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K Schwartz

Publications and source records attributed to K Schwartz.

At least 145 records · Page 8Linked to original sources
PubMed1995

Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy.

Congenital muscular dystrophies (CMDs), are heterogeneous autosomal recessive disorders. Their severe manifestations consist of early hypotonia and weakness, markedly delayed motor milestones and contractures, often associated with joint deformities. Histological changes seen in muscle biopsies consist of large variations in muscle fibre size, a few necrotic and regenerating fibres and a marked increase in endomysial collagen tissue. Diagnosis is based on clinical features and on morphological changes. In several CMD cases, we have demonstrated an absence of one of the components of the extracellular matrix around muscle fibres, the merosin M chain, now referred to as the alpha 2 chain of laminin-2 (ref.3). We localized this CMD locus to chromosome 6q2 by homozygosity mapping and linkage analysis. The laminin alpha 2 chain gene (LAMA2) maps to the same region on chromosome 6q22-23 (ref. 5). We therefore investigated LAMA2 for the presence of disease-causing mutations in laminin alpha 2 chain-deficient CMD families and now report splice site and nonsense mutations in two families leading presumably to a truncated laminin alpha 2 protein.

Adult↗
PubMed1995

Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the interventricular septum and associated with a large extent of myocardial and myofibrillar disarray. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for beta-myosin heavy chain, cardiac troponin T and alpha-tropomyosin. Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins.

Amino Acid Sequence↗
PubMed1995

Differential expression of alpha- and beta-enolase genes during rat heart development and hypertrophy.

We have analyzed the transition between isoforms of the glycolytic enzyme enolase (2-phospho-D-glycerate hydrolyase; EC 4.2.1.11) in rat heart during normal and pathological growth. A striking fall in embryonic alpha-enolase gene expression occurs during cardiac development, mostly controlled at pretranslational steps. In fetal and neonatal hearts, muscle-specific beta-enolase gene expression is a minor contributor to total enolase. Control mechanisms of beta-enolase gene expression must include posttranscriptional steps. Aortic stenosis induces a rapid and drastic decrease in beta-enolase transcript level in cardiomyocytes, followed by the fall in beta-subunit level. In contrast, alpha-enolase transcript level is not significantly altered, although the corresponding subunit level increases in nonmuscle cells. We conclude that, like fetal heart, hypertrophic heart is characterized by a high ratio of alpha- to beta-enolase subunit concentrations. This study indicates that the decrease in beta-enolase gene expression may be linked to beneficial energetic changes in contractile properties occurring during cardiac hypertrophy.

Aging↗
PubMed1995

Loss of a splice donor site at a 'skipped exon' in a gene homologous to apolipoprotein(a) leads to an mRNA encoding a protein consisting of a single kringle domain.

Apolipoprotein(a) [apo(a)] and plasminogen are located in a gene cluster on chromosome 6 together with two other genes that share highly homologous 5' flanking regions. We have isolated the human liver transcript derived from one of these genes, designated apo(a)-related gene C, that encodes a polypeptide of 132 amino acids composed of a secretion signal and a single kringle domain. Although the gene encodes several additional kringle domains, sequence analysis shows that the second kringle is incomplete in the derived mRNA because it lacks an apparent exon present in the gene. Analysis of genomic sequence shows that the predicted exon at this site lacks a canonical splice donor site. This results in "exon skipping" during maturation of the mRNA, causing a coding frame shift and the presence of premature stop codons.

Alternative Splicing↗
PubMed1995

Patterns of expression of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban mRNAs during rat heart development.

This study reports the clonal analysis and sequence of rat phospholamban (PLB) cDNA clones and the temporal appearance and patterns of distribution of the mRNAs encoding sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2) and PLB in the developing rat heart determined by in situ hybridization. Both proteins play a critical role in the contraction-relaxation cycle of the heart. SERCA2 mRNA is already abundantly present in the first stage studied, in the cardiogenic plate of the 9-day-old presomite embryo, before the occurrence of the first contractions. This very early expression makes it an excellent marker for the study of early heart development. Subsequently, SERCA2 mRNA becomes expressed in a craniocaudal gradient, being highest at the venous pole and decreasing in concentration toward the arterial pole of the heart. PLB mRNA can be detected in hearts from 12 days of development onward in a virtually opposite gradient. In essence, these patterns do not change during further development. PLB mRNA levels remain highest in the ventricle and outflow tract, whereas SERCA2 mRNA prevails in the inflow tract and atrium, although the difference between atrium and ventricle becomes less pronounced. These observations are compatible with a model in which the upstream part of the heart (inflow tract and atrium) would have a greater capacity to clear calcium and hence would have a longer duration of the diastole than the downstream compartments (atrioventricular canal, ventricle, and outflow tract), similar to the observed pattern of contraction of the embryonic heart. The sinoatrial and atrioventricular nodes do not reveal an expression pattern of SERCA2 and PLB mRNA that allows one to distinguish them from the surrounding atrial working myocardium. However, the ventricular part of the conduction system, comprising atrioventricular bundle and bundle branches, are almost devoid of SERCA2 mRNA.

