RESUMEN
Acyl-CoA dehydrogenase 9 (ACAD9), linked to chromosome 3q21.3, is one of a family of multimeric mitochondrial flavoenzymes that catalyze the degradation of fatty acyl-CoA from the carnitine shuttle via ß-oxidation (He et al. 2007). ACAD9, specifically, is implicated in the processing of palmitoyl-CoA and long-chain unsaturated substrates, but unlike other acyl-CoA dehydrogenases (ACADs), it has a significant role in mitochondrial complex I assembly (Nouws et al. 2010 & 2014). Mutations in this enzyme typically cause mitochondrial complex I deficiency, as well as a mild defect in long chain fatty acid metabolism (Haack et al. 2010, Kirby et al. 2004, Mcfarland et al. 2003, Nouws et al. 2010 & 2014). The clinical phenotype of ACAD9 deficiency and the associated mitochondrial complex I deficiency reflect this unique duality, and symptoms are variable in severity and onset. Patients classically present with cardiac dysfunction due to hypertrophic cardiomyopathy. Other common features include Leigh syndrome, macrocephaly, and liver disease (Robinson et al. 1998). We report the case of an 11-month old girl presenting with microcephaly, dystonia, and lactic acidosis, concerning for a mitochondrial disorder, but atypical for ACAD9 deficiency. Muscle biopsy showed mitochondrial proliferation, but normal mitochondrial complex I activity. The diagnosis of ACAD9 deficiency was not initially considered, due both to these findings and to her atypical presentation. Biochemical assay for ACAD9 deficiency is not clinically available. Family trio-based whole exome sequencing (WES) identified 2 compound heterozygous mutations in the ACAD9 gene. This discovery led to optimized treatment of her mitochondrial dysfunction, and supplementation with riboflavin, resulting in clinical improvement. There have been fewer than 25 reported cases of ACAD9 deficiency in the literature to date. We review these and compare them to the unique features of our patient. ACAD9 deficiency should be considered in the differential diagnosis of patients with lactic acidosis, seizures, and other symptoms of mitochondrial disease, including those with normal mitochondrial enzyme activities. This case demonstrates the utility of WES, in conjunction with biochemical testing, for the appropriate diagnosis and treatment of disorders of energy metabolism.
RESUMEN
Chromosome 15q11q13 is among the least stable regions in the genome due to its highly complex genomic architecture. Low copy repeat elements at 15q13.3 facilitate recurrent copy number variants (CNVs), with deletions established as pathogenic and CHRNA7 implicated as a candidate gene. However, the pathogenicity of duplications of CHRNA7 is unclear, as they are found in affected probands as well as in reportedly healthy parents and unaffected control individuals. We evaluated 18 children with microduplications involving CHRNA7, identified by clinical chromosome microarray analysis (CMA). Comprehensive phenotyping revealed high prevalence of developmental delay/intellectual disability, autism spectrum disorder, and attention deficit/hyperactivity disorder. As CHRNA7 duplications are the most common CNVs identified by clinical CMA, this study provides anticipatory guidance for those involved with care of affected individuals.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno del Espectro Autista/genética , Variaciones en el Número de Copia de ADN/genética , Discapacidades del Desarrollo/genética , Fenotipo , Receptor Nicotínico de Acetilcolina alfa 7/genética , Niño , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Análisis por Micromatrices , LinajeRESUMEN
The 22q13.3 deletion syndrome results from loss of terminal segments of varying sizes at 22qter. Few genotype-phenotype correlations have been found but all patients have mental retardation and severe delay, or absence of, expressive speech. We carried out clinical and molecular characterization of 13 patients. Developmental delay and speech abnormalities were common to all and comparable in frequency and severity to previously reported cases. Array-based comparative genomic hybridization showed the deletions to vary from 95 kb to 8.5 Mb. We also carried out high-resolution 244K array comparative genomic hybridization in 10 of 13 patients, that defined the proximal and distal breakpoints of each deletion and helped determine the size, extent, and gene content within the deletion. Two patients had a smaller 95 kb terminal deletion with breakpoints within the SHANK3 gene while three other patients had a similar 5.5 Mb deletion implying the recurrent nature of these deletions. The two largest deletions were found in patients with ring chromosome 22. No correlation could be made with deletion size and phenotype although complete/partial SHANK3 was deleted in all patients. There are very few reports on array comparative genomic hybridization analysis on patients with the 22q13.3 deletion syndrome, and we aim to accurately characterize these patients both clinically and at the molecular level, to pave the way for further genotype-phenotype correlations. (c) 2010 Wiley-Liss, Inc.