Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 107
Filtrar
1.
J Med Genet ; 45(1): 15-21, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17873118

RESUMEN

BACKGROUND: PRF1 gene mutations are associated with familial haemophagocytic lymphohistiocytosis type 2 (FHL2). Genotype-phenotype analysis, previously hampered by limited numbers of patients, was for the first time performed by data pooling from five large centres worldwide. PATIENTS AND METHODS: Members of the Histiocyte Society were asked to report cases of FHL2 on specific forms. Data were pooled in a common database and analysed. RESULTS: The 124 patients had 63 different mutations (including 15 novel mutations): 11 nonsense, 10 frameshift, 38 missense and 4 in-frame deletions. Some mutations were found more commonly: 1122 G-->A (W374X), associated with Turkish origin, in 32 patients; 50delT (L17fsX22) associated with African/African American origin, in 21 patients; and 1090-91delCT (L364fsX), in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40, reduced in 6 and normal in 4 patients. Patients presented at a median age of 3 months (quartiles: 2, 3 and 13 months), always with fever, splenomegaly and thrombocytopenia. NK activity was absent in 36 (51%), 5% in 4 (6%), "reduced" in 2 (3%) (not reported, n = 54). Nonsense mutations were significantly associated with younger age at onset (p<0.001) and absent natural killer activity (p = 0.008). CONCLUSION: PRF1 mutations are spread over the functional domains. Specific mutations are strongly associated with Turkish, African American and Japanese ethnic groups. Later onset and residual cytotoxic function are observed in patients with at least one missense mutation.


Asunto(s)
Linfohistiocitosis Hemofagocítica/etnología , Linfohistiocitosis Hemofagocítica/fisiopatología , Mutación , Perforina/genética , Adolescente , Adulto , Niño , Preescolar , Etnicidad , Femenino , Mutación del Sistema de Lectura , Genotipo , Humanos , Lactante , Recién Nacido , Células Asesinas Naturales/inmunología , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/inmunología , Masculino , Mutación Missense , Fenotipo
3.
J Biol Chem ; 276(39): 36809-16, 2001 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-11477068

RESUMEN

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency characterized by extreme susceptibility to Epstein-Barr virus. The XLP disease gene product SH2D1A (SAP) interacts via its SH2 domain with a motif (TIYXXV) present in the cytoplasmic tail of the cell-surface receptors CD150/SLAM, CD84, CD229/Ly-9, and CD244/2B4. Characteristically, the SH2D1A three-pronged interaction with Tyr(281) of CD150 can occur in absence of phosphorylation. Here we analyze the effect of SH2D1A protein missense mutations identified in 10 XLP families. Two sets of mutants were found: (i) mutants with a marked decreased protein half-life (e.g. Y7C, S28R, Q99P, P101L, V102G, and X129R) and (ii) mutants with structural changes that differently affect the interaction with the four receptors. In the second group, mutations that disrupt the interaction between the SH2D1A hydrophobic cleft and Val +3 of its binding motif (e.g. T68I) and mutations that interfere with the SH2D1A phosphotyrosine-binding pocket (e.g. C42W) abrogated SH2D1A binding to all four receptors. Surprisingly, a mutation in SH2D1A able to interfere with Thr -2 of the CD150 binding motif (mutant T53I) severely impaired non-phosphotyrosine interactions while preserving unaffected the binding of SH2D1A to phosphorylated CD150. Mutant T53I, however, did not bind to CD229 and CD224, suggesting that SH2D1A controls several critical signaling pathways in T and natural killer cells. Because no correlation is present between identified types of mutations and XLP patient clinical presentation, additional unidentified genetic or environmental factors must play a strong role in XLP disease manifestations.


