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1.
Bioinformatics ; 35(20): 3906-3912, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30903145

RESUMEN

MOTIVATION: Non-coding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity and uncertainty about relevant non-coding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensive open-source software was developed. RESULTS: We developed Outlier-RV Enrichment (ORE) to identify biologically-meaningful non-coding RVs. We implemented ORE combining whole-genome sequencing and cardiac RNAseq from congenital heart defect patients from the Pediatric Cardiac Genomics Consortium and deceased adults from Genotype-Tissue Expression. Use of rank-based outliers maximized sensitivity while a most extreme outlier approach maximized specificity. Rarer variants had stronger associations, suggesting they are under negative selective pressure and providing a basis for investigating their contribution to Mendelian disorders. AVAILABILITY AND IMPLEMENTATION: ORE, source code, and documentation are available at https://pypi.python.org/pypi/ore under the MIT license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Genómica , Programas Informáticos , Niño , Documentación , Humanos , Incertidumbre , Secuenciación Completa del Genoma
2.
Nat Genet ; 13(4): 417-21, 1996 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8696335

RESUMEN

We demonstrate that a mutation in the homeobox gene, MSX1, causes a common developmental anomaly, familial tooth agenesis. Genetic linkage analyses in a family with autosomal dominant agenesis of second premolars and third molars identified a locus on chromosome 4p, where the MSX1 gene resides. Sequence analyses demonstrated an Arg31Pro missense mutation in the homeodomain of MSX1 in all affected family members. Arg 31 is a highly conserved homeodomain residue that interacts with the ribose phosphate backbone of target DNA. We propose that the Arg31 Pro mutatrion comprises MSX1 interactions, and suggest that MSX1 functions are critical for normal development of specific human teeth.


Asunto(s)
Anodoncia/genética , Cromosomas Humanos Par 4 , Proteínas de Homeodominio/genética , Factores de Transcripción , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Cartilla de ADN/química , Femenino , Genes Dominantes , Genes Homeobox , Ligamiento Genético , Humanos , Factor de Transcripción MSX1 , Masculino , Datos de Secuencia Molecular , Linaje , Mutación Puntual , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Relación Estructura-Actividad
3.
Nat Genet ; 11(4): 434-7, 1995 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7493025

RESUMEN

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disorder manifesting as cardiac hypertrophy with myocyte disarray and an increased risk of sudden death. Mutations in five different loci cause FHC and 3 disease genes have been identified: beta cardiac myosin heavy chain, alpha tropomyosin and cardiac troponin T. Because these genes encode contractile proteins, other FHC loci are predicted also to encode sarcomere components. Two further FHC loci have been mapped to chromosomes 11p13-q13 (CMH4, ref. 6) and 7q3 (ref. 7). The gene encoding the cardiac isoform of myosin binding protein-C (cardiac MyBP-C) has recently been assigned to chromosome 11p11.2 and proposed as a candidate FHC gene. Cardiac MyBP-C is arrayed transversely in sarcomere A-bands and binds myosin heavy chain in thick filaments and titin in elastic filaments. Phosphorylation of MyBP-C appears to modulate contraction. We report that cardiac MyBP-C is genetically linked to CMH4 and demonstrate a splice donor mutation in one family with FHC and a duplication mutation in a second. Both mutations are predicted to disrupt the high affinity, C-terminal, myosin-binding domain of cardiac MyBP-C. These findings define cardiac MyBP-C mutations as the cause of FHC on chromosome 11p and reaffirm that FHC is a disease of the sarcomere.


