50 results on '"Hernández-Chico C"'
Search Results
2. Characterization of NF1 allele containing two nonsense mutations in exon 37 that segregates with neurofibromatosis type 1
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Hernández-Imaz, E, Campos, B, Rodríguez-Álvarez, F J, Abad, O, Melean, G, Gardenyes, J, Martín, Y, and Hernández-Chico, C
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- 2013
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3. The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor
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Bernal, S, Alías, L, Barceló, M J, Also-Rallo, E, Martínez-Hernández, R, Gámez, J, Guillén-Navarro, E, Rosell, J, Hernando, I, Rodríguez-Alvarez, F J, Borrego, S, Millán, J M, Hernández-Chico, C, Baiget, M, Fuentes-Prior, P, and Tizzano, E F
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- 2010
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4. Pendredʼs syndrome and non-syndromic DFNB4 deafness associated with the homozygous T410M mutation in the SLC26A4 gene in siblings
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Arellano, B, Pera, A, Ramírez-Camacho, R, Villamar, M, Trinidad, A, García, J R, Moreno, F, and Hernández-Chico, C
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- 2005
5. The X-linked IAP gene does not contribute to the clinical phenotype of spinal muscular atrophy
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Martín, Y, Valero, A, López-Terradas, J M, Marsal, C, and Hernández-Chico, C
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- 2000
6. Microcins
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Moreno, F., primary, Millán, J.L. San, additional, Hernández-Chico, C., additional, and Kolter, R., additional
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- 1995
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7. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation
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Koczkowska, M. (Magdalena), Callens, T. (Tom), Gomes, A. (Alicia), Sharp, A. (Angela), Chen, Y. (Yunjia), Hicks, A.D. (Alesha D.), Aylsworth, A.S. (Arthur S.), Azizi, A.A. (Amedeo A.), Basel, D.G. (Donald G.), Bellus, G. (Gary), Bird, L.M. (Lynne), Blazo, M. (Maria), Burke, L.W. (Leah W.), Cannon, A. (Ashley), Collins, F. (Felicity), DeFilippo, C. (Colette), Denayer, E. (Ellen), Digilio, M.C. (Maria), Dills, S.K. (Shelley K.), Dosa, L. (Laura), Greenwood, R.S. (Robert S.), Griffis, C. (Cristin), Gupta, P. (Punita), Hachen, R.K. (Rachel K.), Hernández-Chico, C. (Concepción), Janssens, S. (Sandra), Jones, K.J. (Kristi), Jordan, J.T. (Justin T.), Kannu, P. (Peter), Korf, B. (Bruce), Lewis, A.M. (Andrea M.), Listernick, R.H. (Robert H.), Lonardo, F. (Fortunato), Mahoney, M.J. (Maurice J.), Ojeda, M.M. (Mayra Martinez), McDougall, C. (Carey), Mendelsohn, N.J., Miller, D.T. (David T.), Mori, M. (Mari), Oostenbrink, R. (Rianne), Perreault, S. (Sebastien), Pierpont, M.E. (Mary Ella), Piscopo, C. (Carmelo), Pond, D.A. (Dinel A.), Randolph, L.M. (Linda M.), Rauen, K.A. (Katherine), Rednam, S. (Surya), Rutledge, S.L. (S. Lane), Saletti, V. (Veronica), Schaefer, G.B. (G. Bradley), Schorry, E.K. (Elizabeth K.), Scott, D.A., Shugar, A. (Andrea), Siqveland, E. (Elizabeth), Starr, L. (Lois), Syed, A. (Ashraf), Trapane, P.L. (Pamela L.), Ullrich, N.J. (Nicole J.), Wakefield, E.G. (Emily G.), Walsh, L.E. (Laurence E.), Wangler, M.F. (Michael F.), Zackai, E. (Elaine), Claes, K. (Kathleen), McDonald, M.T. (Marie), Wimmer, K. (Katharina), Thornton, A.S. (Andrew), De Luca, A. (Alessandro), Martin, Y. (Yolanda), Legius, E. (Eric), Messiaen, L.M. (Ludwine), Koczkowska, M. (Magdalena), Callens, T. (Tom), Gomes, A. (Alicia), Sharp, A. (Angela), Chen, Y. (Yunjia), Hicks, A.D. (Alesha D.), Aylsworth, A.S. (Arthur S.), Azizi, A.A. (Amedeo A.), Basel, D.G. (Donald G.), Bellus, G. (Gary), Bird, L.M. (Lynne), Blazo, M. (Maria), Burke, L.W. (Leah W.), Cannon, A. (Ashley), Collins, F. (Felicity), DeFilippo, C. (Colette), Denayer, E. (Ellen), Digilio, M.C. (Maria), Dills, S.K. (Shelley K.), Dosa, L. (Laura), Greenwood, R.S. (Robert S.), Griffis, C. (Cristin), Gupta, P. (Punita), Hachen, R.K. (Rachel K.), Hernández-Chico, C. (Concepción), Janssens, S. (Sandra), Jones, K.J. (Kristi), Jordan, J.T. (Justin T.), Kannu, P. (Peter), Korf, B. (Bruce), Lewis, A.M. (Andrea M.), Listernick, R.H. (Robert H.), Lonardo, F. (Fortunato), Mahoney, M.J. (Maurice J.), Ojeda, M.M. (Mayra Martinez), McDougall, C. (Carey), Mendelsohn, N.J., Miller, D.T. (David T.), Mori, M. (Mari), Oostenbrink, R. (Rianne), Perreault, S. (Sebastien), Pierpont, M.E. (Mary Ella), Piscopo, C. (Carmelo), Pond, D.A. (Dinel A.), Randolph, L.M. (Linda M.), Rauen, K.A. (Katherine), Rednam, S. (Surya), Rutledge, S.L. (S. Lane), Saletti, V. (Veronica), Schaefer, G.B. (G. Bradley), Schorry, E.K. (Elizabeth K.), Scott, D.A., Shugar, A. (Andrea), Siqveland, E. (Elizabeth), Starr, L. (Lois), Syed, A. (Ashraf), Trapane, P.L. (Pamela L.), Ullrich, N.J. (Nicole J.), Wakefield, E.G. (Emily G.), Walsh, L.E. (Laurence E.), Wangler, M.F. (Michael F.), Zackai, E. (Elaine), Claes, K. (Kathleen), McDonald, M.T. (Marie), Wimmer, K. (Katharina), Thornton, A.S. (Andrew), De Luca, A. (Alessandro), Martin, Y. (Yolanda), Legius, E. (Eric), and Messiaen, L.M. (Ludwine)
- Abstract
Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972
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- 2018
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8. The ΔF508 mutation and RFLP-linked loci in Spanish cystic fibrosis families
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Peral, B., Hernández-Chico, C., San Millán, J. L., Moreno, F., Granell, R., Molano, J., Carrasco, S., Tellería, J. J., and Devoto, M.
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- 1991
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9. Analysis of whole blood transcriptome of Spinal Muscular Atrophy patients using RNA-seq
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Benguría, A., Finotello, Francesca, Callejas, S., Álvarez, R., Sánchez Cabo, F., DI CAMILLO, Barbara, Hernández Chico, C., and Dopazo, A.
