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1.
Acta Paediatr ; 93(4): 565-7, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15188991

RESUMEN

UNLABELLED: Subglottic stenosis in infants is mostly acquired (secondary) and caused by granulation tissue or submucosal mucous gland hyperplasia after prolonged endotracheal intubation. Subglottic stenosis may also be congenital (primary), and it usually occurs sporadically. There are some reports of its association with inherited anomalies, but there are no previous reports of its familial occurrence in otherwise healthy children. This report describes two pairs of siblings referred for acute inspiratory stridor in whom subglottic stenosis was diagnosed by endoscopy. They were all born at term, and their parents were unrelated. One child had an anteriorly located anus but no other abnormalities. CONCLUSION: Without any surgical intervention all had normal breathing at rest, but inspiratory stridor during respiratory infections and upon physical exercise at follow-up 4-9 y later.


Asunto(s)
Laringoestenosis/congénito , Femenino , Edad Gestacional , Glotis/anomalías , Glotis/patología , Humanos , Recién Nacido , Laringoscopía , Laringoestenosis/diagnóstico , Laringoestenosis/terapia , Masculino , Pruebas de Función Respiratoria , Hermanos
2.
J Med Genet ; 35(6): 513-8, 1998 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9643297

RESUMEN

We describe the clinical findings and biochemical features of a male child suffering from a so far undescribed lethal connective tissue disorder characterised by extreme hypermobility of the joints, lax skin, cataracts, severe growth retardation, and insufficient production of type I and type III procollagens. His features are compared with Ehlers-Danlos type IV, De Barsy syndrome, and geroderma osteodysplastica, as these disorders show some symptoms and signs shared with our patient. The child died because of failure of the connective tissue structures joining the skull and the spine, leading to progressive spinal stenosis. The aortic valve was translucent and insufficient. The clinical symptoms and signs, together with histological findings, suggested a collagen defect. Studies on both skin fibroblast cultures and the patient's serum showed reduced synthesis of collagen types I and III at the protein and RNA levels. The sizes of the mRNAs and newly synthesised proteins were normal, excluding gross structural abnormalities. These findings are not in accordance with any other collagen defect characterised so far.


Asunto(s)
Enfermedades del Colágeno/genética , Colágeno/genética , Enfermedades del Tejido Conjuntivo/genética , Adulto , Envejecimiento Prematuro , Células Cultivadas , Colágeno/biosíntesis , Enfermedades del Colágeno/diagnóstico , Enfermedades del Colágeno/metabolismo , Enfermedades del Tejido Conjuntivo/diagnóstico , Enfermedades del Tejido Conjuntivo/metabolismo , Diagnóstico Diferencial , Síndrome de Ehlers-Danlos/diagnóstico , Resultado Fatal , Femenino , Humanos , Lactante , Masculino , Fragmentos de Péptidos/sangre , Procolágeno/sangre , Piel/metabolismo , Piel/patología , Piel/ultraestructura
3.
DNA Cell Biol ; 17(2): 117-23, 1998 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9502428

RESUMEN

The type VI variant of Ehlers-Danlos syndrome (EDS) is a heritable connective tissue disorder caused by a deficiency in the activity of lysyl hydroxylase, an enzyme required for the post-translational processing of collagens. We have characterized a novel type of mutation in a young female patient with type VI EDS, in which cells possess only 12% of the lysyl hydroxylase activity that is detected in unaffected cells. The syndrome was found to be caused by a homozygous insertion of two thymidines at the 5' splice site consensus sequence of intron 9 in the lysyl hydroxylase gene. The insertion interfered with normal splicing of the primary RNA transcript and resulted in an inframe deletion of the 132 nucleotides coded by exon 9 from the lysyl hydroxylase mRNA. In addition, the mutation caused a marked reduction in the steady-state level of the truncated mRNA, which was less than 15% of the level found in unaffected cells. The mutation also reduced the amount of the enzyme protein produced, which was estimated to be about 20% of that in control cells. However, the mutation did not affect the stability of the abnormally spliced mRNA nor the normal localization of the enzyme protein in the endoplasmic reticulum. According to our results, the reduction in enzymatic activity observed in this patient is caused by low levels of both lysyl hydroxylase mRNA and enzyme protein. The primary cellular defect associated with this mutation, therefore, appears to be at the level of nuclear mRNA metabolism even though the mutation did not create a premature translation termination codon.