Asunto(s)
Cardiomiopatía Hipertrófica/genética , Proteínas Portadoras/genética , Cromosomas Humanos Par 11 , Mutación , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Femenino , Ligamiento Genético , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Empalme del ARN
4.
Nat Genet ; 6(2): 205-9, 1994 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-8162076

RESUMEN

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that is characterized by frequent nosebleeds, mucocutaneous telangiectases and vascular malformations that cause recurrent haemorrhage and arteriovenous shunting. Linkage analyses in one kindred identified an HHT locus on the long arm of chromosome 9 (maximum multipoint lod score = 6.20 between D9S60 and D9S61). Analyses in two other unrelated HHT families demonstrated that the disease in one was not linked to the locus on chromosome 9q3. We conclude that HHT is a genetically heterogeneous disorder. Based on its map location (9q3) and expression in vascular tissues, type V collagen is a possible candidate gene for HHT.


Asunto(s)
Cromosomas Humanos Par 9 , Ligamiento Genético , Telangiectasia Hemorrágica Hereditaria/genética , Adulto , Niño , Mapeo Cromosómico , Europa (Continente) , Femenino , Marcadores Genéticos , Haplotipos , Humanos , Masculino , Linaje , Polimorfismo Genético , Secuencias Repetitivas de Ácidos Nucleicos
5.
Nat Genet ; 3(4): 333-7, 1993 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-7981753

RESUMEN

Familial hypertrophic cardiomyopathy (FHC) is caused by missense mutations in the beta cardiac myosin heavy chain (MHC) gene in less than half of affected individuals. To identify the location of another gene involved in this disorder, a large family with FHC not linked to the beta MHC gene was studied. Linkage was detected between the disease in this family and a locus on chromosome 1q3 (maximum multipoint lod score = 8.47). Analyses in other families with FHC not linked to the beta MHC gene, revealed linkage to the chromosome 1 locus in two and excluded linkage in six. Thus mutations in at least three genetic loci can cause FHC. Three sarcomeric contractile proteins--troponin I, tropomyosin and actin--are strong candidate FHC genes at the chromosome 1 locus.


Asunto(s)
Cardiomiopatía Hipertrófica/genética , Cromosomas Humanos Par 1 , Proteínas Contráctiles/genética , Mutación Puntual , Actinas/genética , Factores de Edad , Secuencia de Bases , Cardiomiopatía Hipertrófica/mortalidad , Niño , Mapeo Cromosómico , Cartilla de ADN , Femenino , Ligamiento Genético , Marcadores Genéticos , Humanos , Intrones , Escala de Lod , Masculino , Datos de Secuencia Molecular , Miosinas/genética , Linaje , Polimorfismo Genético , Probabilidad , Recombinación Genética , Análisis de Supervivencia , Tasa de Supervivencia , Tropomiosina/genética , Troponina/genética , Troponina I
6.
Nat Genet ; 5(2): 201-4, 1993 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8252048

RESUMEN

Alkaptonuria, the first human disorder recognized by Garrod as an inborn error of metabolism, is a rare recessive condition that darkens urine and causes a debilitating arthritis termed ochronosis. We have studied two families with consanguineous parents and four affected children in order to map the gene responsible for alkaptonuria. Coinheritance of either neonatal severe hyperparathyroidism or sucrase-isomaltase deficiency and alkaptonuria provided a candidate location for the mutated genes on chromosome 3. Homozygosity mapping with polymorphic loci identified a 16 centiMorgan region on chromosome 3q2 that contains the alkaptonuria gene. Analysis of two additional nonconsanguineous families supports linkage of alkaptonuria to this single locus (combined lod score = 4.3, theta = 0).


Asunto(s)
Alcaptonuria/genética , Cromosomas Humanos Par 3 , Homocigoto , Adulto , Secuencia de Bases , Niño , Femenino , Ligamiento Genético , Humanos , Masculino , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Linaje , Complejo Sacarasa-Isomaltasa/deficiencia , Complejo Sacarasa-Isomaltasa/genética
7.
Nat Genet ; 15(1): 30-5, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8988165

RESUMEN

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.


