RESUMO
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.
Assuntos
Genômica , Software , Criança , Documentação , Humanos , Incerteza , Sequenciamento Completo do GenomaRESUMO
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.
Assuntos
Anodontia/genética , Cromossomos Humanos Par 4 , Proteínas de Homeodomínio/genética , Fatores de Transcrição , Alelos , Sequência de Aminoácidos , Sequência de Bases , Primers do DNA/química , Feminino , Genes Dominantes , Genes Homeobox , Ligação Genética , Humanos , Fator de Transcrição MSX1 , Masculino , Dados de Sequência Molecular , Linhagem , Mutação Puntual , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Alcaptonúria/genética , Cromossomos Humanos Par 3 , Homozigoto , Adulto , Sequência de Bases , Criança , Feminino , Ligação Genética , Humanos , Masculino , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Linhagem , Complexo Sacarase-Isomaltase/deficiência , Complexo Sacarase-Isomaltase/genéticaRESUMO
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.
Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Cromossomos Humanos Par 11 , Mutação , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Splicing de RNARESUMO
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.
Assuntos
Cardiomiopatia Hipertrófica/genética , Cromossomos Humanos Par 1 , Proteínas Contráteis/genética , Mutação Puntual , Actinas/genética , Fatores Etários , Sequência de Bases , Cardiomiopatia Hipertrófica/mortalidade , Criança , Mapeamento Cromossômico , Primers do DNA , Feminino , Ligação Genética , Marcadores Genéticos , Humanos , Íntrons , Escore Lod , Masculino , Dados de Sequência Molecular , Miosinas/genética , Linhagem , Polimorfismo Genético , Probabilidade , Recombinação Genética , Análise de Sobrevida , Taxa de Sobrevida , Tropomiosina/genética , Troponina/genética , Troponina IRESUMO
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.
Assuntos
Cromossomos Humanos Par 9 , Ligação Genética , Telangiectasia Hemorrágica Hereditária/genética , Adulto , Criança , Mapeamento Cromossômico , Europa (Continente) , Feminino , Marcadores Genéticos , Haplótipos , Humanos , Masculino , Linhagem , Polimorfismo Genético , Sequências Repetitivas de Ácido NucleicoRESUMO
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.
Assuntos
Cálcio/metabolismo , Cromossomos Humanos Par 3 , Ligação Genética , Erros Inatos do Metabolismo dos Metais/genética , Sequência de Bases , Cálcio/sangue , Cálcio/urina , Bandeamento Cromossômico , Mapeamento Cromossômico , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Sondas de DNA , Feminino , Humanos , Escore Lod , Masculino , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Linhagem , Reação em Cadeia da Polimerase/métodos , Polimorfismo GenéticoRESUMO
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.
Assuntos
Cálcio/sangue , Genes Dominantes , Hipocalcemia/genética , Mutação Puntual , Receptores de Superfície Celular/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Análise Mutacional de DNA , DNA Complementar/genética , Feminino , Heterozigoto , Homeostase , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Escore Lod , Masculino , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Oócitos , Linhagem , Receptores de Detecção de Cálcio , Proteínas Recombinantes de Fusão/metabolismo , Tetania/genética , Xenopus laevisRESUMO
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.
Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Modelos Animais de Doenças , Hipercalcemia/genética , Hipercalcemia/metabolismo , Hiperparatireoidismo/genética , Hiperparatireoidismo/metabolismo , Animais , Doenças do Desenvolvimento Ósseo/genética , Cálcio/sangue , Cálcio/urina , Proteínas de Ligação ao Cálcio/genética , Heterozigoto , Homeostase , Homozigoto , Humanos , Hiperplasia , Recém-Nascido , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/sangueRESUMO
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.
Assuntos
Anormalidades Múltiplas/genética , Braço/anormalidades , Cardiopatias Congênitas/genética , Mutação , Proteínas com Domínio T , Fatores de Transcrição/genética , Anormalidades Múltiplas/embriologia , Sequência de Aminoácidos , Animais , Braço/embriologia , Sequência de Bases , Cromossomos Humanos Par 12 , Clonagem Molecular , DNA , Análise Mutacional de DNA , Cardiopatias Congênitas/embriologia , Humanos , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , SíndromeRESUMO
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.