Asunto(s)
Proteínas Portadoras/química , Proteínas Portadoras/genética , Péptidos y Proteínas de Señalización Intracelular , Trastornos Linfoproliferativos/genética , Mutación Missense , Mutación , Secuencia de Aminoácidos , Aminoácidos/química , Animales , Western Blotting , Células COS , Clonación Molecular , Relación Dosis-Respuesta a Droga , Humanos , Células Jurkat , Modelos Moleculares , Datos de Secuencia Molecular , Fenotipo , Fosforilación , Plásmidos/metabolismo , Pruebas de Precipitina , Unión Proteica , Estructura Terciaria de Proteína , Transducción de Señal , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Transfección , Dominios Homologos src
4.
Cancer Gene Ther ; 8(12): 936-47, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11781656

RESUMEN

Co-incubation of a replication-deficient, recombinant adenovirus carrying the wild-type p53 gene (rAd-p53) and hematopoietic stem cell (HSC) products from patients with breast cancer can significantly reduce tumor cell contamination. Whereas this approach provides a powerful tumor cell purging strategy, potential detrimental effects on the HSC population have not been investigated. The ability of human HSC to reconstitute hematopoiesis in severe combined immunodeficient (SCID) mice and to undergo secondary transplantation provides the only nonclinical measure of self-renewing, stem cell function. The objective of this study was to investigate whether co-incubation with rAd-p53 compromised the SCID repopulating activity (SRA) of HSC. Granulocyte colony-stimulating factor-mobilized human CD34+ cells were co-cultured with rAd-p53 at our targeted clinical dose, and the ability of these cells to establish multilineage hematopoiesis in sublethally irradiated, nonobese diabetic (NOD)-SCID mice was investigated. The persistence of human cells in the mice was investigated by flow cytometry, granulocyte-macrophage colony-forming unit assay, and polymerase chain reaction of human Alu sequences. Further, limiting dilution analysis provided a quantitative comparison between the SRA of CD34+ cells co-incubated with rAd-p53 and control CD34+ cells (no rAd-p53 co-incubation). We conclude that co-incubation with rAd-p53 has little effect on the SRA of HSC.


Asunto(s)
Purgación de la Médula Ósea , Genes p53 , Terapia Genética , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/fisiología , Adenoviridae , Animales , Purgación de la Médula Ósea/métodos , Femenino , Vectores Genéticos , Factor Estimulante de Colonias de Granulocitos/farmacología , Hematopoyesis , Movilización de Célula Madre Hematopoyética , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID
5.
Int J Cancer ; 88(3): 439-47, 2000 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-11054674

RESUMEN

The gene defect responsible for the X-linked lymphoproliferative disease (XLP) is associated with an impaired control of Epstein-Barr virus (EBV) infection. The gene has been recently identified and the encoded protein (designated SH2D1A, DSHP or SAP) was characterized. It is a 128 amino acid (aa) protein, containing a single Src homology 2 (SH2) domain. It interacts with signaling lymphocytic activation molecule (SLAM) expressed on the surface of activated T and B cells. We show that activated T, but not activated B, cells express the SH2D1A protein. NK cells express the protein as well. Tumor lines originating from B, T or NK cells exhibited similar SH2D1A protein expression as the corresponding normal cells, with some notable exceptions. EBV-carrying, tumor phenotype representative (type I), but not EBV-carrying lymphoblastoid cell line (LCL)-like (type III) or EBV-negative Burkitt lymphoma (BL) lines expressed SH2D1A. The phenotypic switch from type I to type III in the EBV-carrying BL line Mutu was associated with a down-regulation of SH2D1A and up-regulation of SLAM. In contrast to normal ex vivo and long-term activated NK cells, 2 of 3 NK leukemia lines expressed SLAM. All 3 lines expressed SH2D1A, like their normal counterparts.


