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Biomedical subjects

C E Seidman

Publications and source records attributed to C E Seidman.

At least 73 records · Page 4Linked to original sources
PubMed1998

Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis.

Previously, we found that the cause of autosomal dominant selective tooth agenesis in one family is a missense mutation resulting in an arginine-to-proline substitution in the homeodomain of MSX1. To determine whether the tooth agenesis phenotype may result from haploinsufficiency or a dominant-negative mechanism, we have performed biochemical and functional analyses of the mutant protein Msx1(R31P). We show that Msx1(R31P) has perturbed structure and reduced thermostability compared with wild-type Msx1. As a consequence, the biochemical activities of Msx1(R31P) are severely impaired, since it exhibits little or no ability to interact with DNA or other protein factors or to function in transcriptional repression. We also show that Msx1(R31P) is inactive in vivo, since it does not display the activities of wild-type Msx1 in assays of ectopic expression in the limb. Furthermore, Msx1(R31P) does not antagonize the activity of wild-type Msx1 in any of these assays. Because Msx1(R31P) appears to be inactive and does not affect the action of wild-type Msx1, we propose that the phenotype of affected individuals with selective tooth agenesis is due to haploinsufficiency.

Amino Acid Substitution↗
PubMed1998

U-shape relationship between change in dietary cholesterol absorption and plasma lipoprotein responsiveness and evidence for extreme interindividual variation in dietary cholesterol absorption in humans.

A possible relationship between change in dietary cholesterol absorption and plasma lipoprotein responsiveness was examined in 18 normal subjects fed low fat low cholesterol, high fat low cholesterol, and high fat high cholesterol diets. For the group, neither dietary cholesterol nor dietary fat affected the percentage dietary cholesterol absorption, whereas dietary cholesterol intake raised total and LDL-C and dietary fat raised total, LDL, and HDL-C. On a fixed diet there was approximately a 2-fold variation among subjects in percentage dietary cholesterol absorption. Subjects also varied in response to dietary cholesterol and fat with regard to dietary cholesterol absorption and plasma lipoprotein responsiveness. There was a U-shaped parabolic relationship between dietary cholesterol-induced percent change in LDL-C and the change in percentage dietary cholesterol absorption (R2 = 0.62, P = 0.005). A similar but weaker relationship characterized the responsiveness of HDL-C (R2 = 0.38, P = 0.05). For the group, increased cholesterol intake raised dietary cholesterol mass absorption from 1.6 to 4.6 mg/kg per day, but the range of increase was from 1 to 4.7 mg/kg per day. Increased fat intake also affected dietary cholesterol mass absorption with most subjects displaying a strong inverse relationship between fat intake and mass absorption (r = -0.77, P < 0.003). In summary: i) the percentage change in dietary cholesterol absorption in response to dietary cholesterol does appear to regulate diet responsiveness of LDL and HDL-C, and ii) the large variability in percent absorption and changes in percentage and mass absorption in response to dietary cholesterol suggest the presence of genetically determined differences among individuals in the regulation of dietary cholesterol absorption.

Adult↗
PubMed1997

Effects of two familial hypertrophic cardiomyopathy-causing mutations on alpha-tropomyosin structure and function.

Missense mutations in alpha-tropomyosin can cause familial hypertrophic cardiomyopathy. The effects of two of these, Asp175Asn and Glu180Gly, have been tested on the structure and function of recombinant human tropomyosin expressed in Escherichia coli. The F-actin affinity (measured by cosedimentation) of Glu180Gly was similar to that of wild-type, but Asp175Asn was more than 2-fold weaker, whether or not troponin was present. The mutations had no apparent effect on the affinity of tropomyosin for troponin. The mutations had a small effect on the overall stability (measured using circular dichroism) but caused increased local flexibility or decreased local stability, as evaluated by the higher excimer/monomer ratios of tropomyosin labeled with pyrene maleimide at Cys 190. The pyrene-labeled tropomyosins differed in their response to myosin S1 binding to the actin-tropomyosin filament. The conformations of the two mutants were different from each other and from wild-type in the myosin S1-induced on-state of the thin filament. Even though both mutant tropomyosins bound cooperatively to actin, they did not respond with the same conformational change as wild-type when myosin S1 switched the thin filament from the off- to the on-state.

Actins↗
PubMed1997

Cao-sensing receptor (CaR)-mediated activation of K+ channels is blunted in CaR gene-deficient mouse neurons.