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- 2014
10. Molecular Testing for Fragile X: Analysis of 5062 Tests from 1105 Fragile X Families-Performed in 12 Clinical Laboratories in Spain
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Tejada MI, Glover G, MARTINEZ, F., Guitart M, de Diego-Otero Y, Fernández-Carvajal I, Ramos FJ, Hernández-Chico C, Pintado E, Rosell J, Calvo MT, Ayuso C, Ramos-Arroyo MA, Maortua H, and Milà M
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ALLELE ,FMR1 GENE ,DNA ANALYSIS ,INSTABILITY ,PREMUTATION ,CGG REPEAT ,DIRECT DIAGNOSIS ,EXPANSION ,FRAXA ,FEMALE - Abstract
Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45-54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55-59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of
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- 2014
11. Characterization ofNF1allele containing two nonsense mutations in exon 37 that segregates with neurofibromatosis type 1
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Hernández-Imaz, E, primary, Campos, B, additional, Rodríguez-Álvarez, FJ, additional, Abad, O, additional, Melean, G, additional, Gardenyes, J, additional, Martín, Y, additional, and Hernández-Chico, C, additional
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- 2012
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12. Analysis of the monomeric alphoid sequences in the pericentromeric region of human chromosome 7
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de la Puente, A., primary, Velasco, E., additional, Pérez Jurado, L.A., additional, Hernández-Chico, C., additional, van de Rijke, F.M., additional, Scherer, S.W., additional, Raap, A.K., additional, and Cruces, J., additional
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- 1998
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13. Enfermedad de Werdnig-Hoffmann. Primer diagnóstico prenatal en Cuba
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Rosich-Capablanca G, Moreno F, T Zaldívar-Vaillant, A M Acevedo-López, Hernández-Chico C, and Guerra-Badía R
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Fetus ,Pathology ,medicine.medical_specialty ,Mutation ,Muscle biopsy ,medicine.diagnostic_test ,business.industry ,Chromosome ,Prenatal diagnosis ,General Medicine ,Spinal muscular atrophy ,medicine.disease ,medicine.disease_cause ,medicine ,Microsatellite ,Neurology (clinical) ,business ,Gene - Abstract
INTRODUCTION Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by the degeneration of cells of the spinal cord. The gene was localized on chromosome 5q13 and exists in two almost identical forms, which are distinguished by the change of base on exones 7 and 8. Mutations of the gene of survival motoreneuron (SMN) are the cause of illness. CLINICAL CASE We report, for the first time in Cuba, the prenatal diagnosis of a type II SMA carrier, using molecular methods for direct detection of the mutation on exones 7 and 8 of the SMN gene, and haplo-identification with microsatellite markers of chromosome 5q as an indirect method. A sample of amniotic liquid was taken at 18 weeks of gestation and the DNA extracted. No deletions were detected on exones 7 and 8 of the foetal DNA, which was therefore normal. CONCLUSIONS Detection of deletions on the SMN gene is a method which permits detection of the condition (healthy or unhealthy) of the foetus, quickly and reliably, without requiring investigation of the entire family to obtain a result. The method does not require radio-active PCR, the results are clear and precise and may be obtained within 24 hours. It may also take the place of invasive methods such as muscle biopsy and electro-myography and contribute to genetic assessment in families in which there is no DNA of the affected child.
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- 1999
14. Dinucleotide repeat polymorphisms at the D5S1356, D5S1357 and D7S1480 loci
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Velasco, E., primary, de la Puente, A., additional, Cruces, J., additional, Valero, M. del Carmen, additional, Garcfa-Patino, E., additional, Castillo, l.del, additional, Coloma, A., additional, Moren, F., additional, and Hernández-Chico, C., additional
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- 1994
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15. A hisT::Tn5 mutation affects production of microcins B17, C7, and H47 and colicin V
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Rodríguez-Sáinz, M C, primary, Hernández-Chico, C, additional, and Moreno, F, additional
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- 1991
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16. The peptide antibiotic microcin B17 induces double-strand cleavage of DNA mediated by E. coli DNA gyrase.
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Vizán, J. L., primary, Hernández-Chico, C., additional, del Castillo, I., additional, and Moreno, F., additional
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- 1991
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17. Molecular characterization of pmbA, an Escherichia coli chromosomal gene required for the production of the antibiotic peptide MccB17
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Rodríguez‐Sáinz, M. C., primary, Hernández‐Chico, C., additional, and Moreno, F., additional
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- 1990
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18. Linkage disequilibrium between four intragenic polymorphic microsatellites of the NF1 gene and its implications for genetic counselling.
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Valero, M C, Velasco, E, Valero, A, Moreno, F, and Hernández-Chico, C
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Four intragenic polymorphic microsatellite markers, AAAT Alu repeat, IVS27AC28.4, ACI27.2, and IVS38GT53.0, located along a 65 kb DNA region of the NF1 gene, were used to genotype 64 Spanish families with neurofibromatosis type 1 (NF1). Linkage disequilirium between each pair of markers was evaluated. Three of these markers, AAAT Alu repeat, ACI27.2, and IVS38GT53.0, exhibit linkage disequilibrium between each other. Analysis of extended haplotypes provides further evidence of the disequilibrium within this region since only 11 haplotypes account for 52% of the total chromosomes. Because of linkage disequilibrium, the informativeness of marker combinations for genotyping of NF1 families is diminished. There was no difference in the overall distribution of alleles between affected and normal chromosomes. An at risk haplotype was not found, as expected for a disease with at least 50% of cases being sporadic. [ABSTRACT FROM PUBLISHER]
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- 1996
19. Pendred's syndrome and non-syndromic DFNB4 deafness associated with the homozygous T410M mutation in theSLC26A4gene in siblings.
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Arellano, B., Pera, A., Ramírez-Camacho, R., Villamor, M., Trinidad, A., Garcia, J. R., Moreno, F., and Hernández-Chico, C.
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LETTERS to the editor ,DEAFNESS - Abstract
Presents a letter to the editor regarding Pendred's syndrome.
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- 2005
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20. Induction of a growth‐phase‐dependent promoter triggers transcription of bolA, an Escherichia coli morphogene.
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Aldea, M., Garrido, T., Hernández‐Chico, C., Vicente, M., and Kushner, S.R.
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The bolA gene, which is involved in the morphogenetic pathways of Escherichia coli, was sequenced and two potential promoters were identified. Expression from promoter P1, proximal to the bolA structural gene is specifically induced during the transition to the stationary phase of growth. This promoter contains an unusual‐‐10 region (CGGCTAGTA), which defines a new class of E. coli promoters necessary for the dramatic increase in the rate of synthesis of a large set of proteins during the cessation of logarithmic growth. This conclusion was confirmed by identifying two additional E. coli promoters and one plasmid promoter, which also were induced during the transition to the stationary phase of growth. Analysis of proteins produced during the exponential and stationary phases of growth in a bolA null mutant suggest a possible role for the BolA protein in the induction of the expression of penicillin‐binding protein 6 (PBP6) in the transition to the stationary phase. Supporting this hypothesis is the presence of a putative DNA‐binding domain within the bolA coding sequence.
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- 1989
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21. Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of cBCD541 and SMA phenotype.
