RESUMEN
Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomy of chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K(+) currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca(2+) activated K(+) current (I(K,f)), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active.
Asunto(s)
Cromosomas Humanos Par 21/fisiología , Síndrome de Down/complicaciones , Otitis Media/etiología , Animales , Cóclea , Modelos Animales de Enfermedad , Síndrome de Down/genética , Síndrome de Down/fisiopatología , Potenciales Evocados Auditivos del Tronco Encefálico , Células Ciliadas Auditivas , Audición , Humanos , Ratones , Ratones Transgénicos , Proteínas de NeoplasiasRESUMEN
Gene fusions play a critical role in cancer progression. The mechanisms underlying their genesis and cell type specificity are not well understood. About 50% of human prostate cancers display a gene fusion involving the 5' untranslated region of TMPRSS2, an androgen-regulated gene, and the protein-coding sequences of ERG, which encodes an erythroblast transformation-specific (ETS) transcription factor. By studying human prostate cancer cells with fluorescence in situ hybridization, we show that androgen signaling induces proximity of the TMPRSS2 and ERG genomic loci, both located on chromosome 21q22.2. Subsequent exposure of the cells to gamma irradiation, which causes DNA double-strand breaks, facilitates the formation of the TMPRSS2-ERG gene fusion. These results may help explain why TMPRSS2-ERG fusions are restricted to the prostate, which is dependent on androgen signaling.
Asunto(s)
Cromosomas Humanos Par 21/genética , Dihidrotestosterona/metabolismo , Fusión de Oncogenes , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/genética , Serina Endopeptidasas/genética , Transactivadores/genética , Línea Celular Tumoral , Aberraciones Cromosómicas , Cromosomas Humanos Par 21/fisiología , Roturas del ADN de Doble Cadena , Dihidrotestosterona/farmacología , Humanos , Hibridación Fluorescente in Situ , Masculino , Receptores Androgénicos/metabolismo , Transducción de Señal , Regulador Transcripcional ERGAsunto(s)
Interferón Tipo I/fisiología , Receptor de Interferón alfa y beta/fisiología , Transducción de Señal , Animales , Apoptosis/fisiología , Proliferación Celular , Cromosomas Humanos Par 21/fisiología , Hematopoyesis/fisiología , Humanos , Inmunidad Innata/fisiología , Memoria Inmunológica/fisiología , Infecciones/inmunología , Subunidad beta del Receptor de Interleucina-10/fisiología , Ratones , Ratones Transgénicos , Neoplasias/inmunología , Receptores de Interferón/fisiología , Linfocitos T/inmunología , Receptor de Interferón gammaRESUMEN
The adenovirus E1B-55K and E4orf6 proteins cooperate during virus infection while performing several tasks that contribute to a productive infection, including the selective nucleocytoplasmic transport of late viral mRNA. Previous studies have shown that the E4orf6 protein retains the E1B-55K protein in the nucleus of human and monkey cells, but not in those of rodents, suggesting that primate-specific cellular factors contribute to the E4orf6-mediated retention of the E1B-55K protein in the nucleus. In an effort to identify these proposed primate-specific cellular factors, the interaction of the E1B-55K and E4orf6 proteins was studied in a panel of stable human-rodent monochromosomal somatic cell hybrids. Analysis of this panel of cell lines has demonstrated the existence of an activity associated with human chromosome 21 that permits the E1B-55K and E4orf6 proteins to colocalize in the nucleus of a rodent cell. Additional hybrid cells bearing portions of human chromosome 21 were used to map this activity to a 10-megabase-pair segment of the chromosome, extending from 21q22.12 to a region near the q terminus. Strikingly, this region also facilitates the expression of adenovirus late genes in a rodent cell background while having little impact on the expression of early viral genes.