Adenosine Triphosphatases↗
PubMed1995

Tremor and longevity in relatives of patients with Parkinson's disease, essential tremor, and control subjects.

To study the relation between essential tremor (ET) and Parkinson's disease (PD), we compared the frequency of familial tremor in relatives of patients with PD (N = 391), ET (N = 140), and the combination of ET and PD (N = 125) with the frequency in patients with progressive supranuclear palsy (PSP) (N = 99) and normal age-matched controls (N = 104). Tremor was present in 96 (5.1%) of 1,874 parents and siblings of patients with PD, 152 of 650 (23.4%) relatives of patients with ET, 91 (20.7%) of 439 relatives of patients with ET-PD, 12 of 462 (2.6%) relatives of patients with PSP, and 10 of 448 (2.2%) relatives of normal controls. The high frequency of familial tremor among relatives of patients with PD, and especially those with the ET-PD combination, compared with relatives of patients with PSP or of normal controls suggests that there is an association of PD and familial tremor. Since the most common form of familial tremor is ET, our study provides support for the notion that ET and PD are pathogenetically related. We also found that parents with tremor lived on the average 9.2 years longer than those without tremor. The association of familial tremor with significantly increased longevity suggests that familial tremor confers some anti-aging influence. Alternatively, tremor may be a simple byproduct of the aging process.

Adult↗
PubMed1995

Response and immunoresistance to botulinum toxin injections.

Botulinum toxin antibodies (ABS) may be a reason why occasionally patients do not have a response to injections with botulinum toxin type A (BTX). We tested 86 patients with cervical or oromandibular dystonia for the presence of BTX ABS; 20 were positive and 66 were negative. All patients who tested positive had no response to BTX injections on at least two consecutive treatment sessions. When compared with 22 randomly selected patients with negative BTX ABS results, the patients with positive BTX ABS tests had an earlier age at onset (mean age: 31.8 +/- 16.7 years versus 43.4 +/- 10.5; p < 0.05), higher mean dose per visit (249.2 +/- 32.5 U versus 180.8 +/- 68.7, p < 0.0005), and higher total cumulative dose (mean dose: 1,709 +/- 638 U versus 1,066 +/- 938; p < 0.01). Four out of five patients with positive ABS tests later had a response to botulinum toxin type F injections. Of 26 patients with negative BTX ABS results who were tested because of poor response on at least one visit, 21 had good response after subsequent injection and five had no effect. Except for young age at onset and higher dosages, there were no other factors that could reliably predict which patients would become immunoresistant to BTX type A injections. Treatment with alternate serotypes may offer clinical benefit to this group of patients. Absence of detectable BTX ABS may occur in patients with poor response to BTX injections because of inadequate dosage, injections of inappropriate muscles, or poor sensitivity of the BTX ABS bioassay.

Adolescent↗
PubMed1995

The subperiosteal implant as a viable long-term treatment modality in the severely atrophied mandible: a patient's 40-year case history.

Subperiosteal implants have been a treatment modality for atrophied edentulous mandibles for almost 50 years. A case is presented tracing a patient's 40-year history with treatment of his severely atrophied fully edentulous mandible with a subperiosteal implant and removable implant-borne prosthesis. The subperiosteal implant should be considered as a long-term treatment option in those patients who are unable to wear a lower full denture due to resorption of the ridge and osseous defects that provide inadequate bone for placement of endosseous blade- or root-form implants. This case demonstrates the long-term viability of the subperiosteal implant.

Adult↗
PubMed1995

[Hypertrophic cardiomyopathy: practical application of genetic research].

Hypertrophic cardiomyopathy is usually familial with an autosomal dominant mode of transmission. The condition is genetically heterogeneous. The first defective gene to be described was that of the beta heavy chain of cardiac myosin (beta-MHC, chromosome 14 q11-q12) where over 20 different localised false sense mutations and a hot point of mutation in exon 13 have been reported. This locus seems to be implicated in 30% of families studied. Systematic screening of the genome has led to the detection of new sites on chromosomes 1, 11 and 15. No gene has yet been identified in these three new loci. For all new families, present strategy consists in determining the locus responsible for the disease by linkage analysis. For beta-MHC locus a panel of several markers (the two MYO I and MYO II microsatellites of the beta-MHC gene and two new AFN microsatellites) has been established which allows accurate detection of whether the haplotype cosegregates with the disease, even in relatively small families. It is then necessary to define the mutation by PCR amplification of the exons followed by electrophoresis on Hydrolink-MDE gels and sequencing of the mutant exons. Some subjects are genotypically affected but phenotypically normal and it seems the penetrance varies with the type of mutation. Analysis of the genotype/phenotype relationship should be continued in order to improve our knowledge of the consequences of each mutation. The genotype diagnosis is therefore complex and cannot be undertaken at present of the examination of the propositus. Whole families must be sampled.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiomyopathy, Hypertrophic↗
PubMed1995

Readjusting the localization of long QT syndrome gene on chromosome 11p15.