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Velasco, E, Valero, C, Valero, A, Moreno, F, and Hernández-Chico, C
- Abstract
Spinal muscular atrophy is an autosomal recessive disorder which affects about 1 in 10,000 individuals. The three clinical forms of SMA were mapped to the 5q13 region. Three candidate genes have been isolated and shown to be deleted in SMA patients: the Survival Motor Neuron gene (SMN), the Neuronal Apoptosis Inhibitory Protein gene (NAIP) and the XS2G3 cDNA. In this report we present the molecular analysis of the SMN exons 7 and 8 and NAIP exon 5 in 65 Spanish SMA families. NAIP was mostly deleted in type I patients (67.9%) and SMN was deleted in 92.3% of patients with severe and milder forms. Most patients who lacked the NAIP gene also lacked the SMN gene, but we identified one type II patient deleted for NAIP exon 5 but not for SMN exons 7 and 8. Two other patients carried deletions of NAIP exon 5 and SMN exon 7 but retained the SMN exon 8. Three polymorphic variants from the SMN gene, showing changes on the sequence of the centromeric (cBCD541) and telomeric copies of the SMN gene, were found. In addition, we show several genetic rearrangements of the telomeric SMN gene, which include duplication of this gene in one normal chromosome, and putative gene conversion events in affected and normal chromosomes. Altogether these results corroborate the high genetic variability of the SMA region. Finally, we have determined the ratio between the number of centromeric and telomeric copies of the SMN gene in parents of SMA patients, showing that the majority of parents of types II and III patients carried three or more copies of the cBCD541 gene; we suggest a relationship between the number of copies of cBCD541 and the disease phenotype.
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- 1996
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22. Microcin B17, a novel tool for preparation of maxicells: identification of polypeptides encoded by the IncFII minireplicon pMccB17
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Mayo, O, Hernández-Chico, C, and Moreno, F
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The DNA replication inhibitor peptide microcin B17 is shown to be a useful tool for preparing Escherichia coli maxicells. To illustrate its usefulness, we have identified polypeptides synthesized from pMccB17 and R100 IncFII miniplasmids. After comparing the respective polypeptides and the miniplasmid restriction maps, we concluded that these plasmids share extensive homology in the basic replicon but are different for an adjacent region (parD) that is involved in plasmid stability and maintenance.
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- 1988
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23. Identification, cloning, and expression of bolA, an ftsZ-dependent morphogene of Escherichia coli
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Aldea, M, Hernández-Chico, C, de la Campa, A G, Kushner, S R, and Vicente, M
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A newly found morphogene of Escherichia coli, bolA, mapping at min 10 of the genetic map, was cloned in a 7.2-kilobase BamHI fragment and identified by its ability to produce osmotically stable spherical cells when overexpressed. This gene codes for a polypeptide of 13 kilodaltons. Overexpression of bolA+ was achieved in low-copy-number vectors with operon fusions to the tet and lac promoters, indicating a clockwise direction of transcription. While no modification of any of the penicillin-binding proteins was observed, morphological effects due to overexpression of bolA+ were shown to be dependent on the presence of an active ftsZ gene product. Our results suggest the existence of a mechanism mediated by FtsZ for modifying the conformation of nascent murein in the early steps of septum formation.
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- 1988
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24. Growth phase and ompR regulation of transcription of microcin B17 genes
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Hernández-Chico, C, San Millán, J L, Kolter, R, and Moreno, F
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The synthesis of the peptide antibiotic microcin B17 was shown to occur as the cells entered the stationary phase of growth. This type of growth phase regulation is commonly observed in the production of a number of different bacterial products such as toxins and antibiotics. Microcin B17 synthesis is also dependent on the product of the ompR gene. To determine the role of transcription in this double regulation of microcin B17 production, operon fusions with Mu d1 (Ap lac) were constructed. Insertions were obtained in all four plasmid genes involved in production of microcin B17 (mcbA-D) and in the immunity region. Three classes of fusions were obtained. Fusions into mcbA, mcbB, and mcbC (first class) exhibited an increase in their transcription as the cells approached the stationary phase. These increases as well as basal levels of transcription were dependent on OmpR. Expression of fusions in mcbD and in the immunity region (second class) was also dependent on OmpR, but their expression remained constant throughout growth. One fusion in mcbC (third class) was obtained which was transcribed in the opposite direction than the others. It showed no growth phase regulation and no OmpR dependence. The implications of these results in terms of the transcriptional organization of the mbc genes are discussed.
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- 1986
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25. Gene ompR and regulation of microcin 17 and colicin e2 syntheses
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Hernández-Chico, C, Herrero, M, Rejas, M, San Millán, J L, and Moreno, F
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The production of microcin 17 is controlled by plasmid pRYC17. Chromosomal mutants unable to produce a normal amount of microcin were isolated in Escherichia coli. One of the mutations maps in the ompR locus, indicating that an active OmpR product is required for the synthesis of microcin 17. The same conclusion was obtained for the synthesis of colicin E2. Therefore, two new functions of the regulatory gene ompR have been revealed.
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- 1982
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26. Monozygotic twins with Neurofibromatosis type 1, concordant phenotype and synchronous development of MPNST and metastasis
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Melean German, Hernández Alba, Valero María, Hernández-Imaz Elisabete, Martín Yolanda, and Hernández-Chico Concepción
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Neurofibromatosis type 1 is a common autosomal dominant disorder with full penetrance and variable expression. The condition predisposes individuals to the development of malignant nervous system tumours, most frequently Malignant Peripheral Nerve Sheath Tumours (MPNSTs). Previous studies indicate that genetic factors other than mutations in NF1 may be responsible for the condition's variable expression. Case report Here we present data from a pair of monozygotic twins affected by Neurofibromatosis type 1 resulting from a de novo mutation. Both twins developed a left sciatic plexiform neurofibroma that evolved into MPNST at a similar age and they also developed pulmonary metastasis at the same age. Other concordant traits between the twins were: macrocephaly, psychomotor delay, café-au-lait spots, cutaneous neurofibromas, retroperitoneal, pleural and paraspinal neurofibromas. The main discordant features observed were tibial pseudoarthrosis, pectus carinatum, osteoporosis and thymus hyperplasia. Conclusions This is the first report of monozygotic twins with Neurofibromatosis type 1 that develop MPNSTs, the localization and chronological evolution of which, and its metastasis, is concordant in both twins. These cases suggest that the events involved in the transformation of benign plexiform neurofibromas to MPNSTs in Neurofibromatosis type 1, follow a spatiotemporally programme that is influenced by heritable factors other than NF1 mutations.
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- 2010
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27. Neurofibromatosis type 1 families with first-degree relatives harbouring distinct NF1 pathogenic variants. Genetic counselling and familial diagnosis: what should be offered?
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Garcia B, Catasus N, Ros A, Rosas I, Negro A, Guerrero-Murillo M, Valero AM, Duat-Rodriguez A, Becerra JL, Bonache S, Lázaro Garcia C, Comas C, Bielsa I, Serra E, Hernández-Chico C, Martin Y, Castellanos E, and Blanco I
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- Genes, Neurofibromatosis 1, Genetic Counseling, Genetic Testing, Humans, Male, Neurofibromin 1 genetics, Neurofibromatosis 1 diagnosis, Neurofibromatosis 1 epidemiology, Neurofibromatosis 1 genetics
- Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in NF1 Recently, NF1 testing has been included as a clinical criterion for NF1 diagnosis. Additionally, preconception genetic counselling in patients with NF1 focuses on a 50% risk of transmitting the familial variant as the risk of having a sporadic NF1 is considered the same as the general population., Methods: 829 individuals, 583 NF1 sporadic cases and 246 patients with NF1 with documented family history, underwent genetic testing for NF1. Genotyping and segregation analysis of NF1 familial variants was determined by microsatellite analysis and NF1 sequencing., Results: The mutational analysis of NF1 in 154 families with two or more affected cases studied showed the co-occurrence of two different NF1 germline pathogenic variants in four families. The estimated mutation rate in those families was 3.89×10
-3 , 20 times higher than the NF1 mutation rate (~2×10-4 ) (p=0.0008). Furthermore, the co-occurrence of two different NF1 germline pathogenic variants in these families was 1:39, 60 times the frequency of sporadic NF1 (1:2500) (p=0.003). In all cases, the de novo NF1 pathogenic variant was present in a descendant of an affected male. In two cases, variants were detected in the inherited paternal wild-type allele., Conclusions: Our results, together with previous cases reported, suggest that the offspring of male patients with NF1 could have an increased risk of experiencing de novo NF1 pathogenic variants. This observation, if confirmed in additional cohorts, could have relevant implications for NF1 genetic counselling, family planning and NF1 genetic testing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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28. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.