Asunto(s)
Anomalías Múltiples/genética , Brazo/anomalías , Cardiopatías Congénitas/genética , Mutación , Proteínas de Dominio T Box , Factores de Transcripción/genética , Anomalías Múltiples/embriología , Secuencia de Aminoácidos , Animales , Brazo/embriología , Secuencia de Bases , Cromosomas Humanos Par 12 , Clonación Molecular , ADN , Análisis Mutacional de ADN , Cardiopatías Congénitas/embriología , Humanos , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Síndrome
8.
Nat Genet ; 11(4): 389-94, 1995 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7493018

RESUMEN

Mice lacking the calcium-sensing receptor (Casr) were created to examine the receptor's role in calcium homeostasis and to elucidate the mechanism by which inherited human Casr gene defects cause diseases. Casr+/- mice, analogous to humans with familial hypocalciuric hypercalcemia, had benign and modest elevations of serum calcium, magnesium and parathyroid hormone levels as well as hypocalciuria. In contrast, Casr-/- mice, like humans with neonatal severe hyperparathyroidism, had markedly elevated serum calcium and parathyroid hormone levels, parathyroid hyperplasia, bone abnormalities, retarded growth and premature death. Our findings suggest that Casr mutations cause these human disorders by reducing the number of functional receptor molecules on the cell surface.


Asunto(s)
Proteínas de Unión al Calcio/fisiología , Modelos Animales de Enfermedad , Hipercalcemia/genética , Hipercalcemia/metabolismo , Hiperparatiroidismo/genética , Hiperparatiroidismo/metabolismo , Animales , Enfermedades del Desarrollo Óseo/genética , Calcio/sangre , Calcio/orina , Proteínas de Unión al Calcio/genética , Heterocigoto , Homeostasis , Homocigoto , Humanos , Hiperplasia , Recién Nacido , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Glándulas Paratiroides/patología , Hormona Paratiroidea/sangre
9.
Nat Genet ; 1(4): 295-300, 1992 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-1302026

RESUMEN

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant syndrome of unknown aetiology characterized by lifelong elevation in serum calcium concentration and low urinary calcium excretion. These features suggest that the causal gene is important for maintenance of extracellular calcium homeostasis by the parathyroid gland and kidney. To identify the chromosomal location of FHH gene(s), we clinically evaluated 114 individuals in four unrelated affected families and performed linkage analyses. The disease gene mapped to the long arm of chromosome 3 in each family (combined maximum multipoint lod score = 20.67). We suggest that this is the predominant FHH locus and anticipate that identification of the FHH gene will improve our understanding of the molecular basis for physiologic and pathologic regulation of calcium.


Asunto(s)
Calcio/metabolismo , Cromosomas Humanos Par 3 , Ligamiento Genético , Errores Innatos del Metabolismo de los Metales/genética , Secuencia de Bases , Calcio/sangre , Calcio/orina , Bandeo Cromosómico , Mapeo Cromosómico , ADN/sangre , ADN/genética , ADN/aislamiento & purificación , Sondas de ADN , Femenino , Humanos , Escala de Lod , Masculino , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Linaje , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Genético
10.
Nat Genet ; 8(3): 303-7, 1994 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-7874174

RESUMEN

Defects in the human Ca(2+)-sensing receptor gene have recently been shown to cause familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism. We now demonstrate that a missense mutation (Glu128Ala) in this gene causes familial hypocalcaemia in affected members of one family. Xenopus oocytes expressing the mutant receptor exhibit a larger increase in inositol 1,4,5-triphosphate in response to Ca2+ than oocytes expressing the wild-type receptor. We conclude that this extracellular domain mutation increases the receptor's activity at low Ca2+ concentrations, causing hypocalcaemia in patients heterozygous for such a mutation.


Asunto(s)
Calcio/sangre , Genes Dominantes , Hipocalcemia/genética , Mutación Puntual , Receptores de Superficie Celular/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Análisis Mutacional de ADN , ADN Complementario/genética , Femenino , Heterocigoto , Homeostasis , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Escala de Lod , Masculino , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Oocitos , Linaje , Receptores Sensibles al Calcio , Proteínas Recombinantes de Fusión/metabolismo , Tetania/genética , Xenopus laevis
11.
Nat Genet ; 16(3): 311-5, 1997 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9207801

RESUMEN

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.