Asunto(s)
Codón sin Sentido , Síndrome de Ehlers-Danlos/genética , Exones , Mutación , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/genética , Empalme del ARN/genética , Análisis Mutacional de ADN , Síndrome de Ehlers-Danlos/enzimología , Femenino , Humanos , Recién Nacido , Mutagénesis Insercional , Linaje , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/metabolismo , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Piel/enzimología
4.
Am J Hum Genet ; 55(5): 899-906, 1994 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-7977351

RESUMEN

The type VI variant of the Ehlers-Danlos syndrome (EDS) is a recessively inherited connective-tissue disorder. The characteristic features of the variant are muscular hypotonia, kyphoscoliosis, ocular manifestations, joint hypermobility, skin fragility and hyperextensibility, and other signs of connective-tissue involvement. The biochemical defect in most but not all patients is a deficiency in lysyl hydroxylase activity. Lysyl hydroxylase is an enzyme that catalyzes the formation of hydroxylysine in collagens and other proteins with collagen-like amino acid sequences. We have recently reported an apparently homozygous large-duplication rearrangement in the gene for lysyl hydroxylase, leading to the type VI variant of EDS in two siblings. We now report an identical, apparently homozygous large duplication in an unrelated 49-year-old female originally analyzed by Sussman et al. Our simple-sequence-repeat-polymorphism analysis does not support uniparental isodisomy inheritance for either of the two duplications. Furthermore, we indicate in this study that the duplication in the lysyl hydroxylase gene is caused by an Alu-Alu recombination in both families. Cloning of the junction fragment of the duplication has allowed synthesis of appropriate primers for rapid screening for this rearrangement in other families with the type VI variant of EDS.


Asunto(s)
Síndrome de Ehlers-Danlos/genética , Exones/genética , Familia de Multigenes/genética , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/genética , Recombinación Genética/genética , Secuencia de Bases , Células Cultivadas , Dermatoglifia del ADN , Femenino , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Secuencias Repetitivas de Ácidos Nucleicos , Mapeo Restrictivo
5.
J Biol Chem ; 266(5): 2805-10, 1991 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-1704364

RESUMEN

Lysyl hydroxylase (EC 1.14.11.4), an alpha 2 dimer, catalyzes the formation of hydroxylysine in collagens by the hydroxylation of lysine residues in X-Lys-Gly sequences. We report here on the isolation of cDNA clones coding for the enzyme from a chick embryo lambda gt11 library. Several overlapping clones covering all the coding sequences of the 4-kilobase mRNA and virtually all the noncoding sequences were characterized. These clones encode a polypeptide of 710 amino acid residues and a signal peptide of 20 amino acids. The polypeptide has four potential attachment sites for asparagine-linked oligosaccharides and 9 cysteine residues, at least one of which is likely to be involved in the binding of the Fe2+ atom to a catalytic site. A surprising finding was that no significant homology was found between the primary structures of lysyl hydroxylase and prolyl 4-hydroxylase in spite of the marked similarities in kinetic properties between these two enzymes. A computer-assisted comparison indicated only an 18% identity between lysyl hydroxylase and the alpha-subunit of prolyl 4-hydroxylase and a 19% identity between lysyl hydroxylase and the beta-subunit of prolyl 4-hydroxylase. Visual inspection of the most homologous areas nevertheless indicated the presence of several regions of 20-40 amino acids in which the identity between lysyl hydroxylase and one of the prolyl 4-hydroxylase subunits exceeded 30% or similarity exceeded 40%. Southern blot analyses of chick genomic DNA indicated the presence of only one gene coding for lysyl hydroxylase.