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Anomalías Múltiples/genética , Adolescente , Trastorno Autístico/genética , Proteínas Portadoras/genética , Niño , Preescolar , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Femenino , Estudios de Asociación Genética , Humanos , Trastornos del Desarrollo del Lenguaje/genética , Masculino , Proteínas del Tejido Nervioso , Fenotipo , Síndrome , Adulto JovenRESUMEN
Williams-Beuren syndrome (WBS) is most often caused by hemizygous deletion of a 1.5-Mb interval encompassing at least 17 genes at 7q11.23 (refs. 1,2). As with many other haploinsufficiency diseases, the mechanism underlying the WBS deletion is thought to be unequal meiotic recombination, probably mediated by the highly homologous DNA that flanks the commonly deleted region. Here, we report the use of interphase fluorescence in situ hybridization (FISH) and pulsed-field gel electrophoresis (PFGE) to identify a genomic polymorphism in families with WBS, consisting of an inversion of the WBS region. We have observed that the inversion is hemizygous in 3 of 11 (27%) atypical affected individuals who show a subset of the WBS phenotypic spectrum but do not carry the typical WBS microdeletion. Two of these individuals also have a parent who carries the inversion. In addition, in 4 of 12 (33%) families with a proband carrying the WBS deletion, we observed the inversion exclusively in the parent transmitting the disease-related chromosome. These results suggest the presence of a newly identified genomic variant within the population that may be associated with the disease. It may result in predisposition to primarily WBS-causing microdeletions, but may also cause translocations and inversions.
Asunto(s)
Inversión Cromosómica , Polimorfismo Genético/genética , Síndrome de Williams/genética , Adolescente , Cromosomas Humanos Par 7/genética , Electroforesis en Gel de Campo Pulsado , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Datos de Secuencia Molecular , Mutación/genética , Fenotipo , Mapeo Físico de CromosomaRESUMEN
The potency of the putatively alpha(1B)-adrenoceptor selective drug, 1-[biphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2-ol (AH11110A), to antagonize contraction upon stimulation of alpha(1A)-adrenoceptors in rat vas deferens and rat perfused kidney, alpha(1B)-adrenoceptors in guinea-pig spleen, mouse spleen and rabbit aorta, and alpha(1D)-adrenoceptors in rat aorta and pulmonary artery was evaluated and compared to that of a number of subtype-discriminating antagonists. N-[3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide (Rec 15/2739) and (+/-)-1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl]amino]-2,4(1H,3H)-pyrimidinedione (B8805-033) were confirmed as selective for alpha(1A)-adrenoceptors, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378), 8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro[4.5]decane-7,9-dione (MDL 73005EF), and cystazosin were found to be selective for alpha(1D)-adrenoceptors, whereas spiperone was weakly selective for alpha(1B)-over alpha(1A)-adrenoceptors. However, from the functional affinity profile obtained for AH11110A at alpha(1A)-adrenoceptors (pA(2)=6.41 in rat vas deferens), alpha(1B)-adrenoceptors (pA(2)=5.40-6.54) and alpha(1D)-adrenoceptors (pA(2)=5.47-5.48), the affinity and presumed selectivity previously obtained for AH11110A in radioligand binding studies at native alpha(1B)- and cloned alpha(1b)-adrenoceptors (pK(i)=7.10-7.73) could not be confirmed. Additionally, AH11110A enhanced the general contractility of rat vas deferens, produced a bell-shaped dose-response curve of vasodilation in perfused rat kidney, and its antagonism in most other tissues was not simply competitive. The affinity of AH11110A for prejunctional alpha(2)-adrenoceptors in rabbit vas deferens (pA(2)=5.44) was not much lower than that displayed for alpha(1)-adrenoceptor subtypes, revealing that AH11110A, besides alpha(1)-adrenoceptors, also interacts with alpha(2)-adrenoceptors, and thus may be unsuitable for alpha-adrenoceptor subtype characterization, at least in smooth muscle containing functional studies.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Agonistas alfa-Adrenérgicos/química , Antagonistas Adrenérgicos alfa/química , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Relación Dosis-Respuesta a Droga , Cobayas , Iminas/farmacología , Riñón/efectos de los fármacos , Riñón/fisiología , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Piperidinas/farmacología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiología , Conejos , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 1/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Bazo/efectos de los fármacos , Bazo/fisiología , Conducto Deferente/efectos de los fármacos , Conducto Deferente/fisiología , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