Asunto(s)
Proteínas Portadoras/análisis , Glicoproteínas/análisis , Inmunoglobulinas/análisis , Péptidos y Proteínas de Señalización Intracelular , Leucemia/metabolismo , Linfocitos/química , Secuencia de Aminoácidos , Antígenos CD , Proteínas Portadoras/sangre , Línea Celular , Glicoproteínas/sangre , Humanos , Inmunoglobulinas/sangre , Células Asesinas Naturales/química , Datos de Secuencia Molecular , Receptores de Superficie Celular , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria
6.
Blood ; 96(9): 3118-25, 2000 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-11049992

RESUMEN

The purposes of this study were to determine the frequency of mutations in SH2D1A in X-linked lymphoproliferative disease (XLP) and the role of SH2D1A mutations and Epstein-Barr virus (EBV) infection in determining the phenotype and outcome of patients with XLP. Analysis of 35 families from the XLP Registry revealed 28 different mutations in 34 families-large genomic deletions (n = 3), small intragenic deletions (n = 10), splice-site (n = 3), nonsense (n = 3), and missense (n = 9) mutations. No mutations were found in 25 males, so-called sporadic XLP (males with an XLP phenotype after EBV infection but no family history of XLP) or in 9 patients with chronic active EBV syndrome. Of 304 symptomatic males in the XLP Registry, 38 had no evidence of EBV infection at first clinical manifestation. When fulminant infectious mononucleosis (FIM) was excluded, there was no statistical difference in the frequency of EBV infectivity in the other XLP phenotypes. Furthermore, there was no difference at age of first clinical manifestation between EBV(+) and EBV(-) males or in survival when patients with FIM were excluded. In conclusion, it was found that mutations in the SH2D1A gene are responsible for XLP but that there is no correlation between genotype and phenotype or outcome. It was also found that though EBV infection often results in FIM, it is unnecessary for the expression of other manifestations of XLP, and it correlates poorly with outcome. These results suggest that unidentified factors, either environmental or genetic (eg, modifier genes), contribute to the pathogenesis of XLP.


Asunto(s)
Proteínas Portadoras/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Péptidos y Proteínas de Señalización Intracelular , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/virología , Mutación , Cromosoma X , Empalme Alternativo , Secuencia de Aminoácidos , Mapeo Cromosómico , Exones , Femenino , Marcadores Genéticos , Humanos , Intrones , Masculino , Datos de Secuencia Molecular , Mutación Missense , Linaje , Fenotipo , Polimorfismo de Longitud del Fragmento de Restricción , Valor Predictivo de las Pruebas , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Eliminación de Secuencia , Homología de Secuencia de Aminoácido , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Dominios Homologos src
7.
Cancer Res ; 60(17): 4907-12, 2000 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-10987305

RESUMEN

A DNA fragment frequently hypermethylated in tumor cells was isolated using a novel screening strategy termed methylation-sensitive arbitrarily primed PCR. The isolated sequence corresponded to a CpG island at the 5' end of a previously unknown gene, TPEF (transmembrane protein containing epidermal growth factor and follistatin domains). Expression of TPEF was observed using Northern master blot analysis of a variety of normal tissues including colon, bladder, and prostate tissue. TPEF maps to human chromosome 2q33, where frequent loss of heterozygosity is seen in various human tumors, and TPEF was not expressed in most human colon and various other tumor cell lines examined by reverse transcription-PCR. Nine of 11 tumor cell lines were highly methylated in the 5' region and the first exon of the gene that demonstrated features characteristic of a CpG island. However the other two cell lines, which expressed TPEF, were hypomethylated in the 5' end of the gene. The region was also hypermethylated in 11 of 16 primary bladder tumors and in 3 of 4 primary colon tumors when compared with adjacent normal tissue. Our results suggest that potential tumor suppressor genes can be isolated from human tumors by virtue of their altered methylation patterns.