The extracellular Ca2+ (Cao)-sensing receptor (CaR) is expressed in hippocampus and other brain regions, suggesting that it could mediate some of the well recognized but poorly understood direct actions of Cao on neuronal function. This study presents evidence that the CaR is functionally coupled to Ca(2+)-activated K+ channels. The effects of CaR agonists on these channels in neurons from wild type (WT) and CaR-deficient (CaR -/-) mice were compared. Neomycin (100 mM) and elevation of Cao from 0.5 to 3 mM significantly increased the probability of channel opening (Po) in neurons from WT but not in those from CaR -/- mice. Thus the CaR activates neuronal K+ channels and could potentially inhibit neuronal excitability and neurotransmission via membrane repolarization.

Animals↗
PubMed1997

Amyloid-beta proteins activate Ca(2+)-permeable channels through calcium-sensing receptors.

The amyloid-beta peptides (A beta) are produced in excess in Alzheimer's disease (AD) and may contribute to neuronal dysfunction and degeneration. This study provides strong evidence for a novel cellular target for the actions of A beta, the phospholipase C-coupled, extracellular Ca(2+)-sensing receptor (CaR). We demonstrate that A beta(s) produce a CaR-mediated activation of a Ca(2+)-permeable, nonselective cation channel (NCC), probably via elevation in cytosolic Ca2+ (Cai), in cultured hippocampal pyramidal neurons from normal rats and from wild type mice but not those from mice with targeted disruption of the CaR gene (CaR -/-). A beta(s) also activate NCC in CaR-transfected but not in nontransfected human embryonic kidney (HEK293) cells. Thus aggregates of A beta deposited on hippocampal neurons in AD could appropriately activate the CaR, stimulating Ca(2+)-permeable channels and causing sustained elevation of Cai with resultant neuronal dysfunction.

Amyloid beta-Peptides↗
PubMed1997

Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene.

OBJECTIVES: We studied the clinical and genetic features of familial hypertrophic cardiomyopathy (FHC) caused by an Asp175Asn mutation in the alpha-tropomyosin gene in affected subjects from three unrelated families. BACKGROUND: Correlation of genotype and phenotype has provided important information in FHC caused by beta-cardiac myosin and cardiac troponin T mutations. Comparable analyses of hypertrophic cardiomyopathy caused by alpha-tropomyosin mutations have been hampered by the rarity of these genetic defects. METHODS: The haplotypes of three kindreds with FHC due to an alpha-tropomyosin gene mutation, Asp175Asn, were analyzed. The cardiac histopathologic findings of this mutation are reported. Distribution of left ventricular hypertrophy in affected members was assessed by two-dimensional echocardiography, and patient survival rates were compared. RESULTS: Genetic studies defined unique haplotypes in the three families, demonstrating that independent mutations caused the disease in each. The Asp175Asn mutation caused cardiac histopathologic findings of myocyte hypertrophy, disarray and replacement fibrosis. The severity and distribution of left ventricular hypertrophy varied considerably in affected members from the three families (mean maximal wall thickness +/- SD: 24 +/- 4.5 mm in anterior septum of Family DT; 15 +/- 2.7 mm in anterior septum and free wall of Family DB; 18 +/- 2.1 mm in posterior septum of Family MI), but survival was comparable and favorable. CONCLUSIONS: Nucleotide residue 579 in the alpha-tropomyosin gene may have increased susceptibility to mutation. On cardiac histopathologic study, defects in this sarcomere thin filament component are indistinguishable from other genetic etiologies of hypertrophic cardiomyopathy. The Asp175Asn mutation can elicit different morphologic responses, suggesting that the hypertrophic phenotype is modulated not by genetic etiologic factors alone. In contrast, prognosis reflected genotype; near normal life expectancy is found in hypertrophic cardiomyopathy caused by the alpha-tropomyosin mutation Asp175Asn.

Adolescent↗
PubMed1997

Electrophysiological abnormalities and arrhythmias in alpha MHC mutant familial hypertrophic cardiomyopathy mice.

A new mouse cardiac electrophysiology method was used to study mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+), which results in histological and hemodynamic abnormalities characteristic of familial hypertrophic cardiomyopathy (FHC) and sudden death of uncertain etiology during exercise. Wild-type animals had completely normal cardiac electrophysiology. In contrast, FHC mice demonstrated (a) electrocardiographic abnormalities including prolonged repolarization intervals and rightward axis; (b) electrophysiological abnormalities including heterogeneous ventricular conduction properties and prolonged sinus node recovery time; and (c) inducible ventricular ectopy. These data identify distinct electrophysiologic abnormalities in FHC mice with a specific alpha-myosin mutation, and also validate a novel method to explore in vivo the relationship between specific genotypes and their electrophysiologic phenotypes.

Animals↗
PubMed1997

Various types of hereditary inclusion body myopathies map to chromosome 9p1-q1.