Controversy exists over the distinction between cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome (NS). Several authors have suggested that they are different phenotypes of the same condition. We present the cases of two patients with CFC syndrome to show that it is a distinct condition with a unique combination of findings and a more complex natural history. These patients, both girls, were born with signs of fetal edema following pregnancies complicated by polyhydramnios. Each has short stature with relative macrocephaly; fuzzy, sparse hair; and the typical craniofacial features, including a square forehead. Both have heart abnormalities, failure to thrive, and severe feeding problems requiring gastrostomy. They are markedly hypotonic and developmentally delayed. They show signs of frequent eyelid fluttering and have oral aversion, tactile hypersensitivity, and sensory integration abnormalities. Keratosis pilaris, the characteristic skin symptom, is also present in both patients. In a review we identified 56 cases of CFC syndrome. We scored these cases by 10 clinical criteria and identified a subset with a specific, severe phenotype distinct from that of NS. The serious neurologic and gastrointestinal complications, in addition to the skin abnormalities and characteristic facies in this group, clearly separate these patients from the mildly affected ones, most of whom appear to have NS or another syndrome. We discuss the differences between the severe CFC phenotype and those of overlapping conditions. We set forth stringent diagnostic criteria for CFC syndrome, the initial step toward identifying a molecular basis for this condition.
Asunto(s)
Anomalías del Sistema Digestivo , Expresión Facial , Cardiopatías Congénitas/diagnóstico , Enfermedades del Sistema Nervioso/diagnóstico , Anomalías Cutáneas/diagnóstico , Preescolar , Discapacidades del Desarrollo/diagnóstico , Diagnóstico Diferencial , Párpados/anomalías , Facies , Femenino , Humanos , Hidropesía Fetal , Queratosis/diagnóstico , Hipotonía Muscular/diagnóstico , Fenotipo , SíndromeRESUMEN
Very long chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of long chain fatty acid oxidation in the mitochondria. Patients with VLCAD deficiency have recently been observed with two clinical phenotypes. The cardiac form presents with an early onset cardiomyopathy and a high incidence of infant death, while the hypoglycemic form resembles medium chain acyl-CoA dehydrogenase (MCAD) manifesting with hypoketotic hypoglycemia. In our investigation on the molecular basis for these phenotypes, we identified two novel mutations in one VLCAD patient with the hypoglycemic form, a C953T (Pro318Leu) mutation in exon 10 resulting in a substitution of proline 318 by leucine on one allele, and a C1194A (Tyr398Stop) mutation in exon 12 which created a premature stop codon TAA on another allele. The Tyr398Stop mutation may result in a truncated protein or instable messenger RNA.
Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Carnitina/análogos & derivados , Hipoglucemia/genética , Mutación , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Alelos , Carnitina/análisis , Preescolar , ADN Complementario/química , Exones , Femenino , Fibroblastos/metabolismo , Humanos , Hipoglucemia/sangre , Hipoglucemia/enzimología , Mitocondrias/metabolismo , Palmitoilcarnitina/análisis , FenotipoRESUMEN
Signal transduction in microorganisms and plants is often mediated by His-Asp phosphorelay systems. Two conserved families of proteins are centrally involved: histidine protein kinases and phospho-aspartyl response regulators. The kinases generally function in association with sensory elements that regulate their activities in response to environmental signals. A sequence analysis with 348 histidine kinase domains reveals that this family consists of distinct subgroups. A comparative sequence analysis with 298 available receiver domain sequences of cognate response regulators demonstrates a significant correlation between kinase and regulator subfamilies. These findings suggest that different subclasses of His-Asp phosphorelay systems have evolved independently of one another.