Asunto(s)
Adenoviridae/genética , Proteínas E1B de Adenovirus/metabolismo , Proteínas E4 de Adenovirus/metabolismo , Núcleo Celular/metabolismo , Cromosomas Humanos Par 21/genética , Regulación Viral de la Expresión Génica , Proteínas E1B de Adenovirus/genética , Proteínas E4 de Adenovirus/genética , Animales , Línea Celular , Mapeo Cromosómico , Cromosomas Humanos Par 21/fisiología , Células HeLa , Humanos , Células Híbridas , Ratones , Transfección , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
OBJECTIVE: To determine the meiotic behavior of a ring Y chromosome in a semen sample from a 45,X/46,X,r(Y)/46,X,dic r(Y) patient and the possible interchromosomal effects of the ring on other chromosome pairs. DESIGN: Retrospective analysis. SETTING: Universitat Autònoma de Barcelona. PATIENT: An oligoasthenoteratozoospermic patient who presented for infertility consultation. MAIN OUTCOME MEASURE(S): The sex chromosome content of spermatogenic cells, meiotic figures, and spermatozoa in the ejaculate and the possible interchromosomal effects on chromosomes 13, 18, and 21 were analyzed by using multicolor fluorescence in situ hybridization. Germ-cell aneuploidies were scored. RESULT(S): X0 cells are meiotically incompetent. All meiotic figures were exclusively XY, and 80% showed unpaired sex chromosomes. A high proportion of postreductional cells were XY (45.5%) or nullisomic for sex chromosomes (13.92%). This percentage decreased in spermatozoa to 14.89% and 27.66%, respectively. A statistically significant increase in X-bearing versus Y-bearing cells both in postreductional cells (23.9% vs. 14.3%) and spermatozoa (41.9% vs. 19.3%) was also observed. Evidence for an interchromosomal effect on chromosome 21 was detected. CONCLUSION(S): Data suggest that this patient had a generalized increase incidence of chromosome anomalies, underscoring the importance of incorporating screening for sperm aneuploidies in genetic analysis of affected patients.
Asunto(s)
Infertilidad Masculina/genética , Meiosis/fisiología , Oligospermia/genética , Aberraciones Cromosómicas Sexuales , Espermatozoides/ultraestructura , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 13/fisiología , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 18/fisiología , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 21/fisiología , Cromosomas Humanos X/genética , Cromosomas Humanos X/fisiología , Cromosomas Humanos Y/genética , Cromosomas Humanos Y/fisiología , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Meiosis/genética , Microscopía Fluorescente , Oligospermia/patología , Estudios Retrospectivos , Cromosomas en Anillo , Espermatozoides/citologíaRESUMEN
A decrease in the number and density of neurons is the most common phenotype in the brains of Down syndrome (DS) patients, causing mental retardation. Studies using primary cultured neurons from DS patients or from model mice have suggested that a defect in metabolism of reactive oxygen species, or diminished levels of glutathione, causes mitochondrial and caspase-mediated neuronal apoptosis in vitro. However, it is not well documented whether neuronal apoptosis also occurs in immature DS neurons, owing to the difficulty in isolating or identifying neuronal stem cells in human or mouse fetuses. Here we utilized an in vitro model system for neuronal differentiation, with mouse embryonic stem cells containing human chromosome 21 (TT2F/hChr.21) to examine the effect of an additional hChr.21 on the early phases of neurogenesis. The differentiation profile of TT2F/hChr.21 cells was essentially the same as those of parental TT2F ES cells. In differentiations of both TT2F and TT2F/hChr.21 cells, high level of apoptosis was observed in neuronal stem cells, but the rate of apoptosis in TT2F/hChr.21 cells was significantly higher than that of parental cells. These results suggest that quantitative changes in the level of apoptosis in DS neuronal stem cells may account for the reduction of neuronal number and density in the DS brain.