Asunto(s)
Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/genética , Procolágeno-Prolina Dioxigenasa/genética , Homología de Secuencia de Ácido Nucleico , Secuencia de Aminoácidos , Animales , Northern Blotting , Southern Blotting , Pollos , ADN/genética , Datos de Secuencia Molecular , ARN/análisis , Mapeo Restrictivo
6.
Cytogenet Cell Genet ; 56(3-4): 165-8, 1991.
Artículo en Inglés | MEDLINE | ID: mdl-1647289

RESUMEN

Prolyl 4-hydroxylase, an alpha 2 beta 2 tetramer, catalyzes the formation of 4-hydroxyproline in collagens and related proteins by hydroxylating proline residues in peptide linkages. The beta-subunit of prolyl 4-hydroxylase (P4HB) is a highly unusual multifunctional polypeptide that is identical to the enzyme protein disulfide isomerase and a major cellular thyroid hormone-binding protein and is highly similar to a glycosylation site-binding polypeptide of oligosaccharyl transferase. We report here the regional assignment of the gene for this multifunctional polypeptide. In situ hybridization mapped the gene to 17q25. Southern blot analyses of restricted DNA from a chromosome-mediated gene transfer transfectant panel suggested that the P4HB gene is located distal to the gene for thymidine kinase, either between the genes for thymidine kinase and galactokinase or on the telomeric side of both these genes.


Asunto(s)
Cromosomas Humanos Par 17/ultraestructura , Isomerasas/genética , Procolágeno-Prolina Dioxigenasa/genética , Southern Blotting , Mapeo Cromosómico , Humanos , Hibridación de Ácido Nucleico , Proteína Disulfuro Isomerasas , Transfección
7.
J Biol Chem ; 265(20): 11413-6, 1990 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-1694844

RESUMEN

Mouse F9 teratocarcinoma stem cells differentiate in monolayer cultures in the presence of retinoic acid, dibutyryl cAMP, and isobutyl methylxanthine. This differentiation is associated with a marked increase in the synthesis rates and mRNA concentrations of basement membrane proteins such as type IV collagen. We report here that the differentiation also involves an increase of up to 50-fold in the concentrations of the mRNAs for the alpha and beta subunits of prolyl 4-hydroxylase, the enzyme required for the cotranslational and post-translational hydroxylation of proline residues in collagens. The time courses and magnitudes of increases in these two mRNA concentrations were similar to those observed in the same experiments for the mRNA of the alpha chain of type IV collagen. In the differentiated F9 cells the concentration of the alpha subunit mRNA was about 30% of the beta subunit mRNA concentration. Northern blot analyses indicated that the sizes of the alpha and beta subunit mRNAs in the differentiated mouse F9 cells are similar to those in human skin fibroblasts. The F9 cell differentiation system appears to provide a useful model for studies on the regulation of prolyl 4-hydroxylase synthesis.


Asunto(s)
Colágeno/genética , Regulación de la Expresión Génica , Genes , Procolágeno-Prolina Dioxigenasa/genética , ARN Mensajero/genética , Células Tumorales Cultivadas/citología , 1-Metil-3-Isobutilxantina/farmacología , Animales , Northern Blotting , Bucladesina/farmacología , Diferenciación Celular , Línea Celular , Sondas de ADN , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Cinética , Sustancias Macromoleculares , Ratones , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Teratoma , Tretinoina/farmacología , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismo
8.
Am J Hum Genet ; 45(6): 829-34, 1989 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-2556027

RESUMEN

Prolyl 4-hydroxylase, an alpha 2 beta 2 tetramer, catalyzes the formation of 4-hydroxyproline in collagens by the hydroxylation of proline residues in peptide linkages and plays a crucial role in the synthesis of these proteins. The gene for the beta-subunit of prolyl 4-hydroxylase has recently been mapped to the long arm of human chromosome 17, at band 17q25. We report here chromosomal localization of the gene for the catalytically and regulatorily important alpha-subunit of human prolyl 4-hydroxylase. Analysis of 24 rodent x human cell hybrids by Southern blotting with cDNA probes for the human alpha-subunit indicated complete cosegregation of the gene for the alpha-subunit with human chromosome 10. A cell hybrid containing only part of chromosome 10 mapped the gene to 10q11----qter. In situ hybridization mapped the gene to 10q21.3-23.1. The gene for the alpha-subunit is thus not physically linked to that for the beta-subunit of the enzyme.