Asunto(s)
Metilación de ADN , Factor de Crecimiento Epidérmico/genética , Glicoproteínas/genética , Proteínas de la Membrana/genética , Proteínas de Neoplasias , Neoplasias/genética , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 2/genética , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Islas de CpG/genética , Islas de CpG/fisiología , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Factor de Crecimiento Epidérmico/biosíntesis , Folistatina , Regulación Neoplásica de la Expresión Génica/fisiología , Silenciador del Gen/fisiología , Glicoproteínas/biosíntesis , Humanos , Proteínas de la Membrana/biosíntesis , Datos de Secuencia Molecular , Neoplasias/metabolismo , Estructura Terciaria de Proteína/genética , Homología de Secuencia de Aminoácido , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo
8.
Am J Hum Genet ; 66(4): 1199-210, 2000 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10729113

RESUMEN

Usher syndrome type IIa (USHIIa) is an autosomal recessive disorder characterized by moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa. This disorder maps to human chromosome 1q41. Recently, mutations in USHIIa patients were identified in a novel gene isolated from this chromosomal region. The USH2A gene encodes a protein with a predicted molecular weight of 171.5 kD and possesses laminin epidermal growth factor as well as fibronectin type III domains. These domains are observed in other protein components of the basal lamina and extracellular matrixes; they may also be observed in cell-adhesion molecules. The intron/exon organization of the gene whose protein we name "Usherin" was determined by direct sequencing of PCR products and cloned genomic DNA with cDNA-specific primers. The gene is encoded by 21 exons and spans a minimum of 105 kb. A mutation search of 57 independent USHIIa probands was performed with a combination of direct sequencing and heteroduplex analysis of PCR-amplified exons. Fifteen new mutations were found. Of 114 independent USH2A alleles, 58 harbored probable pathologic mutations. Ten cases of USHIIa were true homozygotes and 10 were compound heterozygotes; 18 heterozygotes with only one identifiable mutation were observed. Sixty-five percent (38/58) of cases had at least one mutation, and 51% (58/114) of the total number of possible mutations were identified. The allele 2299delG (previously reported as 2314delG) was the most frequent mutant allele observed (16%; 31/192). Three new missense mutations (C319Y, N346H, and C419F) were discovered; all were restricted to the previously unreported laminin domain VI region of Usherin. The possible significance of this domain, known to be necessary for laminin network assembly, is discussed in the context of domain VI mutations from other proteins.


Asunto(s)
Exones/genética , Proteínas de la Matriz Extracelular/genética , Pérdida Auditiva Sensorineural/genética , Intrones/genética , Mutación/genética , Retinitis Pigmentosa/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Codón de Terminación/genética , Análisis Mutacional de ADN , Femenino , Mutación del Sistema de Lectura/genética , Genotipo , Análisis Heterodúplex , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Datos de Secuencia Molecular , Mutación Missense/genética , Empalme del ARN/genética , Alineación de Secuencia , Síndrome
9.
Gene ; 239(2): 259-71, 1999 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-10548727

RESUMEN

We have partially sequenced more than 1000 NotI linking clones isolated from human chromosome 3-specific libraries. Of these clones, 152 were unique chromosome 3-specific clones. The clones were precisely mapped using a combination of fluorescence in situ hybridization (FISH) and hybridization to somatic cell or radiation hybrids. Two- and three-color FISH was used to order the clones that mapped to the same chromosomal region, and in some cases, chromosome jumping was used to resolve ambiguous mapping. When this NotI restriction map was compared with the yeast artificial chromosome (YAC) based chromosome 3 map, significant differences in several chromosome 3 regions were observed. A search of the EMBL nucleotide database with these sequences revealed homologies (90-100%) to more than 100 different genes or expressed sequence tags (ESTs). Many of these homologies were used to map new genes to chromosome 3. These results suggest that sequencing NotI linking clones, and sequencing CpG islands in general, may complement the EST project and aid in the discovery of all human genes by sequencing random cDNAs. This method may also yield information that cannot be obtained by the EST project alone; namely, the identification of the 5' ends of genes, including potential promoter/enhancer regions and other regulatory sequences


Asunto(s)
Cromosomas Humanos Par 3/genética , ADN/genética , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Biblioteca de Genes , Animales , Línea Celular , Mapeo Cromosómico , ADN/química , ADN/metabolismo , Bases de Datos Factuales , Etiquetas de Secuencia Expresada , Humanos , Células Híbridas , Hibridación Fluorescente in Situ , Ratones , Alineación de Secuencia , Análisis de Secuencia de ADN
10.
Mol Cell ; 4(4): 555-61, 1999 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-10549287