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Koczkowska M, Callens T, Chen Y, Gomes A, Hicks AD, Sharp A, Johns E, Uhas KA, Armstrong L, Bosanko KA, Babovic-Vuksanovic D, Baker L, Basel DG, Bengala M, Bennett JT, Chambers C, Clarkson LK, Clementi M, Cortés FM, Cunningham M, D'Agostino MD, Delatycki MB, Digilio MC, Dosa L, Esposito S, Fox S, Freckmann ML, Fauth C, Giugliano T, Giustini S, Goetsch A, Goldberg Y, Greenwood RS, Griffis C, Gripp KW, Gupta P, Haan E, Hachen RK, Haygarth TL, Hernández-Chico C, Hodge K, Hopkin RJ, Hudgins L, Janssens S, Keller K, Kelly-Mancuso G, Kochhar A, Korf BR, Lewis AM, Liebelt J, Lichty A, Listernick RH, Lyons MJ, Maystadt I, Martinez Ojeda M, McDougall C, McGregor LK, Melis D, Mendelsohn N, Nowaczyk MJM, Ortenberg J, Panzer K, Pappas JG, Pierpont ME, Piluso G, Pinna V, Pivnick EK, Pond DA, Powell CM, Rogers C, Ruhrman Shahar N, Rutledge SL, Saletti V, Sandaradura SA, Santoro C, Schatz UA, Schreiber A, Scott DA, Sellars EA, Sheffer R, Siqveland E, Slopis JM, Smith R, Spalice A, Stockton DW, Streff H, Theos A, Tomlinson GE, Tran G, Trapane PL, Trevisson E, Ullrich NJ, Van den Ende J, Schrier Vergano SA, Wallace SE, Wangler MF, Weaver DD, Yohay KH, Zackai E, Zonana J, Zurcher V, Claes KBM, Eoli M, Martin Y, Wimmer K, De Luca A, Legius E, and Messiaen LM
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- Amino Acid Substitution, Cross-Sectional Studies, Heterozygote, Humans, Phenotype, Alleles, Genetic Association Studies, Genetic Predisposition to Disease, Mutation, Missense, Neurofibromatosis 1 diagnosis, Neurofibromatosis 1 genetics, Neurofibromin 1 genetics
- Abstract
We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)
- Published
- 2020
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29. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.
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Koczkowska M, Callens T, Gomes A, Sharp A, Chen Y, Hicks AD, Aylsworth AS, Azizi AA, Basel DG, Bellus G, Bird LM, Blazo MA, Burke LW, Cannon A, Collins F, DeFilippo C, Denayer E, Digilio MC, Dills SK, Dosa L, Greenwood RS, Griffis C, Gupta P, Hachen RK, Hernández-Chico C, Janssens S, Jones KJ, Jordan JT, Kannu P, Korf BR, Lewis AM, Listernick RH, Lonardo F, Mahoney MJ, Ojeda MM, McDonald MT, McDougall C, Mendelsohn N, Miller DT, Mori M, Oostenbrink R, Perreault S, Pierpont ME, Piscopo C, Pond DA, Randolph LM, Rauen KA, Rednam S, Rutledge SL, Saletti V, Schaefer GB, Schorry EK, Scott DA, Shugar A, Siqveland E, Starr LJ, Syed A, Trapane PL, Ullrich NJ, Wakefield EG, Walsh LE, Wangler MF, Zackai E, Claes KBM, Wimmer K, van Minkelen R, De Luca A, Martin Y, Legius E, and Messiaen LM
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Learning Disabilities physiopathology, Male, Mutation, Missense genetics, Neurofibroma, Plexiform physiopathology, Neurofibromatosis 1 pathology, Sequence Deletion, Young Adult, Learning Disabilities genetics, Neurofibroma, Plexiform genetics, Neurofibromatosis 1 genetics, Neurofibromin 1 genetics
- Abstract
Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors., Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study., Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del., Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
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- 2019
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30. Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.
- Author
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Koczkowska M, Callens T, Gomes A, Sharp A, Chen Y, Hicks AD, Aylsworth AS, Azizi AA, Basel DG, Bellus G, Bird LM, Blazo MA, Burke LW, Cannon A, Collins F, DeFilippo C, Denayer E, Digilio MC, Dills SK, Dosa L, Greenwood RS, Griffis C, Gupta P, Hachen RK, Hernández-Chico C, Janssens S, Jones KJ, Jordan JT, Kannu P, Korf BR, Lewis AM, Listernick RH, Lonardo F, Mahoney MJ, Ojeda MM, McDonald MT, McDougall C, Mendelsohn N, Miller DT, Mori M, Oostenbrink R, Perreault S, Pierpont ME, Piscopo C, Pond DA, Randolph LM, Rauen KA, Rednam S, Rutledge SL, Saletti V, Schaefer GB, Schorry EK, Scott DA, Shugar A, Siqveland E, Starr LJ, Syed A, Trapane PL, Ullrich NJ, Wakefield EG, Walsh LE, Wangler MF, Zackai E, Claes KBM, Wimmer K, van Minkelen R, De Luca A, Martin Y, Legius E, and Messiaen LM
- Abstract
A correction has been published to this Article. The PDF and HTML have been updated accordingly.
- Published
- 2019
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31. Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases.
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Calucho M, Bernal S, Alías L, March F, Venceslá A, Rodríguez-Álvarez FJ, Aller E, Fernández RM, Borrego S, Millán JM, Hernández-Chico C, Cuscó I, Fuentes-Prior P, and Tizzano EF
- Subjects
- Databases, Genetic, Female, Gene Dosage, Genetic Predisposition to Disease, Genotype, Humans, Male, Mutation, Phenotype, Prognosis, Spain, Survival of Motor Neuron 2 Protein genetics, DNA Copy Number Variations, Genetic Association Studies, Muscular Atrophy, Spinal genetics
- Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss or mutations in SMN1. According to age of onset, achieved motor abilities, and life span, SMA patients are classified into type I (never sit), II (never walk unaided) or III (achieve independent walking abilities). SMN2, the highly homologous copy of SMN1, is considered the most important phenotypic modifier of the disease. Determination of SMN2 copy number is essential to establish careful genotype-phenotype correlations, predict disease evolution, and to stratify patients for clinical trials. We have determined SMN2 copy numbers in 625 unrelated Spanish SMA patients with loss or mutation of both copies of SMN1 and a clear assignation of the SMA type by clinical criteria. Furthermore, we compiled data from relevant worldwide reports that link SMN2 copy number with SMA severity published from 1999 to date (2834 patients with different ethnic and geographic backgrounds). Altogether, we have assembled a database with a total of 3459 patients to delineate more universal prognostic rules regarding the influence of SMN2 copy number on SMA phenotype. This issue is crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatments., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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32. Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.
