiratory-chain activities was identified in muscle biopsy, circulating lymphocytes, and cultured skin fibroblasts. Undetectable coenzyme Q10 and results of radiolabelling experiments in cultured fibroblasts supported the diagnosis of widespread coenzyme Q10 deficiency. Stimulation of respiration and fibroblast enzyme activities by exogenous quinones in vitro prompted us to treat the patients with oral ubidecarenone (5 mg/kg daily), which resulted in a substantial improvement of their condition over 3 years of therapy. INTERPRETATION: Particular attention should be paid to multiple quinone-responsive respiratory-chain enzyme deficiency because this rare disorder can be successfully treated by oral ubidecarenone.

Administration, Oral↗
PubMed2000

Expression of the PAX2 gene in human embryos and exclusion in the CHARGE syndrome.

The CHARGE syndrome comprises ocular coloboma, heart malformation, choanal atresia, retarded growth and development, central nervous system malformations, genital hypoplasia, ear abnormalities, or deafness. The cause of the CHARGE syndrome remains unknown. In the present study, we analyzed the distribution pattern of the PAX2 gene in human embryos and found that PAX2 gene expression occurs in the primordia affected in the CHARGE syndrome. These data prompted us to consider the PAX2 gene a candidate gene in the CHARGE "association." We analyzed the PAX2 gene in 34 patients fulfilling the diagnostic criteria of the CHARGE syndrome for deletion and nucleotidic variations of the coding sequence and identified only polymorphisms. Our data suggest that mutation of the PAX2 gene is not a cause of the CHARGE association. However, the pattern of expression of PAX2 suggests that genes encoding downstream targets effectors could be candidate genes for the CHARGE syndrome.

Abnormalities, Multiple↗
PubMed2000

Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.

Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-kappaB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells.

Exons↗
PubMed2000

A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency.

Cytochrome c oxidase (COX) defects are found in a clinically and genetically heterogeneous group of mitochondrial disorders. To date, mutations in only two nuclear genes causing COX deficiency have been described. We report here a genetic linkage study of a consanguineous family with an isolated COX defect and subsequent identification of a mutation in a third nuclear gene causing a deficiency of the enzyme. A genome-wide search for homozygosity allowed us to map the disease gene to chromosome 17p13.1-q11.1 (Z (max)= 2.46; theta = 0.00 at the locus D17S799). This region encompasses two genes, SCO1 and COX10, encoding proteins involved in COX assembly. Mutation analysis followed by a complementation study in yeast permitted us to ascribe the COX deficiency to a homozygous missense mutation in the COX10 gene. This gene encodes heme A:farnesyltransferase, which catalyzes the first step in the conversion of protoheme to the heme A prosthetic groups of the enzyme. All three nuclear genes now linked to isolated COX deficiency are involved in the maturation and assembly of COX, emphasizing the major role of such genes in COX pathology.

Abnormalities, Multiple↗