RESUMEN

SAP, the product of the gene mutated in X-linked lymphoproliferative syndrome (XLP), consists of a single SH2 domain that has been shown to bind the cytoplasmic tail of the lymphocyte coreceptor SLAM. Here we describe structures that show that SAP binds phosphorylated and nonphosphorylated SLAM peptides in a similar mode, with the tyrosine or phosphotyrosine residue inserted into the phosphotyrosine-binding pocket. We find that specific interactions with residues N-terminal to the tyrosine, in addition to more characteristic C-terminal interactions, stabilize the complexes. A phosphopeptide library screen and analysis of mutations identified in XLP patients confirm that these extended interactions are required for SAP function. Further, we show that SAP and the similar protein EAT-2 recognize the sequence motif TIpYXX(V/I).


Asunto(s)
Proteínas Portadoras/química , Glicoproteínas/química , Inmunoglobulinas/química , Péptidos y Proteínas de Señalización Intracelular , Trastornos Linfoproliferativos/genética , Dominios Homologos src , Secuencia de Aminoácidos , Antígenos CD , Sitios de Unión , Proteínas Portadoras/genética , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Fragmentos de Péptidos/química , Biblioteca de Péptidos , Fosfopéptidos/química , Fosfotirosina/química , Unión Proteica , Receptores de Superficie Celular , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Factores de Transcripción/química
11.
Nucleic Acids Res ; 27(11): 2291-8, 1999 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-10325416

RESUMEN

DNA methylation in mammals is required for embryonic development, X chromosome inactivation and imprinting. Previous studies have shown that methylation patterns become abnormal in malignant cells and may contribute to tumorigenesis by improper de novo methylation and silencing of the promoters for growth-regulatory genes. RNA and protein levels of the DNA methyltransferase DNMT1 have been shown to be elevated in tumors, however murine stem cells lacking Dnmt1 are still able to de novo methylate viral DNA. The recent cloning of a new family of DNA methyltransferases (Dnmt3a and Dnmt3b) in mouse which methylate hemimethylated and unmethylated templates with equal efficiencies make them candidates for the long sought de novo methyltransferases. We have investigated the expression of human DNMT1, 3a and 3b and found widespread, coordinate expression of all three transcripts in most normal tissues. Chromosomal mapping placed DNMT3a on chromosome 2p23 and DNMT3b on chromosome 20q11.2. Significant overexpression of DNMT3b was seen in tumors while DNMT1 and DNMT3a were only modestly over-expressed and with lower frequency. Lastly, several novel alternatively spliced forms of DNMT3b, which may have altered enzymatic activity, were found to be expressed in a tissue-specific manner.


Asunto(s)
Neoplasias del Colon/enzimología , ADN (Citosina-5-)-Metiltransferasas/genética , Neoplasias Renales/enzimología , Neoplasias Pancreáticas/enzimología , Neoplasias de la Vejiga Urinaria/enzimología , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 2 , Cromosomas Humanos Par 20 , Neoplasias del Colon/genética , ADN Metiltransferasa 3A , ADN Complementario , Expresión Génica , Humanos , Neoplasias Renales/genética , Ratones , Datos de Secuencia Molecular , Neoplasias Pancreáticas/genética , ARN Mensajero , Homología de Secuencia de Aminoácido , Distribución Tisular , Neoplasias de la Vejiga Urinaria/genética , ADN Metiltransferasa 3B
13.
Cell Mol Life Sci ; 56(3-4): 258-67, 1999 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-11212353

RESUMEN

The Usher syndrome, an autosomal recessive deafness and blindness, is genetically and clinically heterogeneous. In the past 4 years, genes mutated in Usher syndrome type Ib and type IIa have been described. The Usher Ib gene encodes the motor protein myosin VIIa and was identified as the human homolog of the mouse shaker-1 gene. The Usher type IIa gene was identified by positional cloning and encodes a protein with homology to extracellular matrix proteins and cell adhesion molecules. This review summarizes the current knowledge regarding both the genetic and molecular aspects of Usher syndrome in the context of recent scientific advances in the areas of sensorineural deafness and retinitis pigmentosa.