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Koczkowska M, Chen Y, Callens T, Gomes A, Sharp A, Johnson S, Hsiao MC, Chen Z, Balasubramanian M, Barnett CP, Becker TA, Ben-Shachar S, Bertola DR, Blakeley JO, Burkitt-Wright EMM, Callaway A, Crenshaw M, Cunha KS, Cunningham M, D'Agostino MD, Dahan K, De Luca A, Destrée A, Dhamija R, Eoli M, Evans DGR, Galvin-Parton P, George-Abraham JK, Gripp KW, Guevara-Campos J, Hanchard NA, Hernández-Chico C, Immken L, Janssens S, Jones KJ, Keena BA, Kochhar A, Liebelt J, Martir-Negron A, Mahoney MJ, Maystadt I, McDougall C, McEntagart M, Mendelsohn N, Miller DT, Mortier G, Morton J, Pappas J, Plotkin SR, Pond D, Rosenbaum K, Rubin K, Russell L, Rutledge LS, Saletti V, Schonberg R, Schreiber A, Seidel M, Siqveland E, Stockton DW, Trevisson E, Ullrich NJ, Upadhyaya M, van Minkelen R, Verhelst H, Wallace MR, Yap YS, Zackai E, Zonana J, Zurcher V, Claes K, Martin Y, Korf BR, Legius E, and Messiaen LM
- Subjects
- Adolescent, Amino Acid Sequence, Child, Cohort Studies, Computer Simulation, Demography, Female, Heterozygote, Humans, Male, Neurofibromin 1 chemistry, Phenotype, Young Adult, Codon genetics, Genetic Association Studies, Mutation, Missense genetics, Neurofibromatosis 1 genetics, Neurofibromin 1 genetics
- Abstract
Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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33. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.
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Rojnueangnit K, Xie J, Gomes A, Sharp A, Callens T, Chen Y, Liu Y, Cochran M, Abbott MA, Atkin J, Babovic-Vuksanovic D, Barnett CP, Crenshaw M, Bartholomew DW, Basel L, Bellus G, Ben-Shachar S, Bialer MG, Bick D, Blumberg B, Cortes F, David KL, Destree A, Duat-Rodriguez A, Earl D, Escobar L, Eswara M, Ezquieta B, Frayling IM, Frydman M, Gardner K, Gripp KW, Hernández-Chico C, Heyrman K, Ibrahim J, Janssens S, Keena BA, Llano-Rivas I, Leppig K, McDonald M, Misra VK, Mulbury J, Narayanan V, Orenstein N, Galvin-Parton P, Pedro H, Pivnick EK, Powell CM, Randolph L, Raskin S, Rosell J, Rubin K, Seashore M, Schaaf CP, Scheuerle A, Schultz M, Schorry E, Schnur R, Siqveland E, Tkachuk A, Tonsgard J, Upadhyaya M, Verma IC, Wallace S, Williams C, Zackai E, Zonana J, Lazaro C, Claes K, Korf B, Martin Y, Legius E, and Messiaen L
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Dwarfism genetics, Female, Genetic Association Studies, Humans, Infant, Male, Middle Aged, Neurofibromin 1 chemistry, Young Adult, Amino Acid Substitution, Codon, Mutation, Missense, Neurofibromin 1 genetics, Noonan Syndrome diagnosis, Noonan Syndrome genetics, Phenotype
- Abstract
Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients., (© 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)
- Published
- 2015
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34. Functional Analysis of Mutations in Exon 9 of NF1 Reveals the Presence of Several Elements Regulating Splicing.
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Hernández-Imaz E, Martín Y, de Conti L, Melean G, Valero A, Baralle M, and Hernández-Chico C
- Subjects
- Alternative Splicing, Base Sequence, Cell Line, Heterogeneous Nuclear Ribonucleoprotein A1, Heterogeneous-Nuclear Ribonucleoprotein Group A-B metabolism, Humans, Molecular Sequence Data, Protein Binding, RNA Splice Sites, Ribonucleoproteins metabolism, Exons, Genes, Neurofibromatosis 1, Mutation, RNA Splicing, Regulatory Sequences, Nucleic Acid
- Abstract
Neurofibromatosis type 1 (NF1) is one of the most common human hereditary disorders, predisposing individuals to the development of benign and malignant tumors in the nervous system, as well as other clinical manifestations. NF1 is caused by heterozygous mutations in the NF1 gene and around 25% of the pathogenic changes affect pre-mRNA splicing. Since the molecular mechanisms affected by these mutations are poorly understood, we have analyzed the splicing mutations identified in exon 9 of NF1, which is particularly prone to such changes, to better define the possible splicing regulatory elements. Using a minigene approach, we studied the effect of five splicing mutations in this exon described in patients. These highlighted three regulatory motifs within the exon. An in vivo splicing analysis of an extensive collection of changes generated in the minigene demonstrated that the CG motif at c.910-911 is critical for the recognition of exon 9. We also found that the GC motif at c.945-946 is involved in exon recognition through SRSF2 and that this motif is part of a Composite Exon Splicing Regulatory Element made up of physically overlapping enhancer and silencer elements. Finally, through an in vivo splicing analysis and in vitro binding assays, we demonstrated that the c.1007G>A mutation creates an Exonic Splicing Silencer element that binds the hnRNPA1 protein. The complexity of the splicing regulatory elements present in exon 9 is most likely responsible for the fact that mutations in this region represent 25% of all exonic changes that affect splicing in the NF1 gene.
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- 2015
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35. RNA-based analysis of two SMARCB1 mutations associated with familial schwannomatosis with meningiomas.
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Melean G, Velasco A, Hernández-Imaz E, Rodríguez-Álvarez FJ, Martín Y, Valero A, and Hernández-Chico C
- Subjects
- Adult, Child, Female, Germ-Line Mutation, Humans, Infant, Newborn, Magnetic Resonance Imaging methods, Male, Models, Genetic, Pedigree, Protein Isoforms, RNA metabolism, RNA Splicing, RNA, Messenger metabolism, SMARCB1 Protein, Tomography, X-Ray Computed methods, Chromosomal Proteins, Non-Histone genetics, DNA-Binding Proteins genetics, Meningeal Neoplasms genetics, Meningioma genetics, Mutation, Neurilemmoma genetics, Neurofibromatoses genetics, Skin Neoplasms genetics, Transcription Factors genetics
- Abstract
Germline mutations in the SMARCB1 gene cause familial schwannomatosis, a condition characterized by the presence of multiple schwannomas, although mutations in SMARCB1 have also been associated with rhadboid tumor predisposition syndrome 1 (RTPS1). Both schwannomatosis and RTPS1 are autosomal dominant conditions that predispose individuals to develop distinct types of tumors. We clinically and genetically characterized two families with schwannomatosis associated with SMARCB1 mutations. Eight affected members of these families developed different numbers of schwannomas and/or meningiomas at distinct ages, evidence that meningiomas are variably expressed in this condition. We identified two germline mutations in SMARCB1 associated with the familial disease, c.233-1G>A and the novel c.207_208dupTA mutation, which both proved to affect the main SMARCB1 isoforms at the RNA level distinctly. Interestingly, the c.207_208dupTA mutation had no effect on the coding sequence, pre-mRNA splicing or the level of expression of the SMARCB1 isoform 2. Furthermore, SMARCB1 isoforms harboring a premature termination codon were largely eliminated via the nonsense-mediated mRNA decay pathway. Our results highlight the importance of RNA-based studies to characterize SMARCB1 germline mutations in order to determine their impact on protein expression and gain further insight into the genetic basis of conditions associated with SMARCB1 mutations.