Asunto(s)
Cromosomas Humanos Par 10 , Procolágeno-Prolina Dioxigenasa/genética , Animales , Southern Blotting , Catálisis , Mapeo Cromosómico , Cricetinae , ADN/genética , Humanos , Células Híbridas , Cariotipificación , Ratones
9.
Cytogenet Cell Genet ; 52(3-4): 190-3, 1989.
Artículo en Inglés | MEDLINE | ID: mdl-2630191

RESUMEN

The gene coding for the alpha 1 chain of human type XIII collagen. COL13A1, is assigned to chromosome region 10q11----qter by Southern blot hybridization of DNA from 24 human x rodent somatic cell hybrids using a cloned cDNA as probe. A number of previous reports indicate that 10 of the collagen genes are located on six autosomes, but no other collagen genes have been found on chromosome 10. The data therefore provide further evidence for the dispersion of members of the collagen gene family throughout the genome.


Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 10/ultraestructura , Colágeno/genética , Genes/genética , Animales , Southern Blotting , Cromosomas Humanos Par 10/análisis , Cricetinae , Cricetulus , ADN/análisis , ADN/genética , Sondas de ADN , Biblioteca Genómica , Humanos , Células Híbridas/citología , Células Híbridas/ultraestructura , Ratones , Hibridación de Ácido Nucleico
10.
Biochem J ; 253(2): 489-96, 1988 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-3140780

RESUMEN

Human placental lysyl hydroxylase gave two bands in SDS/polyacrylamide-slab-gel electrophoresis: a broad, diffuse, major band corresponding to an apparent Mr of 80,000-85,000, and a sharp minor band with Mr 78,000. Mouse and chick-embryo lysyl hydroxylases gave only the broad, diffuse band, whereas the sharp band could not be detected. Polyclonal antibodies were prepared to the two bands of the human enzyme separately, and monoclonal antibodies were prepared to the whole purified enzyme preparation. Both types of polyclonal antibody inhibited and precipitated the enzyme activity, and both stained the two polypeptide bands in immunoblotting after SDS/polyacrylamide-gel electrophoresis. Only one out of five monoclonal antibodies inhibited the enzyme activity, whereas they all precipitated the activity when studied with antibody coupled to Sepharose. All five monoclonal antibodies stained the whole broad band in immunoblotting, and at least three of them also stained the sharp band. Peptide maps produced from the two polypeptide species by digestion with Staphylococcus aureus V8 protease were highly similar. Experiments with endoglycosidase H demonstrated that the Mr-80,000-85,000 polypeptide contains asparagine-linked carbohydrate units, which are required for maximal lysyl hydroxylase activity. The data suggest that the lysyl hydroxylase dimer consists of only one type of monomer, the heterogeneity of which is due to differences in glycosylation.


Asunto(s)
Anticuerpos , Oxigenasas de Función Mixta , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa , Acetilglucosaminidasa , Animales , Anticuerpos Monoclonales , Embrión de Pollo , Electroforesis en Gel de Poliacrilamida , Femenino , Humanos , Inmunoelectroforesis , Sustancias Macromoleculares , Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidasa , Ratones , Oxigenasas de Función Mixta/inmunología , Oligosacáridos/farmacología , Mapeo Peptídico , Placenta/enzimología , Embarazo , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/inmunología , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/metabolismo
11.
Cytogenet Cell Genet ; 47(1-2): 37-41, 1988.
Artículo en Inglés | MEDLINE | ID: mdl-2833378

RESUMEN

The chromosomal location of the human gene coding for both the beta-subunit of prolyl 4-hydroxylase (P4HB) and the enzyme disulfide isomerase (PDI) was determined using mouse x human somatic cell hybrids and three different methods for identifying either the human P4HB/PDI protein or the respective gene: (1) immunoblotting with species-specific monoclonal antibodies; (2) radioimmunoassay with species-specific polyclonal antibodies; and (3) Southern blotting after cleavage of the DNA with EcoRI, HindIII, or BamHI, followed by hybridization with a mixture of two cDNA probes for human P4HB. All three methods gave identical data, demonstrating complete cosegregation of the human protein or its gene in all 17 cell hybrids tested with human chromosome 17. A cell hybrid lacking an intact chromosome 17 localized the gene to 17p11----qter.