Asunto(s)
Anomalías Múltiples/genética , Glándulas Apocrinas/anomalías , Brazo/anomalías , Genitales/anomalías , Mutación , Proteínas de Dominio T Box , Factores de Transcripción/genética , Secuencia de Aminoácidos , Secuencia de Bases , Mama/anomalías , Cromosomas Humanos Par 12 , Análisis Mutacional de ADN , Femenino , Regulación del Desarrollo de la Expresión Génica , Humanos , Intrones/genética , Masculino , Datos de Secuencia Molecular , Alineación de Secuencia , Síndrome , Factores de Transcripción/química
12.
Nat Genet ; 20(3): 299-303, 1998 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9806553

RESUMEN

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology. Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9. All three residues mutated in DFNA9 are conserved in mouse and chicken Coch, and are found in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human cochlear and vestibular organs, occurs in the chicken inner ear in the regions of the auditory and vestibular nerve fibres, the neural and abneural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients.


Asunto(s)
Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/fisiopatología , Mutación Missense , Proteínas/genética , Vestíbulo del Laberinto/fisiopatología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Pollos , Secuencia Conservada , Cartilla de ADN/genética , Proteínas de la Matriz Extracelular , Femenino , Genes Dominantes , Pérdida Auditiva Sensorineural/patología , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Linaje , Homología de Secuencia de Aminoácido , Vestíbulo del Laberinto/patología
13.
J Exp Med ; 183(2): 413-20, 1996 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-8627154

RESUMEN

We have created embryonic stem (ES) cells and mice lacking the predominant isoform (alpha) of the calcineurin A subunit (CNA alpha) to study the role of this serine/threonine phosphatase in the immune system. T and B cell maturation appeared to be normal in CNA alpha -/- mice. CNA alpha -/- T cells responded normally to mitogenic stimulation (i.e., PMA plus ionomycin, concanavalin A, and anti-CD3 epsilon antibody). However, CNA alpha -/- mice generated defective antigen-specific T cell responses in vivo. Mice produced from CNA alpha -/- ES cells injected into RAG-2-deficient blastocysts had a similar defective T cell response, indicating that CNA alpha is required for T cell function per se, rather than for an activity of other cell types involved in the immune response. CNA alpha -/- T cells remained sensitive to both cyclosporin A and FK506, suggesting that CNA beta or another CNA-like molecule can mediate the action of these immunosuppressive drugs. CNA alpha -/- mice provide an animal model for dissecting the physiologic functions of calcineurin as well as the effects of FK506 and CsA.


Asunto(s)
Proteínas de Unión a Calmodulina/deficiencia , Proteínas de Unión al ADN , Activación de Linfocitos , Fosfoproteínas Fosfatasas/deficiencia , Linfocitos T/inmunología , Animales , Secuencia de Bases , Calcineurina , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/metabolismo , Quimera , Ciclosporina/farmacología , Relación Dosis-Respuesta a Droga , Inmunosupresores/farmacología , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Ratones , Mitógenos/farmacología , Datos de Secuencia Molecular , Ovalbúmina/inmunología , Fosfoproteínas Fosfatasas/genética , Fosfoproteínas Fosfatasas/metabolismo , Proteínas/genética , Células Madre , Tacrolimus/farmacología
14.
J Exp Med ; 182(6): 1905-11, 1995 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-7500036