Asunto(s)
Proteínas Quinasas/fisiología , Secuencia de Aminoácidos , Archaea/enzimología , Archaea/genética , Bacterias/enzimología , Bacterias/genética , Evolución Molecular , Histidina Quinasa , Datos de Secuencia Molecular , Proteínas Quinasas/clasificación , Proteínas Quinasas/genética , Homología de Secuencia de Aminoácido , Transducción de SeñalRESUMEN
The affinity for functional alpha1-adrenoceptor subtypes of buspirone in comparison with its close structural analogs and selective alpha1D-adrenoceptor antagonists, BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]dec ane-7,9-dione) and MDL 73005EF (8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro+ ++[4.5]decane-7,9-dione), was determined, namely at subtype A in rat vas deferens and perfused kidney, at subtype B in guinea-pig and mouse spleen, at subtype L in rabbit spleen, and at subtype D in rat aorta and pulmonary artery against noradrenaline-evoked contractions. BMY 7378 and MDL 73005EF were confirmed as 30- and 20-fold selective antagonists, respectively, for alpha1D- over both alpha1A- and alpha1B-adrenoceptors. Buspirone was a weak antagonist without intrinsic activity at alpha1A-adrenoceptors in rat vas deferens (pA2 = 6.12), at alpha1B-adrenoceptors in guinea-pig and mouse spleen (pA2 = 5.54 and 5.59) and at alpha1L-adrenoceptors in rabbit spleen (pA2 = 4.99), but caused partial vasoconstriction in rat kidney that was attenuable by the subtype D-selective adrenoceptor antagonist BMY 7378, but hardly by the subtype A-selective adrenoceptor antagonist B8805-033 ((+/-)-1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-be nzodioxin-5-yl)-1-piperazinyl]propyl]amino]-2,4(1H,3H)-pyrimidinedion e), confirming the additional presence of alpha1D-adrenoceptors mediating rat renal vasoconstriction. Buspirone behaved as a partial agonist at alpha1D-adrenoceptors in rat aorta (pD2 = 6.77, intrinsic activity (i.a.)= 0.40) and pulmonary artery (pD2 = 7.16, i.a. = 0.59). With buspirone as agonist in these tissues, the pA2 values of subtype-discriminating antagonists were consistent with their alpha1D-adrenoceptor affinity determined in rat aorta against noradrenaline and with published binding data on cloned alpha1d-adrenoceptors. The results provide pharmacological evidence that (1) in functional preparations for the A subtype, like rat vas deferens and perfused kidney, for the B subtype, like guinea-pig and mouse spleen, and for the L subtype, like rabbit spleen, buspirone is a weak antagonist without intrinsic activity, but (2) behaves as a partial agonist in rat aorta and pulmonary artery as models for the D subtype and (3) detects an additional vasoconstrictor alpha1D-adrenoceptor in rat kidney. Buspirone, like its close analogs BMY 7378 and MDL 73005EF, thus might also be a useful tool for functionally discriminating alpha1D- from alpha1A-, alpha1B- and alpha1L-adrenoceptors in various tissues.
Asunto(s)
Agonistas Adrenérgicos/farmacología , Antagonistas Adrenérgicos/farmacología , Buspirona/farmacología , Receptores Adrenérgicos/metabolismo , Animales , Aorta Torácica , Dioxinas/farmacología , Cobayas , Técnicas In Vitro , Riñón/efectos de los fármacos , Riñón/metabolismo , Modelos Lineales , Masculino , Ratones , Piperazinas/farmacología , Arteria Pulmonar , Conejos , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Compuestos de Espiro/farmacología , Bazo/efectos de los fármacos , Bazo/metabolismo , Conducto Deferente/efectos de los fármacos , Conducto Deferente/metabolismo , Vasoconstricción/efectos de los fármacosRESUMEN
The beta-lactams are by far the most widely used and efficacious of all antibiotics. Over the past few decades, however, widespread resistance has evolved among most common pathogens. Streptococcus pneumoniae has become a paradigm for understanding the evolution of resistance mechanisms, the simplest of which, by far, is the production of beta-lactamases. As these enzymes are frequently plasmid encoded, resistance can readily be transmitted between bacteria. Despite the fact that pneumococci are naturally transformable organisms, no beta-lactamase-producing strain has yet been described. A much more complex resistance mechanism has evolved in S. pneumoniae that is mediated by a sophisticated restructuring of the targets of the beta-lactams, the penicillin-binding proteins (PBPs); however, this may not be the whole story. Recently, a third level of resistance mechanisms has been identified in laboratory mutants, wherein non-PBP genes are mutated and resistance development is accompanied by deficiency in genetic transformation. Two such non-PBP genes have been described: a putative glycosyltransferase, CpoA, and a histidine protein kinase, CiaH. We propose that these non-PBP genes are involved in the biosynthesis of cell wall components at a step prior to the biosynthetic functions of PBPs, and that the mutations selected during beta-lactam treatment counteract the effects caused by the inhibition of penicillin-binding proteins.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas , Proteínas Portadoras/metabolismo , Hexosiltransferasas , Muramoilpentapéptido Carboxipeptidasa/metabolismo , Peptidil Transferasas , Streptococcus pneumoniae/efectos de los fármacos , beta-Lactamas/farmacología , Glicosiltransferasas/genética , Histidina Quinasa , Modelos Moleculares , Mutación , Proteínas de Unión a las Penicilinas , Proteínas Quinasas/genética , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/metabolismo , Resistencia betalactámicaRESUMEN
The components of the Escherichia coli chemosensory system have been identified and their activities characterized, but how sensory information is processed to give an integrated response remains an open question.