Asunto(s)
Cromosomas Humanos Par 17 , Isomerasas/genética , Procolágeno-Prolina Dioxigenasa/genética , Animales , Anticuerpos Monoclonales/inmunología , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 17/ultraestructura , ADN/genética , Genes , Humanos , Células Híbridas , Isomerasas/inmunología , Ratones , Hibridación de Ácido Nucleico , Procolágeno-Prolina Dioxigenasa/inmunología , Proteína Disulfuro Isomerasas , Radioinmunoensayo
12.
J Immunol Methods ; 41(3): 343-9, 1981.
Artículo en Inglés | MEDLINE | ID: mdl-7229387

RESUMEN

A sensitive direct radioimmunoassay for the detection of H-Y antigen on human blood mononuclear leukocytes is described. The cells were incubated with antisera obtained by immunization of inbred female rats or mice with male cells and tissues. The bound antibodies were detected by 125I-labeled protein A. Results are expressed as cpm bound to the cells.


Asunto(s)
Antígeno H-Y/análisis , Leucocitos/inmunología , Radioinmunoensayo/métodos , Complejo Antígeno-Anticuerpo , Relación Dosis-Respuesta Inmunológica , Femenino , Humanos , Masculino , Proteína Estafilocócica A/inmunología
14.
Hum Genet ; 52(2): 157-67, 1979 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-511171

RESUMEN

This paper reports an attempt to determine whether the short arm of one of the X chromosomes in XX males is longer than normal. In a blind study comparing coded photomicrographs of 15 G-banded mitoses from each of five XX males and five control females, the results were ambiguous and somewhat contradictory, but gave the impression of, or were compatible with, an XXp+ phenomenon in at least two of the five XX males. Measurements of the X chromosomes from the above cells and, in addition, from 15 mitoses from each of six XXY males, failed to disclose any XXp+ phenomenon. Statistical analysis indicated that in the five XX males there was no difference in the lengths of the two Xp arms. The reasons for the apparent discrepancy between the results of ocular inspection and measurement are discussed. The putative heteromorphism might be an alteration in shape, staining intensity, or position of bands, neither of which necessarily leads to an increase in length. We conclude that our results do not indicate any XXp+ phenomenon in the five XX males tested. However, the presence or absence of XXp+ is not in itself evidence for or against interchange betweenthe X and Y in the paternal meiosis. Our results emphasize that the etiology of XX males is likely to be heterogeneous.


Asunto(s)
Aberraciones Cromosómicas Sexuales/genética , Cromosomas Sexuales , Cromosoma X , Femenino , Humanos , Cariotipificación , Masculino , Mitosis
16.
Cytogenet Cell Genet ; 18(3): 136-48, 1977.
Artículo en Inglés | MEDLINE | ID: mdl-405179

RESUMEN

A human-mouse hybrid, DUR 4 (Solomon et al., 1976), containing a human X/15 translocation chromosome and also chromosome 5, among other human chromosomes, was used in a double selection system to obtain hybrids of four different types: X/15+ 5+, X/15- 5+, X/15+, 5-. Standard positive and negative selection systems were used for the X chromosome, and negative selection for chromosome 5 was done with diphtheria toxin. The assignment of HEXB and presently only when both the X/15 chromosome and chromosome 5 were present. A "HEXA-like" band segregated with chromosome 15 (or X/15) but independently of chromosome 5. This component, unlike HEXA, does not contain human HEXbeta antigen.


Asunto(s)
Hexosaminidasas/análisis , Células Híbridas/enzimología , Animales , Células Cultivadas , Células Clonales , Electroforesis en Gel de Almidón , Fibroblastos/enzimología , Fibroblastos/inmunología , Humanos , Células Híbridas/inmunología , Inmunodifusión , Ratones , Translocación Genética
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