Asunto(s)
Pérdida Auditiva Sensorineural/genética , Dineínas , Proteínas de la Matriz Extracelular/genética , Humanos , Miosina VIIa , Miosinas/genética , Síndrome
14.
Hum Genet ; 103(4): 523-4, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9856501

RESUMEN

The eukaryotic LAMMER protein kinase family is encoded by at least three loci in the human genome, designated CLK1, 2, and 3. We have mapped these loci to 2q33, 1q21, and 15q24, respectively, by fluorescent in situ hybridization. Additionally, a CLK2 pseudo-gene has been located to 7p15-21.


Asunto(s)
Cromosomas Humanos Par 15 , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 2 , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Mapeo Cromosómico , Cromosomas Humanos Par 7 , Humanos , Hibridación Fluorescente in Situ , Seudogenes
15.
Eur J Hum Genet ; 6(5): 509-17, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9801876

RESUMEN

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterised by selective susceptibility to Epstein-Barr virus and frequent association with malignant lymphomas chiefly located in the ileocecal region, liver, kidney and CNS. Taking advantage of a large bacterial clone contig, we obtained a genomic sequence of 197620 bp encompassing a deletion (XLP-D) of 116 kb in an XLP family, whose breakpoints were identified. The study of potential exons from this region in 40 unrelated XLP patients did not reveal any mutation. To define the critical region for XLP and investigate the role of the XLP-D deletion, detailed haplotypes in a region of approximately 20 cM were reconstructed in a total of 87 individuals from 7 families with recurrence of XLP. Two recombination events in a North American family and a new microdeletion (XLP-G) in an Italian family indicate that the XLP gene maps in the interval between DXS1001 and DXS8057, approximately 800 kb centromeric to the previously reported familial microdeletion XLP-D.


Asunto(s)
Ligamiento Genético , Trastornos Linfoproliferativos/genética , Cromosoma X , Secuencia de Bases , Clonación Molecular , Cartilla de ADN , Femenino , Eliminación de Gen , Haplotipos , Humanos , Masculino , Linaje
16.
Nat Genet ; 20(2): 129-35, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9771704

RESUMEN

X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in many tissues involved in the immune system. The identification of SH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.


Asunto(s)
Proteínas Portadoras/genética , Infecciones por Herpesviridae/complicaciones , Herpesvirus Humano 4 , Péptidos y Proteínas de Señalización Intracelular , Trastornos Linfoproliferativos/genética , Mutación , Dominios Homologos src/genética , Antígenos CD , Linfocitos B/inmunología , Linfocitos B/virología , Proteínas Portadoras/metabolismo , Clonación Molecular , Femenino , Ligamiento Genético , Glicoproteínas/metabolismo , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Humanos , Inmunoglobulinas/metabolismo , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/virología , Masculino , Datos de Secuencia Molecular , Linaje , Receptores de Superficie Celular , Alineación de Secuencia , Eliminación de Secuencia , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Linfocitos T/inmunología , Linfocitos T/virología , Cromosoma X
18.
Science ; 280(5370): 1753-7, 1998 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-9624053

RESUMEN

Usher syndrome type IIa (OMIM 276901), an autosomal recessive disorder characterized by moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa, maps to the long arm of human chromosome 1q41 between markers AFM268ZD1 and AFM144XF2. Three biologically important mutations in Usher syndrome type IIa patients were identified in a gene (USH2A) isolated from this critical region. The USH2A gene encodes a protein with a predicted size of 171.5 kilodaltons that has laminin epidermal growth factor and fibronectin type III motifs; these motifs are most commonly observed in proteins comprising components of the basal lamina and extracellular matrixes and in cell adhesion molecules.