Long QT syndrome (LQT) is an autosomal dominant cardiac disease characterized by ventricular arrhythmia. A first locus for LQT has been identified on chromosome 11p15.5 (LQT1), closely linked to HRAS. To refine the location of LQT1, microsatellites were genotyped in 8 French families and the following order was determined: tel-HRAS-DRD4-D11S922-D11S4046- IGF2-INS-TH-D11S1318-D11S1323-D11S1338-D11S90 9-D11S1346-cen. By haplotype analysis, 12 crossing-over events were identified in affected and unaffected subjects, delineating the LQT1 candidate region to 7 cM. This new delineated localization between D11S1318 and D11S1323 is in a more centromeric region than previously thought and is 5 cM proximal to HRAS.

Chromosome Mapping↗
PubMed1995

Cloning of OL1, a putative olfactory receptor and its expression in the developing rat heart.

By using a strategy based on nucleotide sequence homology, we have cloned an intronless DNA encoding a new putative member of G protein-coupled receptors. The deduced amino acid sequence of the rat OL1 receptor, together with its expression at high levels in a small subset of cells in the olfactory neuroepithelium indicate that OL1 is related to the recently discovered olfactory multigene family. PCR and in situ hybridization analyses showed the OL1 transcripts to be not only expressed in the olfactory epithelium, but also in the heart. This unexpected cardiac expression was developmentally regulated, being maximal at early postnatal stages and hardly detectable at adult stages. Moreover, this observation was not restricted to OL1 since it was extended to other putative olfactory receptors. Although its functional significance remains unknown, this transient cardiac expression suggests that receptors belonging to the olfactory superfamily, could be not only involved in odor coding, but also in cardiac morphogenesis. Another olfactory-specific gene transcript encoding PTP NE-3, a recently cloned receptor-type protein-tyrosine phosphatase, could also be detected in heart. The very low levels of expression observed in rat embryo and at early postnatal stages as compared to adult stages, suggest that protein-tyrosine phosphatases, as well as protein-tyrosine kinases, may play a role in the control of cardiac cell growth and morphogenetic processes.

Amino Acid Sequence↗
PubMed1994

Molecular genetics of familial hypertrophic cardiomyopathy.

Familial Hypertrophic Cardiomyopathy is the first inherited primary cardiomyopathy for which genetic studies have been conducted. It is an autosomal dominant inherited disease, and represents an important cause of sudden death particularly in otherwise healthy young individuals such as athletes. The first chromosomal locus has been mapped on chromosome 14 at q11-q12 where the putative gene is that encoding beta-myosin heavy chain. Several missense mutations have been identified in this gene, almost all of them are located in the region coding for the globular head of the molecule, and codon 403 is a hot-spot for mutations. Mutant alleles are expressed in both cardiac and skeletal muscles of patients where histological studies showed that gross alterations in myosin assembly do not occur. However in vitro experiments strongly suggest that mutant myosins have an impaired ability to form filaments and to interact with actin. The exact mechanisms by which myosin mutations cause FHC are not known. Very recently, three novel chromosomal loci for FHC have been identified on chromosomes 1q3, 11p13-q13, and 15q22. The challenges for the future are the identification of the other genes causing FHC, the demonstration of causal relations between the various gene defects and the development of the disease, the establishment of phenotype/genotype relationships and finally the use of genetic data for diagnostic, prognostic and maybe therapeutic purposes.

Cardiomyopathy, Hypertrophic↗
PubMed1994

Identification of a mutation near a functional site of the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy.

Several mutations within the gene coding for the cardiac beta myosin heavy chain (designed MYH7) have been shown to be responsible for Familial Hypertrophic Cardiomyopathy (FHC) in several families, and evidence of genetic heterogeneity has been reported. To investigate the MYH7 gene as the cause of the disease in a small family with FHC, inheritance of the disease and chromosome 14 q11-q12 markers haplotype were studied, exons coding for the head domain of the cardiac beta myosin heavy chain (beta MHC) were analysed for mutations by MDE gel electrophoresis, and sequenced. We report a mutation within exon eight of the MYH7 gene at a very conserved amino acid at position 232, which results in the conversion of an asparagine to serine. This residue Asn-232 is located in a MHC area that has been recently identified as a critical site for ATPase activity. According to recent results on the three-dimensional structure of the myosin head or subfragment-1 (S1), Asn-232 is located in an alpha-helix which forms part of the nucleotide binding pocket. Although this mutation affects an active site, it seems to be associated with a favourable prognosis and a weak penetrance in this family.

Adult↗