Asunto(s)
Apoptosis/fisiología , Diferenciación Celular/fisiología , Cromosomas Humanos Par 21/fisiología , Neuronas/fisiología , Células Madre/fisiología , Animales , Biomarcadores , Separación Celular , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Síndrome de Down/genética , Síndrome de Down/fisiopatología , Embrión de Mamíferos/citología , Citometría de Flujo , Humanos , Etiquetado Corte-Fin in Situ , Cariotipificación , Ratones , Neuronas/citologíaRESUMEN
We have investigated the distribution of PEP-19, a neuron-specific protein, in the adult human brain. Immunohistochemistry for PEP-19 appears to define the basal ganglia and related structures. The strongest immunoreactivity is seen in the caudate nucleus and putamen, each of which showed both cell body and neuropil PEP-19 immunoreactivity. The substantia nigra and both segments of the globus pallidus showed PEP-19 immunoreactivity only in the neuropil. Cell bodies and dendrites of the thalamic nuclei ventralis lateralis and ventralis anterioralis were less strongly immunoreactive. Cerebellar Purkinje cells and their dendrites were immunoreactive, as were the presubiculum/subiculum regions and dentate gyrus granule cells of the hippocampus. The CA zones of the hippocampus were not immunoreactive. Preliminary data from immunoblotting experiments indicate that PEP-19 immunoreactivity is significantly reduced in cerebellum in Alzheimer's disease. While there were no apparent alterations of immunoreactivity in Down's syndrome or in Parkinson's disease, immunohistochemical analysis showed a massive loss of PEP-19 immunoreactivity in the caudate nucleus, putamen, globus pallidus and substantia nigra in Huntington's disease. These results show that PEP-19, a neuron-specific, calmodulin-binding protein, is distributed in specific areas of the adult human brain. The reduction in PEP-19 immunoreactivity in Alzheimer's disease and Huntington's disease suggests that PEP-19 may play a role in the pathophysiology of these diseases through a mechanism of calcium/calmodulin disregulation. This may be especially apparent in Huntington's disease where the distribution of the product of the abnormal gene, huntingtin, alone is not sufficient to explain the pattern of pathology. Abnormal huntingtin associates more strongly with calmodulin than does normal huntingtin [Bao et al. (1996) Proc. natn. Acad. Sci. U.S.A., 93, 5037-5042] suggesting a disruption of calmodulin-mediated intracellular mechanism(s), very likely involving PEP-19.
Asunto(s)
Ganglios Basales/metabolismo , Química Encefálica/fisiología , Enfermedad de Huntington/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Proteínas de Unión a Calmodulina , Mapeo Cromosómico , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 21/fisiología , Síndrome de Down/metabolismo , Femenino , Humanos , Immunoblotting , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , RatasRESUMEN
Interleukin 6 (IL-6) serves as a growth factor for mouse plasmacytomas. As a model for IL-6-mediated growth of plasmacytomas, we study IL-6-dependent B-cell hybridomas, which can be generated through fusion of B lymphocytes with a plasmacytoma cell line, e.g., SP2/0. In the present report, we have investigated the peculiar behavior of B-cell hybridomas with respect to IL-6 dependence. We demonstrate that although newly generated hybridomas are IL-6 dependent, many hybridomas lose this dependency at frequencies as high as 50%, shortly after fusion. We speculated that the loss of IL-6-dependent growth is due to the well-known chromosomal instability of B-cell hybridomas. Consequently, loss of IL-6 dependence is the result of loss of a specific chromosome(s). This model implies the existence of an "IL-6 dependency" gene, the loss of which makes hybridomas capable of proliferating in the absence of IL-6. Because SP2/0 is IL-6 independent, the IL-6-dependent phenotype of B-cell hybridomas, and hence the IL-6 dependency gene, must be derived from the B lymphocyte. We have tested this model by generating human/mouse B-cell hybridomas through fusion of human B lymphocytes with SP2/0. We then analyzed the human chromosome content of 10 IL-6-dependent and 14 IL-6-independent subclones. From that analysis we concluded that the presence of human chromosome 21 correlated with IL-6 dependence. This correlation was confirmed by microcell fusion experiments in which a single copy of chromosome 21 was introduced into IL-6-independent hybridomas, resulting in reconstitution of the IL-6-dependent phenotype. We therefore conclude that chromosome 21 carries an IL-6 dependency gene.