Hereditary inclusion body myopathies are a clinically heterogeneous group of disorders characterized by adult-onset, slowly progressive muscle weakness and typical histopathology: rimmed vacuoles and filamentous inclusions. The disorders are usually inherited as an autosomal recessive trait. The gene responsible for the disease found in Iranian Jews, who present with quadriceps-sparing myopathy, maps to chromosome 9p1-q1. We address the question of whether hereditary inclusion myopathies are genetically as well as clinically heterogeneous disorders. We mapped the disease gene segregating in two families of Afghani-Jewish and one family of Iraqi-Jewish descent to the chromosome 9 locus. Similarly, the disease gene segregating in a non-Jewish family from India mapped to the same locus. By contrast, the disease gene segregating in a French-Canadian family in which affected individuals had central nervous system involvement as well as hereditary inclusion body myopathy, did not map to this locus. We conclude that many but not all forms of autosomal recessive hereditary inclusion body myopathy are caused by a gene defect that maps to chromosome 9p1-q1.

Adult↗
PubMed1997

A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome.

OBJECTIVE: To describe a multigenerational family with transmission of an autosomal dominant disorder characterized by pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne. MATERIAL AND METHODS: We present a detailed case report of a 39-year-old man with arthritic changes in several joints, pyoderma gangrenosum, and cystic acne. Several relatives from three generations of his family underwent clinical and genetic investigations. The findings in this kindred are reported. RESULTS: Ten affected family members in three generations manifested variable expression of a pauciarticular, nonaxial, destructive, corticosteroid-responsive arthritis that began in childhood; pyoderma gangrenosum; and severe cystic acne in adolescence and beyond. Other less commonly associated features included adult-onset insulin-dependent diabetes mellitus, proteinuria, abscess formation at the site of parenteral injections, and cytopenias attributable to sulfonamide medications. Laboratory evaluation was nondiagnostic. Genetic studies excluded linkage to the major histocompatibility locus. CONCLUSION: The acronym of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) is suggested for this newly recognized pleiotropic autosomal dominant disorder. The nature of the genetic alteration in PAPA syndrome is unknown.

Acne Vulgaris↗
PubMed1997

Deficient cation channel regulation in neurons from mice with targeted disruption of the extracellular Ca2+-sensing receptor gene.

This study presents evidence that a receptor sensitive to the concentration of extracellular Ca2+ (Ca[2+]o) (CaR) is functionally coupled to ion channels involved in modulation of neuronal excitability. This receptor is expressed in hippocampus and other brain regions, suggesting that it could mediate some of the well-recognized but poorly understood direct actions of extracellular Ca2+ (Ca[2+]o) on neuronal function. The effects of polycationic CaR agonists on the activity of a nonselective cation channel (NCC) in cultured hippocampal neurons from wild-type mice and from mice homozygous for targeted disruption of the CaR gene (CaR -/-) were compared in this study. The CaR agonists, neomycin (100 microM), spermine (300 microM), and elevation of Ca(2+)o from 0.75 to 3 mM, significantly increased the probability of channel opening (Po) in wild-type neurons. None of these agents, however, produced any effect on Po in neurons from mice lacking the CaR. The same NCC, however, could be activated by thapsigargin in neurons from both wild-type mice and CaR-deficient mice, most likely through an associated increase in the cytosolic free calcium concentration (Ca[i]). Thus the CaR regulates the activity of Ca2+-permeable NCC in hippocampal neurons and could potentially modulate key neuronal functions, including neurotransmission and neuronal excitability, via membrane depolarization.

Animals↗
PubMed1997

Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome.

Holt-Oram syndrome is characterized by upper limb malformations and cardiac septation defects. Here, we demonstrate that mutations in the human TBX5 gene underlie this disorder. TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T-box transcription factor family. A nonsense mutation in TBX5 causes Holt-Oram syndrome in affected members of one family; a TBX5 missense mutation was identified in affected members of another. We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome.

Abnormalities, Multiple↗
PubMed1997

Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome.

Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.

Abnormalities, Multiple↗
PubMed1997

Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia.

To identify mutations that cause hereditary hemorrhagic telangiectasia (HHT, or Rendu-Osler-Weber syndrome), clinical evaluations and genetic studies were performed on 32 families. Linkage studies in four of eight families indicated an endoglin (ENG) gene mutation. ENG sequences of affected members of the four linked families and probands from the 24 small families were screened for mutations, by Southern blot analyses and by cycle sequencing of PCR-amplified DNA. Seven novel mutations were identified in eight families. Two mutations (a termination codon in exon 4 and a large genomic deletion extending 3' of intron 8) did not produce a stable ENG transcript in lymphocytes. Five other mutations (two donor splice-site mutations and three deletions) produce altered mRNAs that are predicted to encode markedly truncated ENG proteins. Mutations in other families are predicted to lie in ENG-regulatory regions or in one of the additional genes that may cause HHT. These data suggest that the molecular mechanism by which ENG mutations cause HHT is haploinsufficiency. Furthermore, because the clinical manifestation of disease in these eight families was similar, we hypothesize that phenotypic variation of HHT is not related to a particular ENG mutation.