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- 2012
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36. Progress and challenges in developing a molecular diagnostic test for neurofibromatosis type 1.
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Martín Y, Dopazo A, and Hernández-Chico C
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- Humans, Neurofibromatosis 1 genetics, Neurofibromin 1 genetics, Molecular Diagnostic Techniques, Neurofibromatosis 1 diagnosis
- Published
- 2011
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37. Accuracy of marker analysis, quantitative real-time polymerase chain reaction, and multiple ligation-dependent probe amplification to determine SMN2 copy number in patients with spinal muscular atrophy.
- Author
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Alías L, Bernal S, Barceló MJ, Also-Rallo E, Martínez-Hernández R, Rodríguez-Alvarez FJ, Hernández-Chico C, Baiget M, and Tizzano EF
- Subjects
- Genetic Markers genetics, Humans, Infant, Ligase Chain Reaction standards, Microsatellite Repeats genetics, Models, Biological, Multiplex Polymerase Chain Reaction standards, Muscular Atrophy, Spinal diagnosis, Pedigree, Real-Time Polymerase Chain Reaction standards, Reproducibility of Results, Sensitivity and Specificity, Survival of Motor Neuron 2 Protein genetics, Gene Dosage, Ligase Chain Reaction methods, Multiplex Polymerase Chain Reaction methods, Muscular Atrophy, Spinal genetics, Real-Time Polymerase Chain Reaction methods
- Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by absence of or mutations in the survival motor neuron1 gene (SMN1). All SMA patients have a highly homologous copy of SMN1, the SMN2 gene. Severe (type I) SMA patients present one or two SMN2 copies, whereas milder chronic forms (type II-III) usually have three or four SMN2 copies. SMN2 dosage is important to stratify patients for motor function tests and clinical trials. Our aim was to compare three methods, marker analysis, real-time quantitative polymerase chain reaction using the LightCycler instrument, and multiple ligation-dependent probe amplification (MLPA), to characterize their accuracy in quantifying SMN2 genes. We studied a group of 62 genetically confirmed SMA patients, 54 with homozygous absence of exons 7 and 8 of SMN1 and 8 with SMN2-SMN1 hybrid genes. A complete correlation using the three methods was observed in 32 patients (51.6%). In the remaining 30 patients, discordances between the three methods were found, including under or overestimation of SMN2 copies by marker analysis with respect to the quantitative methods (LightCycler and MLPA) because of lack of informativeness of markers, 3' deletions of SMN genes, and breakpoints in SMN2-SMN1 hybrid genes. The technical limitations and advantages and disadvantages of these methods are discussed. We conclude that the three methods complement each other in estimating the SMN2 copy number in most cases. However, MLPA offers additional information to characterize SMA cases with particular rearrangements such as partial deletions and hybrid genes.
- Published
- 2011
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38. Plastin 3 expression in discordant spinal muscular atrophy (SMA) siblings.
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Bernal S, Also-Rallo E, Martínez-Hernández R, Alías L, Rodríguez-Alvarez FJ, Millán JM, Hernández-Chico C, Baiget M, and Tizzano EF
- Subjects
- Adult, Cells, Cultured, Female, Fibroblasts metabolism, Fibroblasts pathology, Humans, Male, Membrane Glycoproteins genetics, Microfilament Proteins genetics, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal pathology, Pedigree, Phenotype, Sex Characteristics, Membrane Glycoproteins metabolism, Microfilament Proteins metabolism, Muscular Atrophy, Spinal metabolism, Siblings
- Abstract
Spinal muscular atrophy (SMA) is caused by loss or mutations of the survival motor neuron 1 gene (SMN1). Its highly homologous copy, SMN2, is present in all SMA cases and is a phenotypic modifier. There are cases where asymptomatic siblings of typical SMA patients possess a homozygous deletion of SMN1 just like their symptomatic brothers or sisters. Plastin 3 (PLS3) when over expressed in lymphoblasts from females has been suggested to act as a genetic modifier of SMA. We studied PLS3 expression in four Spanish SMA families with discordant siblings haploidentical for the SMA locus. We excluded PLS3 as a possible modifier in two of our families with female discordant siblings. In the remaining two, we observed small differences in PLS3 expression between male and female discordant siblings. Indeed, we found that values of PLS3 expression in lymphoblasts and peripheral blood ranged from 12 to 200-fold less than those in fibroblasts. These findings warrant further investigation in motor neurons derived from induced pluripotential stem cells of these patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
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39. A highly sensitive genetic protocol to detect NF1 mutations.
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Valero MC, Martín Y, Hernández-Imaz E, Marina Hernández A, Meleán G, Valero AM, Javier Rodríguez-Álvarez F, Tellería D, and Hernández-Chico C
- Subjects
- DNA Copy Number Variations, Humans, Molecular Diagnostic Techniques, Reproducibility of Results, Sensitivity and Specificity, Chromatography, High Pressure Liquid methods, DNA Mutational Analysis methods, Genes, Neurofibromatosis 1, Germ-Line Mutation, Neurofibromatosis 1 diagnosis, Neurofibromatosis 1 genetics, Polymerase Chain Reaction methods
- Abstract
Neurofibromatosis type 1 (NF1) is a hereditary disorder caused by mutations in the NF1 gene. Detecting mutation in NF1 is hindered by the gene's large size, the lack of mutation hotspots, the presence of pseudogenes, and the wide variety of possible lesions. We developed a method for detecting germline mutations by combining an original RNA-based cDNA-PCR mutation detection method and denaturing high-performance liquid chromatography (DHPLC) with multiplex ligation-dependent probe amplification (MLPA). The protocol was validated in a cohort of 56 blood samples from NF1 patients who fulfilled NIH diagnostic criteria, identifying the germline mutation in 53 cases (95% sensitivity). The efficiency and reliability of this approach facilitated detection of different types of mutations, including single-base substitutions, deletions or insertions of one to several nucleotides, microdeletions, and changes in intragenic copy number. Because mutational screening for minor lesions was performed using cDNA and the characterization of mutated alleles was performed at both the RNA and genomic DNA level, the analysis provided insight into the nature of the different mutations and their effect on NF1 mRNA splicing. After validation, we implemented the protocol as a routine test. Here we present the overall unbiased spectrum of NF1 mutations identified in 93 patients in a cohort of 105. The results indicate that this protocol is a powerful new tool for the molecular diagnosis of NF1., (Copyright © 2011 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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40. Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene.