Asunto(s)
Células Quimiorreceptoras/fisiología , Quimiotaxis , Escherichia coli/fisiología , Proteínas Bacterianas , Escherichia coli/efectos de los fármacos , Modelos BiológicosRESUMEN
A 9-month-old boy with pre- and post-natal growth retardation, microcephaly, plagiocephaly, and several minor anomalies had the initial karyotype: 46,XY,der(1)t(1;?) (p36.1;?). Further analysis showed that the der(1) was derived from an unfavorable segregation of a maternal complex chromosome rearrangement, i.e., 46,XX,der(1)t(1;?) (p36.1;?), der(4)t(4;?)(q?;?). Whole chromosome fluorescence in situ hybridization (FISH) and chromosome microdissection were used to clarify the maternal karyotype as: 46,XX,der(1)t(1;4)(4qter-->4q33::1p36.13-->1qter),der( 4)t(1;4)inv(4)(4pter-->4q31.3::1p36.33-->1p36.13::4q33 -->4q31.3::1p36.33-->1pter). Therefore, the karyotype of the boy actually was 46,XY,der(1)t(1;4) (p36.13;q33). Clinical comparison of the patient's clinical findings showed similarities to individuals with partial del(1p) and dup(4q). To our knowledge the above cytogenetic abnormalities have not been described previously. This case further demonstrates the advantages of chromosome microdissection and FISH in the identification of anomalous chromosome regions and breakpoints.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 4/genética , Anomalías Craneofaciales/genética , Enfermedades Fetales/genética , Translocación Genética , Bandeo Cromosómico , Mapeo Cromosómico , Cromosomas Humanos Par 1/ultraestructura , Cromosomas Humanos Par 4/ultraestructura , Sondas de ADN , Femenino , Trastornos del Crecimiento/genética , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Cariotipificación , Masculino , Metafase , Linaje , Embarazo , Diagnóstico Prenatal , SíndromeRESUMEN
The lack of normally active paternal genes in 15q11-q13, as an outcome of either a paternal deletion or maternal disomy, accounts for >95% of all patients with Prader-Willi syndrome. Other mechanisms, including imprinting mutations and unbalanced translocations involving pat 15q11-q13, have been described elsewhere. In this study, we present a patient with a rare balanced, de novo translocation-46,XY,t(2;15)(q37.2;q11.2)-involving breakage within the Prader-Willi/Angelman syndrome region of the paternal homologue, without an apparent deletion. The patient demonstrated several manifestations of the Prader-Willi syndrome but was clinically atypical. Cytogenetic and molecular studies of this case demonstrated the translocation breakpoint to be between SNRPN and IPW, with mRNA expression of SNRPN and PAR-5 but absence of IPW and PAR-1 expression. These results suggest that disruption of either IPW expression or a nearby gene by an upstream break may contribute to the Prader-Willi syndrome phenotype and that expression of SNRPN or other upstream genes is responsible for other aspects of the classical Prader-Willi syndrome phenotype.