Adult↗
PubMed1997

Targeted ablation of the murine alpha-tropomyosin gene.

We created a mouse that lacks a functional alpha-tropomyosin gene using gene targeting in embryonic stem cells and blastocyst-mediated transgenesis. Homozygous alpha-tropomyosin "knockout" mice die between embryonic day 9.5 and 13.5 and lack alpha-tropomyosin mRNA. Heterozygous alpha-tropomyosin knockout mice have approximately 50% as much cardiac alpha-tropomyosin mRNA as wild-type littermates but similar alpha-tropomyosin protein levels. Cardiac gross morphology, histology, and function (assessed by working heart preparations) of heterozygous alpha-tropomyosin knockout and wild-type mice were indistinguishable. Mechanical performance of skinned papillary muscle strips derived from mutant and wild-type hearts also revealed no differences. We conclude that haploinsufficiency of the alpha-tropomyosin gene produces little or no change in cardiac function or structure, whereas total alpha-tropomyosin deficiency is incompatible with life. These findings imply that in heterozygotes there is a regulatory mechanism that maintains the level of myofibrillar tropomyosin despite the reduction in alpha-tropomyosin mRNA.

Animals↗
PubMed1997

beta-Arrestin1 knockout mice appear normal but demonstrate altered cardiac responses to beta-adrenergic stimulation.

beta-Arrestin1 knockout mice were studied to define the physiological role of beta-arrestin1 in the regulation of G protein-coupled receptors. beta-Arrestin1 is thought to be involved in the desensitization of many G protein-associated cell surface receptors, particularly beta-adrenergic receptors. Homozygous knockout mice are overtly normal. Resting cardiovascular parameters modulated by beta-adrenergic receptors such as heart rate, blood pressure, and left ventricular ejection fraction are not changed. However, homozygous mutants are more sensitive to beta-receptor agonist-stimulated increases in ejection fraction, consistent with a role of beta-arrestin1 in beta-adrenergic receptor desensitization. We conclude that beta-arrestin1 is important for in vivo G protein-coupled receptor desensitization and that this aspect of desensitization represents a mechanism for fine-tuning responses. However, beta-arrestin1 does not appear to be required for development or for other essential biological functions.

Animals↗
PubMed1997

Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency.

Isolated GnRH deficiency is a heritable condition characterized by a functional deficit in GnRH secretion. Familial cases with different modes of inheritance have been described, and the gene responsible for the X-linked form (KAL-1) has been identified. However, sporadic cases with no documented family history of GnRH deficiency account for the majority of the affected patients. For this reason, we sought to determine the frequency with which KAL-1 gene mutations occur in patients with sporadic GnRH deficiency. Only 1 of 21 patients with sporadic GnRH deficiency was found to bear a defect in the KAL-1 gene (a deletion of 14 bases starting at codon 464). Three types of polymorphic single base substitutions with no apparent correlation with GnRH deficiency were also detected in several patients. In each of 3 different patients with an X-linked mode of inheritance, 3 genetic defects, 2 point mutations and a small intragenic deletion, were detected. These defects consist of a single base mutation introducing a stop codon at position 328, a single base mutation resulting in a phenylalanine to leucine substitution at position 517, and a 9-base deletion at the 3'-exon-intron splice site of exon 8, respectively. All identified genetic defects occur within the fibronectin type III repeats of the predicted protein encoded by the KAL-1 gene. In conclusion, our study indicates that the incidence of genetic defects within the coding region of the KAL-1 gene in patients with sporadic GnRH deficiency is low (5-8%), thus supporting the idea that the X-linked form of inheritance represents the least common form of the disease.

Base Sequence↗
PubMed1996

Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. Evidence for a dominant negative action.

Mutations in the beta-myosin heavy chain gene are believed to cause hypertrophic cardiomyopathy (HCM) by acting as dominant negative alleles. In contrast, a truncated cardiac troponin T (TnT) that causes HCM implies that altered stoichiometry of contractile proteins may also cause cardiac hypertrophy. Wild-type and HCM-mutant (truncated) TnT were studied in a novel quail myotube expression system. Unexpectedly, antibody staining demonstrated incorporation of both forms of human cardiac TnT into the sarcomeres of quail myotubes. Functional studies of wild type and mutant transfected myotubes of normal appearance revealed that calcium-activated force of contraction was normal upon incorporation of wild type TnT, but greatly diminished for the mutant TnT. These findings indicate that HCM-causing mutations in TnT and beta-myosin heavy chain share abnormalities in common, acting as dominant negative alleles that impair contractile performance. This diminished force output is the likely stimulus for hypertrophy in the human heart.

Amino Acid Sequence↗