Asunto(s)
Cromosomas Humanos Par 21/fisiología , Hibridomas , Interleucina-6/genética , Animales , Linfocitos B , División Celular/genética , Cromosomas Humanos Par 21/genética , Femenino , Humanos , Hibridomas/citología , Interleucina-6/fisiología , Cariotipificación , Ratones , FenotipoRESUMEN
Interphasic nuclear organization has a key function in genome biology. We demonstrate that p21WAF-1, by influencing gene expression and inducing chromosomal repositioning in tumor suppression, plays a major role as a nuclear organizer. Transfection of U937 tumor cells with p21WAF-1 resulted in expression of the HUMSIAH (human seven in absentia homologue), Rb, and Rbr-2 genes and strong suppression of the malignant phenotype. p21(WAF-1) drastically modified the compartmentalization of the nuclear genome. DNase I genome exposure and fluorescence in situ hybridization show, respectively, a displacement of the sensitive sites to the periphery of the nucleus and repositioning of chromosomes 13, 16, 17, and 21. These findings, addressing nuclear architecture modulations, provide potentially significant perspectives for the understanding of tumor suppression.
Asunto(s)
Núcleo Celular/fisiología , Transformación Celular Neoplásica/genética , Cromosomas/fisiología , Ciclinas/fisiología , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Cromosomas Humanos Par 13/fisiología , Cromosomas Humanos Par 16/fisiología , Cromosomas Humanos Par 17/fisiología , Cromosomas Humanos Par 21/fisiología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , Desoxirribonucleasa I/metabolismo , Humanos , Proteínas Nucleares , Fenotipo , Fosfoproteínas/biosíntesis , Fosfoproteínas/genética , Biosíntesis de Proteínas , Proteínas/genética , Proteína de Retinoblastoma/biosíntesis , Proteína de Retinoblastoma/genética , Proteína p130 Similar a la del Retinoblastoma , Transfección , Células Tumorales Cultivadas , Ubiquitina-Proteína LigasasRESUMEN
In order to define a functional human centromere sequence, an artificial chromosome was constructed as a reproducible DNA molecule. Mammalian telomere repeats and a selectable marker were introduced into yeast artificial chromosomes (YACs) containing alphoid DNA from the centromere region of human chromosome 21 in a recombination-deficient yeast host. When these modified YACs were introduced into cultured human cells, a YAC with the alphoid DNA from the alpha21-I locus, containing CENP-B boxes at a high frequency and a regular repeat array, efficiently formed minichromosomes that were maintained stably in the absence of selection and bound CENP-A, CENP-B, CENP-C and CENP-E. The minichromosomes, 1-5 Mb in size and composed of multimers of the introduced YAC DNA, aligned at metaphase plates and segregated to opposite poles correctly in anaphase. Extensive cytological analyses strongly suggested that the minichromosomes had not acquired host sequences and were formed in all cases by a de novo mechanism. In contrast, minichromosomes were never produced with a modified YAC containing alphoid DNA from the alpha21-II locus, which contains no CENP-B boxes and has a less regular sequence arrangement. We conclude that alpha21-I alphoid DNA can induce de novo assembly of active centromere/kinetochore structures on minichromosomes.
Asunto(s)
Autoantígenos , Centrómero/fisiología , Cromosomas Humanos Par 21/fisiología , Proteínas de Unión al ADN , Células Cultivadas , Proteína B del Centrómero , Proteínas Cromosómicas no Histona/fisiología , Segregación Cromosómica , Cromosomas Artificiales de Levadura , Clonación Molecular , Humanos , Hibridación Fluorescente in Situ , Cinetocoros , Proteínas Nucleares , Secuencias Repetitivas de Ácidos Nucleicos , Huso Acromático , Telómero , TransfecciónRESUMEN
Down syndrome (DS) is associated with mental retardation, immune disorders and congenital heart diseases. Although it is usually caused by the presence of an extra chromosome 21, a subset of the diagnostic phenotypic features may be caused by the presence of the band 21q22, called the "Down syndrome region". Many proteins important for the immune and nervous systems as CuZn-superoxide dismutase (SOD-1), CD18-beta chain of LFA-1, interferon receptor, APP-amyloid precursor protein, protein S-100 beta are coded by chromosome 21. Overexpression of these molecules may contribute to the thymic derangement that results in anomalous maturation leading to functionally impaired T cells. Many factors have been shown to contribute to the immune deficiency which results in high susceptibility to infections, high rate of malignancies, and autoimmune phenomena in persons with DS. The main disorders in the immune system include thymus abnormalities, changes in cell-mediated immunity, phagocytosis, antibodies-mediated immunity and a high prevalence of autoantibodies in persons with DS. Furthermore, the duplication of chromosome 21 genes may generate most of the pathological changes in the central nervous system. There is an increased prevalence of seizure disorders. Such widespread alterations in the cortical areas seem to account for specific impairments observed in short-term and long-term memory, language skills, and cognitive and learning processes. If all principles of optimal health care and adequate education were followed without exception for persons with DS, then the quality of their life could be improved significantly and they would be able to become productive citizens in the society. (Tab. 5, Fig. 3, Ref. 42.)