Asunto(s)
Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 2/genética , Síndrome de Prader-Willi/genética , Proteínas Quinasas , Ribonucleoproteínas Nucleares Pequeñas , Translocación Genética , Animales , Autoantígenos/genética , Preescolar , Bandeo Cromosómico , Rotura Cromosómica , Cricetinae , Metilación de ADN , Padre , Expresión Génica , Impresión Genómica , Humanos , Células Híbridas , Hibridación Fluorescente in Situ , Factores de Transcripción de Tipo Kruppel , Masculino , Fenotipo , Síndrome de Prader-Willi/patología , Mapeo Restrictivo , Factores de Transcripción/genética , Proteínas Nucleares snRNPRESUMEN
The muscarinic receptor mediating contraction of the guinea-pig isolated gallbladder, currently being disputed to belong either to the M3 or M4 subtype, was characterized by subtype-preferring agonists and discriminating antagonists. Highly significant correlations of agonist potencies to contract the gallbladder, e.g., arecaidine propargyl ester, oxotremorine, 5-methylfurtrethonium > arecoline, arecaidine 2-butyne-1,4-diyl bisester > (R)-nipecotic acid ethyl ester > 4-[[N-(4-chlorophenyl)carbamyl]oxy]-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343), (S)-nipecotic acid ethyl ester > 4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyltrimethylammonium chloride (McN-A-343) were found with muscarinic M3 receptors mediating contraction of the guinea-pig ileum and vasodilation in rat perfused kidney. Functional affinities at guinea-pig gallbladder muscarinic receptors of antagonists known to distinguish between native or cloned muscarinic M3/m3 and M4/m4 receptors, e.g., himbacine, methoctramine, mefurtramine, tripitramine, idaverine, zamifenacin and 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyr ido(2,3-b)(1,4)benzodiazepin-6-one (AQ-RA 741), were consistent with those at guinea-pig ileal muscarinic M3 receptors but not with published data at recently defined muscarinic M4 receptors in rabbit anococcygeus muscle or at muscarinic M1 and M2 receptors in rabbit vas deferens. Antagonist affinities at guinea-pig gallbladder correlated also best with published binding data on native or cloned muscarinic M3/m3 receptors but not with those for muscarinic M4/m4 receptors. The agonist potencies and antagonist affinities suggest that smooth muscle contraction elicited by muscarinic stimuli in guinea-pig gallbladder is mediated by functional muscarinic M3 receptors.
Asunto(s)
Vesícula Biliar/efectos de los fármacos , Agonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacología , Contracción Muscular/efectos de los fármacos , Receptores Muscarínicos/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Riñón/efectos de los fármacos , Modelos Lineales , Masculino , Conejos , Ratas , Conducto Deferente/efectos de los fármacosRESUMEN
Pallister-Hall syndrome is a human developmental disorder that is inherited in an autosomal dominant pattern. The phenotypic features of the syndrome include hypothalamic hamartoma, polydactyly, imperforate anus, laryngeal clefting, and other anomalies. Here we describe the clinical characterisation of a family with 22 affected members and the genetic mapping of the corresponding locus. Clinical, radiographic, and endoscopic evaluations showed that this disorder is a fully penetrant trait with variable expressivity and low morbidity. By analysing 60 subjects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta = 0, near the GLI3 locus. Deletions and translocations in GLI3 are associated with the Greig cephalopolysyndactyly syndrome. Although Greig cephalopolysyndactyly syndrome has some phenotypic overlap with Pallister-Hall syndrome, these two disorders are clinically distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hall syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall syndrome. The linkage data reported here suggest that these larger, mildly affected families may also have mutations in GLI3.
Asunto(s)
Anomalías Múltiples/genética , Mapeo Cromosómico , Ligamiento Genético , Hamartoma/genética , Enfermedades Hipotalámicas/genética , Polidactilia/genética , Ano Imperforado/genética , Femenino , Genes Dominantes , Marcadores Genéticos , Hamartoma/patología , Humanos , Enfermedades Hipotalámicas/patología , Lactante , Laringe/anomalías , Imagen por Resonancia Magnética , Masculino , Linaje , Fenotipo , Polidactilia/diagnóstico por imagen , Radiografía , SíndromeRESUMEN
Piperacillin resistance in Streptococcus pneumoniae was mediated by mutations in a novel gene, cpoA, that also confer transformation deficiency and a decrease in penicillin-binding protein la. cpoA is part of an operon located downstream of the primary sigma factor of S. pneumoniae. The deduced protein, CpoA, and the peptide encoded by the adjacent 3' open reading frame contained domains homologous to glycosyltransferases of procaryotes and eucaryotes that act on membrane-associated substrates, such as enzymes functioning in lipopolysaccharide core biosynthesis of gram-negative bacteria, RodD of Bacillus subtilis, which is involved in teichoic acid biosynthesis, and the human PIG-A protein, which is required for early steps of glycosylphosphatidylinositol anchor biosynthesis. This suggests that the cpo operon has a similar function related to cell surface components.