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Alías L, Bernal S, Fuentes-Prior P, Barceló MJ, Also E, Martínez-Hernández R, Rodríguez-Alvarez FJ, Martín Y, Aller E, Grau E, Peciña A, Antiñolo G, Galán E, Rosa AL, Fernández-Burriel M, Borrego S, Millán JM, Hernández-Chico C, Baiget M, and Tizzano EF
- Subjects
- DNA Mutational Analysis, Female, Humans, Male, Molecular Sequence Data, Mutation, Spain, Muscular Atrophy, Spinal genetics, Survival of Motor Neuron 1 Protein genetics
- Abstract
Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene. We have studied the molecular pathology of SMA in 745 unrelated Spanish patients using PCR-RFLP, SMN gene dosage analysis, linkage studies, long-range PCR and direct sequencing. Our systematic approach allowed us to complete genetic testing and risk assessment in 736 SMA patients (98.8%). Females were more frequently affected by the acute form of the disease (type I), whereas chronic forms (type II-III) predominated in males (p<0.008). Absence of the SMN1 gene was detected in 671 patients (90%), and hybrid SMN1-SMN2 genes were observed in 37 cases (5%). Furthermore, we detected 13 small mutations in 28 patients (3.8%), four of which were previously identified in other populations (c.91dupT; c.770_780dup11; p.Tyr272Cys and p.Thr274Ile), while five mutations were found to date only in Spanish patients (c.399_402delAGAG, p.Ile116Phe, p.Gln136Glu, c.740dupC and c.834+2T>G). The c.399_402delAGAG mutation accounted for 1.9% of all Spanish SMA patients. Finally, we discovered four novel mutations: c.312dupA, c.411delT, p.Trp190X and p.Met263Thr. Our results confirm that most SMA cases are due to large genetic rearrangements in the repetitive region of the SMA locus, resulting in absence-dysfunction of the SMN1 gene. By contrast, ancestrally inherited small mutations are responsible for only a small number of cases. Four prevalent changes in exons 3 and 6 (c.399_402delAGAG; c.770_780dup11; p.Tyr272Cys; p.Thr274Ile) accounted for almost 70% of our patients with these subtle mutations. An SMN-SMN dimer model featuring tight hydrophobic-aromatic interactions is proposed to explain the impact of mutations at the C-terminal end of the protein.
- Published
- 2009
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41. Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA.
- Author
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Pera A, Dossena S, Rodighiero S, Gandía M, Bottà G, Meyer G, Moreno F, Nofziger C, Hernández-Chico C, and Paulmichl M
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Cohort Studies, Genes, Recessive, Genotype, Humans, Molecular Sequence Data, Open Reading Frames, Phenotype, Polymorphism, Genetic, Sequence Homology, Amino Acid, Sulfate Transporters, Syndrome, Alleles, Hearing Loss, Sensorineural genetics, Membrane Transport Proteins genetics, Mutation, Vestibular Aqueduct abnormalities
- Abstract
Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, with malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) to Mondini malformation, and deficient iodide organification in the thyroid gland. Nonsyndromic EVA (ns-EVA) is a separate type of sensorineural hearing loss showing normal thyroid function. Both Pendred syndrome and ns-EVA seem to be linked to the malfunction of pendrin (SLC26A4), a membrane transporter able to exchange anions between the cytosol and extracellular fluid. In the past, the pathogenicity of SLC26A4 missense mutations were assumed if the mutations fulfilled two criteria: low incidence of the mutation in the control population and substitution of evolutionary conserved amino acids. Here we show that these criteria are insufficient to make meaningful predictions about the effect of these SLC26A4 variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the SLC26A4 ORF, and consistently found that on the protein level, an addition or omission of a proline or a charged amino acid in the SLC26A4 sequence is detrimental to its function. These types of changes may be adequate for predicting SLC26A4 functionality in the absence of direct functional tests.
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- 2008
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42. A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.
- Author
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Pera A, Villamar M, Viñuela A, Gandía M, Medà C, Moreno F, and Hernández-Chico C
- Subjects
- Family, Female, Humans, Male, Pedigree, Sulfate Transporters, Syndrome, Hearing Loss, Sensorineural genetics, Membrane Transport Proteins genetics, Mutation genetics, Polymorphism, Single Nucleotide genetics, Vestibular Aqueduct pathology
- Abstract
Pendred syndrome (PS) and DFNB4, a non-syndromic sensorineural hearing loss with enlargement of the vestibular aqueduct (EVA), are caused by mutations in the SLC26A4 gene. Both disorders are recessive, and yet only one mutated SLC26A4 allele, or no mutations, are identified in many cases. Here we present the genetic characterization of 105 Spanish patients from 47 families with PS or non-syndromic EVA and 20 families with recessive non-syndromic hearing loss, which segregated with the DFNB4 locus. In this cohort, two causative SLC26A4 mutations could be characterized in 18 families (27%), whereas a single mutated allele was found in a patient with unilateral hearing loss and EVA in the same ear. In all, 24 different causative mutations were identified, including eight novel mutations. The novel p.Q514K variant was the most prevalent mutation in SLC26A4, accounting for 17% (6/36) of the mutated alleles identified in this study, deriving from a founder effect. We also characterized a novel multiexon 14 kb deletion spanning from intron 3 to intron 6 (g.8091T_22145Cdel). This study also revealed the first case of a de novo recessive mutation p.Q413P causing PS that arose in the proband's paternal allele, the maternal one carrying the p.L445W. The relevance of our results for genetic diagnosis of PS and non-syndromic EVA hearing loss is discussed.
- Published
- 2008
- Full Text
- View/download PDF
43. Genetic study of SMA patients without homozygous SMN1 deletions: identification of compound heterozygotes and characterisation of novel intragenic SMN1 mutations.
- Author
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Martín Y, Valero A, del Castillo E, Pascual SI, and Hernández-Chico C
- Subjects
- Alleles, Base Sequence, Cyclic AMP Response Element-Binding Protein, DNA genetics, DNA Mutational Analysis, Gene Deletion, Gene Dosage, Heterozygote, Homozygote, Humans, Polymerase Chain Reaction, Promoter Regions, Genetic, RNA-Binding Proteins, SMN Complex Proteins, Spain, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein, Muscular Atrophy, Spinal genetics, Mutation, Nerve Tissue Proteins genetics
- Abstract
Autosomal recessive spinal muscular atrophy (SMA) is a disease resulting from mutations in the telomeric survival motor neuron gene ( SMN1). In our sample of 150 Spanish SMA families, 87% of patients had homozygous deletions of SMN1. To identify patients who retained a single SMN1 copy, SMN dosage analysis was performed by a fluorescent quantitative PCR assay. In five out of 19 patients tested we detected one SMN1 copy. An extensive SMN gene analysis in these patients led to identification of four intragenic mutations, including two novel ones: a frameshift mutation in exon 6 (773insC) and a splice site mutation in intron 6 (c.867+2T-->G). Two previously described mutations were also found: a deletion in exon 3 (430del4), identified in several Spanish patients, and a frequently occurring mutation in exon 6 (813ins/dup11), reported in several populations. Although the spectrum of intragenic mutations is small, only 27 reported up to now, identification of three mutations found exclusively in the Spanish population indicates that the occurrence of different intragenic mutations depends on the ethnic origin of SMA patients. In the remaining patient, who had a single SMN1 copy and three SMN2 copies, we found that the SMN1 allele was non-functional; the patient did not show any SMN1 transcript. Sequencing of the SMN promoter regions revealed various differences between promoters of the patient's four SMN genes, in particular a change in the length of a polyA run removing a putative YY1 binding site, which may affect the expression of SMN genes.