RESUMEN

We have created J chain knockout mice to define the physiologic role of the J chain in immunoglobulin synthesis and transport. The J chain is covalently associated with pentameric immunoglobulin (Ig) M and dimeric IgA and is also expressed in most IgG-secreting cells. J chain-deficient mice have normal serum IgM and IgG levels but markedly elevated serum IgA. Although polymeric IgA was present in the mutant mice, a larger proportion of their serum IgA was monomeric than was found in wild-type mouse serum. Bile and fecal IgA levels were decreased in J chain-deficient mice compared with wild-type mice, suggesting inefficient transport of J chain-deficient IgA by hepatic polymeric immunoglobulin receptors (pIgR). The pIgR-mediated transport of serum-derived IgA from wild-type and mutant mice was assessed in Madin-Darby canine kidney (MDCK) cells transfected with the pIgR. These studies revealed selective transport by pIgR-expressing MDCK cells of wild-type IgA but not J chain-deficient IgA. We conclude that although the J chain is not required for IgA dimerization, it does affect the efficiency of polymerization or have a role in maintaining IgA dimer stability. Furthermore, the J chain is essential for efficient hepatic pIgR transport of IgA.


Asunto(s)
Inmunoglobulina A/metabolismo , Cadenas J de Inmunoglobulina/metabolismo , Hígado/metabolismo , Animales , Secuencia de Bases , Bilis/metabolismo , Transporte Biológico , Células Cultivadas , Cartilla de ADN/química , Perros , Genes de Inmunoglobulinas , Inmunoglobulina A/química , Sustancias Macromoleculares , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Mapeo Restrictivo
15.
Science ; 226(4679): 1206-9, 1984 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-6542248

RESUMEN

Mouse and human atrial natriuretic factor (ANF) genes have been cloned and their nucleotide sequences determined. Each ANF gene consists of three coding blocks separated by two intervening sequences. The 5' flanking sequences and those encoding proANF are highly conserved between the two species, while the intervening sequences and 3' untranslated regions are not. The conserved sequences 5' of the gene may play an important role in the regulation of ANF gene expression.


Asunto(s)
Factor Natriurético Atrial , Proteínas/genética , Animales , Secuencia de Bases , Clonación Molecular , Regulación de la Expresión Génica , Genes , Atrios Cardíacos/metabolismo , Humanos , Ratones , Natriuréticos , Precursores de Proteínas/genética , Receptores de Glucocorticoides/metabolismo
16.
Science ; 283(5405): 1161-4, 1999 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-10024241

RESUMEN

The vertebrate heart consists of two types of chambers, the atria and the ventricles, which differ in their contractile and electrophysiological properties. Little is known of the molecular mechanisms by which these chambers are specified during embryogenesis. Here a chicken iroquois-related homeobox gene, Irx4, was identified that has a ventricle-restricted expression pattern at all stages of heart development. Irx4 protein was shown to regulate the chamber-specific expression of myosin isoforms by activating the expression of the ventricle myosin heavy chain-1 (VMHC1) and suppressing the expression of the atrial myosin heavy chain-1 (AMHC1) in the ventricles. Thus, Irx4 may play a critical role in establishing chamber-specific gene expression in the developing heart.


Asunto(s)
Miosinas Atriales , Proteínas Aviares , Regulación del Desarrollo de la Expresión Génica , Atrios Cardíacos/embriología , Ventrículos Cardíacos/embriología , Proteínas de Homeodominio/fisiología , Proteínas Musculares/genética , Miosinas/genética , Secuencia de Aminoácidos , Animales , Embrión de Pollo , Atrios Cardíacos/metabolismo , Atrios Cardíacos/virología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/virología , Proteínas de Homeodominio/química , Proteínas de Homeodominio/genética , Hibridación in Situ , Datos de Secuencia Molecular , Cadenas Pesadas de Miosina/genética , Fenotipo , Proteínas Recombinantes de Fusión , Retroviridae/genética , Retroviridae/fisiología
17.
Science ; 230(4730): 1168-71, 1985 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-2933808

RESUMEN

Rat atrial natriuretic factor (ANF) is translated as a 152-amino acid precursor preproANF. PreproANF is converted to the 126-amino acid proANF, the storage form of ANF in the atria. ANF isolated from the blood is approximately 25 amino acids long. It is demonstrated here that rat cardiocytes in culture store and secrete proANF. Incubation of proANF with serum produced a smaller ANF peptide. PreproANF seems to be processed to proANF in the atria, and proANF appears to be released into the blood, where it is converted by a protease to a smaller peptide.