Asunto(s)
Cromosomas Humanos Par 21/fisiología , Síndrome de Down/genética , Expresión Génica , Inmunidad , Sistema Nervioso/fisiopatología , Cognición , Síndrome de Down/inmunología , Síndrome de Down/fisiopatología , Síndrome de Down/psicología , HumanosRESUMEN
Lymphocytes with different chromosome numbers (46,XX and 47,XX + 21) in cultures, were obtained from the blood of a mosaic of a Down's syndrome patient. Their distinctive susceptibility to chromosome damage induced by bleomycin radiomimetic was tested and compared with lymphocytes from healthy individuals. The test showed that the presence of an extra chromosome 21 occurred in parallel with the rise of an intrinsic basal rate of chromosome damage in trisomic cells.
Asunto(s)
Bleomicina/farmacología , Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 21/fisiología , Cromosomas Humanos/genética , Daño del ADN , Síndrome de Down/genética , Antimetabolitos Antineoplásicos/farmacología , Células Cultivadas/efectos de los fármacos , Células Cultivadas/fisiología , Trastornos de los Cromosomas , Daño del ADN/genética , Diploidia , Femenino , Humanos , Recién Nacido , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/fisiología , Mosaicismo , TrisomíaRESUMEN
The nonrandom chromosomal translocation t(8;21)(q22;q22) can be found frequently in acute myelogenous leukemia with maturation (AML-M2). The breakpoint of this translocation has been cloned and characterized, and fusion transcript AML1/ETO has been identified. Reverse transcription polymerase chain reaction (RT-PCR) can be used to amplify the breakpoint site of AML1/ETO in t(8;21)-positive AML-M2 patients. The chimeric transcript can be detected in all 16 (100%) t(8;21)-positive AML-M2 patients. In all samples, the size of the amplified DNA fragments and pattern of restriction digest were identical, indicating that the t(8;21) translocation breakpoint occurs within a single intron of the AML1 and ETO genes. Interestingly, this fusion transcript was also detected in one of 13 AML-M2 patients without the t(8;21) translocation, indicating that a masked translocation involving chromosomes 8 and 21, exists in AML. Minimal residual disease was detected by semi-nested RT-PCR in all four patients tested, who had been in complete remission for 12, 15, 34, and 52 months, respectively. These results indicate that RT-PCR amplification of the AML1/ETO fusion transcript is a powerful tool for diagnosing and monitoring minimal residual disease in AML-M2 patients.
Asunto(s)
Cromosomas Humanos Par 21/fisiología , Cromosomas Humanos Par 8/fisiología , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Transcripción Genética/genética , Translocación Genética/genética , Adolescente , Adulto , Anciano , Secuencia de Bases , Cartilla de ADN/genética , Femenino , Humanos , Intrones/genética , Cariotipificación , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa/métodos , ADN Polimerasa Dirigida por ARN/metabolismo , Proteínas Recombinantes de Fusión/genética , Sensibilidad y EspecificidadRESUMEN
The karyotype of a boy with acute lymphoblastic leukemia (ALL) presenting with numerical and structural chromosome aberrations as determined by Giemsa-banding was further investigated using chromosome painting (CP). A translocation t(11;18)(q23;q21) was verified by this approach, and gain of chromosome 21 material due to a structural rearrangement was detected. Moreover, an unbalanced translocation of the long arm of chromosome 1, resembling the well known translocation t(1;19), was demonstrated to involve chromosome 22 instead of chromosome 19. Immunophenotyping of the leukemic blasts led to the diagnosis common ALL (CD19+, CD10+, clg-). Our case indicates that in ALL a translocation t(1;19) may be mimicked by other chromosomal rearrangements, and that CP may efficiently complement conventional cytogenetics in the exact characterization of the involved chromosomes.