Assuntos
Anormalidades Múltiplas/genética , Glândulas Apócrinas/anormalidades , Braço/anormalidades , Genitália/anormalidades , Mutação , Proteínas com Domínio T , Fatores de Transcrição/genética , Sequência de Aminoácidos , Sequência de Bases , Mama/anormalidades , Cromossomos Humanos Par 12 , Análise Mutacional de DNA , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Íntrons/genética , Masculino , Dados de Sequência Molecular , Alinhamento de Sequência , Síndrome , Fatores de Transcrição/químicaRESUMO
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.
Assuntos
Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Mutação de Sentido Incorreto , Proteínas/genética , Vestíbulo do Labirinto/fisiopatologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Galinhas , Sequência Conservada , Primers do DNA/genética , Proteínas da Matriz Extracelular , Feminino , Genes Dominantes , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Homologia de Sequência de Aminoácidos , Vestíbulo do Labirinto/patologiaRESUMO
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.
Assuntos
Imunoglobulina A/metabolismo , Cadeias J de Imunoglobulina/metabolismo , Fígado/metabolismo , Animais , Sequência de Bases , Bile/metabolismo , Transporte Biológico , Células Cultivadas , Primers do DNA/química , Cães , Genes de Imunoglobulinas , Imunoglobulina A/química , Substâncias Macromoleculares , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Mapeamento por RestriçãoRESUMO
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.
Assuntos
Proteínas de Ligação a Calmodulina/deficiência , Proteínas de Ligação a DNA , Ativação Linfocitária , Fosfoproteínas Fosfatases/deficiência , Linfócitos T/imunologia , Animais , Sequência de Bases , Calcineurina , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Quimera , Ciclosporina/farmacologia , Relação Dose-Resposta a Droga , Imunossupressores/farmacologia , Interferon gama/metabolismo , Interleucina-2/metabolismo , Camundongos , Mitógenos/farmacologia , Dados de Sequência Molecular , Ovalbumina/imunologia , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Proteínas/genética , Células-Tronco , Tacrolimo/farmacologiaRESUMO
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.
Assuntos
Miosinas Atriais , Proteínas Aviárias , Regulação da Expressão Gênica no Desenvolvimento , Átrios do Coração/embriologia , Ventrículos do Coração/embriologia , Proteínas de Homeodomínio/fisiologia , Proteínas Musculares/genética , Miosinas/genética , Sequência de Aminoácidos , Animais , Embrião de Galinha , Átrios do Coração/metabolismo , Átrios do Coração/virologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/virologia , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/genética , Hibridização In Situ , Dados de Sequência Molecular , Cadeias Pesadas de Miosina/genética , Fenótipo , Proteínas Recombinantes de Fusão , Retroviridae/genética , Retroviridae/fisiologiaRESUMO
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.
Assuntos
Fator Natriurético Atrial , Proteínas/genética , Animais , Sequência de Bases , Clonagem Molecular , Regulação da Expressão Gênica , Genes , Átrios do Coração/metabolismo , Humanos , Camundongos , Natriuréticos , Precursores de Proteínas/genética , Receptores de Glucocorticoides/metabolismoRESUMO
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.
Assuntos
Bloqueio Cardíaco/genética , Comunicação Interatrial/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Proteínas de Xenopus , Sequência de Aminoácidos , Animais , Nó Atrioventricular/fisiopatologia , Mapeamento Cromossômico , Cromossomos Humanos Par 5 , Códon , Feminino , Genes Dominantes , Ligação Genética , Bloqueio Cardíaco/fisiopatologia , Comunicação Interatrial/fisiopatologia , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Mutação , Linhagem , Biossíntese de Proteínas , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Cardiomiopatia Hipertrófica/genética , Modelos Animais de Doenças , Coração/fisiopatologia , Miocárdio/patologia , Cadeias Pesadas de Miosina/genética , Animais , Sequência de Bases , Débito Cardíaco , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Feminino , Técnicas de Transferência de Genes , Heterozigoto , Homozigoto , Humanos , Masculino , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Mutação , Miocárdio/química , Esforço Físico , Caracteres Sexuais , Função Ventricular EsquerdaRESUMO
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.
Assuntos
Fator Natriurético Atrial/biossíntese , Miocárdio/citologia , Precursores de Proteínas/biossíntese , Sequência de Aminoácidos , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Autorradiografia , Células Cultivadas , Eletroforese em Gel de Poliacrilamida , Coração/fisiologia , Soros Imunes/imunologia , Miocárdio/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , RNA Mensageiro/genética , Coelhos/imunologia , RatosRESUMO
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.