Asunto(s)
Proteínas Bacterianas , Proteínas Portadoras , Glicosiltransferasas/genética , Muramoilpentapéptido Carboxipeptidasa , Resistencia a las Penicilinas/genética , Streptococcus pneumoniae/enzimología , Streptococcus pneumoniae/genética , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , Genes Bacterianos , Hexosiltransferasas/genética , Datos de Secuencia Molecular , Complejos Multienzimáticos/genética , Mutagénesis Insercional , Mutación , Operón , Proteínas de Unión a las Penicilinas , Peptidil Transferasas/genética , Fenotipo , Plásmidos/aislamiento & purificación , Análisis de Secuencia de ADN , Especificidad de la Especie , Transcripción GenéticaRESUMEN
HISTORY AND ADMISSION FINDINGS: A 54-year-old huntsman who 3 days previously had shot a wild pig, developed severe headache, nausea and vomiting over the last 10 hours. Physical examination was unremarkable except for an 8 x 4 cm large reddening of the skin over the right tibia and fever (38.2 degrees C). INVESTIGATIONS: Cranial computed tomography was normal. Cerebrospinal fluid showed pleocytosis (5.200 cells/mm3). Gram-stained (CSF) smear showed gram-positive cocci and an increased white cell count (14,000/microliters) was found in blood. DIAGNOSIS, TREATMENT AND COURSE: After the diagnosis of bacterial meningitis had been made antibiotics were given intravenously (penicillin G 10 mill. IU, three times daily on days 1 to 16: at first with cefotaxim, three times daily 2 g on days 1 to 3, then with gentamicin twice 80 mg on days 3 to 13). The acute neurological signs quickly regressed, the pretibial reddening (presumably at the port of entry) disappeared, as did the fever on the 4th day of the illness. The streptococci isolated from CSF and blood were identified as 5. suis type 2 (Lancefield group R). But despite the early and effective antibiotic treatment cochleovestibular symptoms (hearing impairment, vertigo and unsteady gait) set in after initial improvement, a frequent complication of S. suis meningitis. CONCLUSION: S. suis should be considered as the causative organism of generalized septicaemia and meningitis in adults, if the history reveals contact with domestic or wild pigs and there are early cochleovestibular signs.
Asunto(s)
Meningitis Bacterianas/microbiología , Infecciones Estreptocócicas/microbiología , Streptococcus suis , Diagnóstico Diferencial , Humanos , Masculino , Meningitis Bacterianas/complicaciones , Meningitis Bacterianas/diagnóstico , Meningitis Bacterianas/tratamiento farmacológico , Persona de Mediana Edad , Infecciones Estreptocócicas/complicaciones , Infecciones Estreptocócicas/diagnóstico , Infecciones Estreptocócicas/tratamiento farmacológico , Streptococcus suis/aislamiento & purificaciónRESUMEN
We report on a two-generation family exhibiting dominant inheritance of complex polysyndactyly associated with hypothalamic hamartoma. These individuals have some manifestations of Pallister-Hall syndrome (PHS), but their phenotype is milder. The proposita is a 16-year-old girl with polysyndactyly of the hands and feet, short stature, and a large hypothalamic hamartoma. Her brother and father also have polysyndactyly and a hypothalamic mass on MRI scan. All three have normal appearance and intelligence, with normal pituitary function. Several other paternal relatives have polysyndactyly as well. We propose that this family may represent a clinically and perhaps genetically distinct entity from PHS, based on normal survival, normal intelligence, lack of endocrine dysfunction or facial anomalies, and few other structural malformations. Linkage analysis is in progress to determine whether this represents a benign form of PHS or a genetically separate condition. The phenotypic differences between these cases and classic PHS have important prognostic and recurrence risk implications.
Asunto(s)
Dedos/anomalías , Hamartoma/diagnóstico , Enfermedades Hipotalámicas/diagnóstico , Polidactilia/genética , Sindactilia/genética , Dedos del Pie/anomalías , Adolescente , Adulto , Femenino , Hamartoma/complicaciones , Deformidades de la Mano/genética , Humanos , Enfermedades Hipotalámicas/complicaciones , Masculino , Linaje , Fenotipo , SíndromeRESUMEN
Erythromycin resistance determinants include Erm methylases, efflux pumps, and inactivating enzymes. To distinguish the different mechanisms of resistance in clinical isolates, PCR primers were designed so that amplification of the partial gene products could be detected in multiplex PCRs. This methodology enables the direct sequencing of amplified PCR products that can be used to compare resistance determinants in clinical strains. Further, this methodology could be useful in surveillance studies of erythromycin-resistant determinants.