Asunto(s)
Cromosomas Humanos Par 19/fisiología , Cromosomas Humanos Par 1/fisiología , Cromosomas Humanos Par 22/fisiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética/genética , Niño , Aberraciones Cromosómicas , Cromosomas Humanos Par 11/fisiología , Cromosomas Humanos Par 18/fisiología , Cromosomas Humanos Par 21/fisiología , Sondas de ADN/genética , Reordenamiento Génico/genética , Humanos , Hibridación in Situ , Cariotipificación , MasculinoRESUMEN
Leukemic cells from an 8-year-old girl with ANLL-M2 expressed precursor B-cell antigen CD19, but none of the myeloid antigens CD11b, CD13, CD14 and CD33. After culture, the cells expressed CD11b and CD13. The cells carried a high number of granulocyte colony-stimulating factor (G-CSF) receptors. In chromosome analysis, metaphase cells were obtained only in the case of culture with G-CSF. The karyotype was a variant of t(8;21)(q22;q22). Southern blot analysis revealed rearrangement of the AMLI gene located on chromosome 21. These observations may suggest that even without myeloid surface antigens and with precursor B-cell antigen, ANLL-M2 with t(8;21)(q22;q22) has apparent myeloid characteristics.
Asunto(s)
Antígenos de Neoplasias/análisis , Cromosomas Humanos Par 21/fisiología , Cromosomas Humanos Par 8/fisiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Receptores de Factor Estimulante de Colonias de Granulocito/análisis , Translocación Genética/genética , Antígenos de Superficie/análisis , Médula Ósea/inmunología , Niño , Femenino , Humanos , Linfocitos/inmunologíaRESUMEN
A human cDNA corresponding to the porcine pancreatic spasmolytic protein (PSP) was isolated, and the recombinant clone was originally termed hSP for human spasmolytic protein. Later, the term SML1 for spasmolysin was suggested for the human gene. This protein shows a remarkable sequence homology to pS2, a protein coded by an estrogen-induced gene isolated from the breast carcinoma cell line MCF-7. Although, at the DNA level, the gene sequences pS2 and hSP/SML1 display insufficient homology for cross-hybridization, their expression in tumor cells occurs with remarkable coordination. The human pS2 gene sequence has been assigned to chromosome 21, and we have therefore attempted to map the hSP/SML1 gene by using cDNA and Southern blotting of genomic DNAs from a panel of human-rodent somatic cell hybrids carrying different complements of human chromosomes. Interestingly, the hSP/SML1 gene is also localized on chromosome 21.
Asunto(s)
Cromosomas Humanos Par 21/fisiología , Mucinas , Proteínas Musculares , Neuropéptidos , Péptidos/genética , Southern Blotting , Mapeo Cromosómico , Humanos , Células Híbridas , Péptidos y Proteínas de Señalización Intercelular , Factor Trefoil-2 , Factor Trefoil-3RESUMEN
Short of discovering how to silence selectively one of the 3 chromosomes 21, no rational medication can be envisaged before pathogenesis has been unraveled, at least partially. A biochemical scheme of impairment of mental efficiency is presented, and the possible deleterious effects of a given gene overdose are discussed. Cu/Zn SOD, cystathionine beta synthase, S 100 beta protein, phosphofructokinase, purine synthesis and adenosine pharmacology, thyroid disturbance, and elevated TSH with low rT3 as well as biopterin metabolism interferences are reviewed. These metabolic paths are tightly related by their effects, just as if synteny was in some way related to biochemical cooperation or mutual regulation. Experiments in vitro have demonstrated a peculiar sensitivity of trisomic 21 lymphocytes to methotrexate, and systematic research of special sensitivities has begun. Clinical observations and relevant statistical methods allow study of the speed of mental development under various medications. The interest of regulating thyroid metabolism, when needed, is exemplified. Re-equilibration of monocarbon metabolism is discussed and the seemingly favourable effect of folinic acid medication in pseudo Alzheimer complication is presented.