Asunto(s)
Proteínas de la Matriz Extracelular/genética , Pérdida Auditiva Sensorineural/genética , Retinitis Pigmentosa/genética , Secuencia de Aminoácidos , Animales , Moléculas de Adhesión Celular/química , Mapeo Cromosómico , Cromosomas Humanos Par 1 , Cóclea/química , Factor de Crecimiento Epidérmico/química , Proteínas de la Matriz Extracelular/química , Proteínas de la Matriz Extracelular/fisiología , Femenino , Fibronectinas/química , Mutación del Sistema de Lectura , Expresión Génica , Genes Recesivos , Glicosilación , Humanos , Laminina/química , Masculino , Datos de Secuencia Molecular , Linaje , Retina/química , Síndrome , Células Tumorales Cultivadas
19.
Genomics ; 43(1): 104-6, 1997 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-9226380

RESUMEN

Usher syndrome type 1 (USH1) is an autosomal recessive, genetically heterogeneous disorder causing severe congenital deafness, retinitis pigmentosa, and vestibular dysfunction. The USHla locus located on 14q32 has been linked to the genetic markers D14S250 and D14S78. Using D14S250 and D14S78, we have isolated two nonchimeric YACs, 878g10 and 844g2, and a single BAC (135i20) and PAC (194e17) clone and have arranged them into a contig spanning over the D14S250 and D14S78 markers. The analysis of the YACs, BAC, and PAC revealed that the physical distance between D14S250 and D14S78 is less than 25 kb. Iterative cDNA library screening initiated with the EST 219670 found in the vicinity of the D14S78 marker yielded a cDNA contig. The nucleotide sequence of the cDNA encodes a protein of 717 amino acids in length, showing a high level of homology to the Echinoderm 77-kDa microtubule-associated protein (EMAP). The human homologue of Echinoderm microtubule-associated protein defines a novel human gene. We propose that the human EMAP is a strong candidate for the USH1a gene based on its genomic location and the proposed function of the protein.


Asunto(s)
Cromosomas Humanos Par 14/genética , Sordera/genética , Equinodermos/genética , Proteínas Asociadas a Microtúbulos/genética , Animales , Secuencia de Bases , Mapeo Cromosómico , ADN Complementario/genética , Sordera/congénito , Ligamiento Genético , Marcadores Genéticos , Humanos , Datos de Secuencia Molecular , Retinitis Pigmentosa/genética , Lugares Marcados de Secuencia , Especificidad de la Especie , Síndrome , Enfermedades Vestibulares/genética
20.
Genomics ; 40(1): 73-9, 1997 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-9070921

RESUMEN

Usher syndrome type Ib is a recessive autosomal disorder manifested by congenital deafness, vestibular dysfunction, and progressive retinal degeneration. Mutations in the human myosin VIIa gene (MYO7A) have been reported to cause Usher type Ib. Here we report the genomic organization of MYO7A. An STS content map was determined to discover the YAC clones that would cover the critical region for Usher syndrome type Ib. Three of the YACs (802A5, 966D6, and 965F10) were subcloned into cosmids and used to assemble a preliminary cosmid contig of the critical region. Part of the gene encoding human myosin VIIa was found in the preliminary cosmid contig. A cosmid, P1, PAC, and long PCR contig that contained the entire MYO7A gene was assembled. Primers were designed from the composite cDNA sequence and used to detect intron-exon junctions by directly sequencing cosmid, P1, PAC, and genomic PCR DNA. Alternatively spliced products were transcribed from the MYO7A gene: the largest transcript (7.4 kb) contains 49 exons. The MYO7A gene is relatively large, spanning approximately 120 kb of genomic DNA on chromosome 11q13.


Asunto(s)
Anomalías Múltiples/genética , Miosinas/genética , Cromosomas Artificiales de Levadura , Cósmidos , Dineínas , Exones , Pérdida Auditiva Sensorineural/genética , Humanos , Intrones , Miosina VIIa , Reacción en Cadena de la Polimerasa , Degeneración Retiniana/genética , Lugares Marcados de Secuencia , Síndrome , Enfermedades Vestibulares/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...