Asunto(s)
Factor Natriurético Atrial/biosíntesis , Miocardio/citología , Precursores de Proteínas/biosíntesis , Secuencia de Aminoácidos , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Autorradiografía , Células Cultivadas , Electroforesis en Gel de Poliacrilamida , Corazón/fisiología , Sueros Inmunes/inmunología , Miocardio/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , ARN Mensajero/genética , Conejos/inmunología , Ratas
18.
Science ; 281(5373): 108-11, 1998 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-9651244

RESUMEN

Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease. A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located. Three different NKX2-5 mutations were identified. Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding. These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life.


Asunto(s)
Bloqueo Cardíaco/genética , Defectos del Tabique Interatrial/genética , Proteínas de Homeodominio/genética , Factores de Transcripción/genética , Proteínas de Xenopus , Secuencia de Aminoácidos , Animales , Nodo Atrioventricular/fisiopatología , Mapeo Cromosómico , Cromosomas Humanos Par 5 , Codón , Femenino , Genes Dominantes , Ligamiento Genético , Bloqueo Cardíaco/fisiopatología , Defectos del Tabique Interatrial/fisiopatología , Proteína Homeótica Nkx-2.5 , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Mutación , Linaje , Biosíntesis de Proteínas , Factores de Transcripción/metabolismo
19.
Science ; 225(4659): 324-6, 1984 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-6234658

RESUMEN

The structure of rat preproatrial natriuretic factor ( preproANF ) was determined by nucleotide sequence analysis of an ANF complementary DNA clone. PreproANF is composed of a hydrophobic leader segment (20 amino acids), a precursor containing one glycosylation site (106 amino acids), and ANF (24 amino acids). Atrial natriuretic factor is located at the carboxyl terminus of the precursor molecule. The human, mouse, and rat genomes each contain a single ANF gene which is highly conserved.


Asunto(s)
Clonación Molecular , ADN/genética , Proteínas Musculares/genética , Natriuresis , Animales , Factor Natriurético Atrial , Secuencia de Bases , Hibridación de Ácido Nucleico , Ratas
20.
Science ; 272(5262): 731-4, 1996 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-8614836

RESUMEN

A mouse model of familial hypertrophic cardiomyopathy (FHC) was generated by the introduction of an Arg 403 --> Gln mutation into the alpha cardiac myosin heavy chain (MHC) gene. Homozygous alpha MHC 403/403 mice died 7 days after birth, and sedentary heterozygous alpha MHC 403/+ mice survived for 1 year. Cardiac histopathology and dysfunction in the alpha MHC 403/+ mice resembled human FHC. Cardiac dysfunction preceded histopathologic changes, and myocyte disarray, hypertrophy, and fibrosis increased with age. Young male alpha MHC 403/+ mice showed more evidence of disease than did their female counterparts. Preliminary results suggested that exercise capacity may have been compromised in the alpha MHC 403/+ mice. This mouse model may help to define the natural history of FHC.


Asunto(s)
Cardiomiopatía Hipertrófica/genética , Modelos Animales de Enfermedad , Corazón/fisiopatología , Miocardio/patología , Cadenas Pesadas de Miosina/genética , Animales , Secuencia de Bases , Gasto Cardíaco , Cardiomiopatía Hipertrófica/patología , Cardiomiopatía Hipertrófica/fisiopatología , Femenino , Técnicas de Transferencia de Gen , Heterocigoto , Homocigoto , Humanos , Masculino , Ratones , Ratones Mutantes , Datos de Secuencia Molecular , Mutación , Miocardio/química , Esfuerzo Físico , Caracteres Sexuales , Función Ventricular Izquierda
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