- Published
- 2002
- Full Text
- View/download PDF
44. Characterisation of SMN hybrid genes in Spanish SMA patients: de novo, homozygous and compound heterozygous cases.
- Author
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Cuscó I, Barceló MJ, del Rio E, Martín Y, Hernández-Chico C, Bussaglia E, Baiget M, and Tizzano EF
- Subjects
- Alleles, Base Sequence, Cyclic AMP Response Element-Binding Protein, DNA chemistry, DNA genetics, DNA isolation & purification, DNA Mutational Analysis, Family Health, Female, Gene Frequency, Genotype, Haplotypes, Heterozygote, Homozygote, Humans, Male, Molecular Sequence Data, Mutation, Neuronal Apoptosis-Inhibitory Protein, Pedigree, Phenotype, RNA-Binding Proteins, SMN Complex Proteins, Spain, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein, Muscular Atrophy, Spinal genetics, Nerve Tissue Proteins genetics
- Abstract
Autosomal recessive spinal muscular atrophy (SMA) is classified, by age of onset and maximal motor milestones achieved, into type I (severe form), type II (intermediate form) and type III (mild/moderate form). SMA is caused by mutations in the survival motor neuron telomeric gene (SMN1) and a centromeric functional copy of this gene (SMN2) exists, both genes being located at 5q13. Homozygous deletion of exons 7 and 8 of SMN1 has been detected in approx 85% of Spanish SMA patients regardless of their phenotype. Nineteen cases with the sole deletion of exon 7 but not exon 8 (2 cases of type I, 13 cases of type II, four cases of type III) were further analysed for the presence of SMN2-SMN1 hybrid genes. We detected four different hybrid structures. Most of the patients were carriers of a hybrid structure: centromeric intron 6- centromeric exon 7- telomeric exon 8 (CCT), with or without neuronal apoptosis-inhibitor protein (NAIP). In two patients, a different hybrid structure, viz. telomeric intron 6- centromeric exon 7- telomeric exon 8 (TCT), was detected with or without NAIP. A phenotype-genotype correlation comparing the different structures of the hybrid alleles was delineated. Type I cases in our series are attributable to intrachromosomal deletion with a smaller number of SMN2 copies. Most cases with hybrid genes are type II occurring by a combination of a classical deletion in one chromosome and a hybrid gene in the other. Type III cases are closely associated with homozygozity or compound heterozygozity for hybrid genes resulting from two conversion events and have more copies of hybrid genes and SMN2 than type I or II cases.
- Published
- 2001
- Full Text
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45. [Werdnig-Hoffmann disease. The first prenatal diagnosis in Cuba].
- Author
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Acevedo-López AM, Zaldívar-Vaillant T, Hernández-Chico C, Moreno F, Rosich-Capablanca G, and Guerra-Badía R
- Subjects
- Chromosomes, Human, Pair 5 genetics, Cuba, Exons genetics, Gene Deletion, Gene Expression genetics, Humans, Pedigree, Point Mutation genetics, Spinal Muscular Atrophies of Childhood genetics, Prenatal Diagnosis methods, Spinal Muscular Atrophies of Childhood epidemiology
- Abstract
Introduction: Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by the degeneration of cells of the spinal cord. The gene was localized on chromosome 5q13 and exists in two almost identical forms, which are distinguished by the change of base on exones 7 and 8. Mutations of the gene of survival motoreneuron (SMN) are the cause of illness., Clinical Case: We report, for the first time in Cuba, the prenatal diagnosis of a type II SMA carrier, using molecular methods for direct detection of the mutation on exones 7 and 8 of the SMN gene, and haplo-identification with microsatellite markers of chromosome 5q as an indirect method. A sample of amniotic liquid was taken at 18 weeks of gestation and the DNA extracted. No deletions were detected on exones 7 and 8 of the foetal DNA, which was therefore normal., Conclusions: Detection of deletions on the SMN gene is a method which permits detection of the condition (healthy or unhealthy) of the foetus, quickly and reliably, without requiring investigation of the entire family to obtain a result. The method does not require radio-active PCR, the results are clear and precise and may be obtained within 24 hours. It may also take the place of invasive methods such as muscle biopsy and electro-myography and contribute to genetic assessment in families in which there is no DNA of the affected child.
- Published
- 1999
46. Analysis of the monomeric alphoid sequences in the pericentromeric region of human chromosome 7.
- Author
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de la Puente A, Velasco E, Pérez Jurado LA, Hernández-Chico C, van de Rijke FM, Scherer SW, Raap AK, and Cruces J
- Subjects
- Cells, Cultured, Chromatin genetics, Contig Mapping, DNA analysis, DNA genetics, DNA, Satellite genetics, Genetic Markers, Humans, In Situ Hybridization, Fluorescence, Restriction Mapping, Centromere genetics, Chromosomes, Human, Pair 7 genetics, DNA, Satellite analysis
- Abstract
To further define the structure of the pericentromeric region of human chromosome 7, we have identified and characterized a YAC clone (YAC 311.H5) containing the D7S1480 locus, which maps to the short arm near the centromere of this chromosome, by linkage in CEPH families and radiation hybrid analysis. This YAC contains two new blocks of alphoid DNA (named Z5 and Z6). Both Z5 and Z6 show monomeric structures and a lack of higher-order repeats, and, therefore, belong to suprachromosomal family type 4 (M1). The orientation of the two blocks and the physical distances over the region were defined by pulsed-field gel electrophoresis (PFGE) and fluorescence in situ hybridization on chromatin fibers (FiberFISH). A YAC contig spanning the centromeric region has been developed by STS content.
- Published
- 1998
- Full Text
- View/download PDF
47. Identification of de novo deletions at the NF1 gene: no preferential paternal origin and phenotypic analysis of patients.
- Author
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Valero MC, Pascual-Castroviejo I, Velasco E, Moreno F, and Hernández-Chico C
- Subjects
- Adolescent, Adult, Child, Preschool, Female, Humans, Male, Molecular Sequence Data, Neurofibromin 1, Pedigree, Phenotype, Gene Deletion, Genomic Imprinting, Proteins genetics
- Abstract
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder. To date, a relatively small number of NF1 mutations have been characterized, thus precluding genotype-phenotype correlations. By genotyping 75 NF1 families, we have detected six hemizygous patients (two of whom are members of the same family). The five presumed deletions were confirmed by two quantitative methods of analysis of NF1 copy number: Southern hybridization with cDNA probes and a single-strand conformation polymorphism analysis that discriminates between the NF1 gene and the pseudogene sequences. The five deletions remove most of the NF1 gene, at least 225 kb, from exon 9 to the 3' end of the coding sequence. The origin of de novo mutations in the NF1 gene has been reported to be mainly paternal but we have determined that four of the de novo deletions involved the maternal chromosome and one the paternal chromosome. The six patients with deletions exhibited precocious, multiple clinical features of the disease. The incidence of tumor complications, particularly plexiform neurofibromas and intracranial tumors, among this group of patients is higher than the observed incidence in our NF1 population, suggesting that NF1 haploinsufficiency may cause a more severe phenotype with regard to tumor development. In contrast to other reports that associated large deletions with mildly dysmorphic facies, mental retardation and a large number of cutaneous neurofibromas, only one out of our six patients presented this phenotype.
- Published
- 1997
- Full Text
- View/download PDF
48. Isolation of microsatellites from the spinal muscular atrophy (SMA) candidate region on chromosome 5q and linkage analysis in Spanish SMA families.
- Author
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Velasco E, Valero C, García E, de la Puente A, Cruces J, San Millán JL, del Castillo I, Coloma A, Moreno F, and Hernández-Chico C
- Subjects
- Base Sequence, Chromosomes, Artificial, Yeast, Female, Genetic Markers, Humans, Lod Score, Male, Molecular Sequence Data, Polymerase Chain Reaction, Polymorphism, Genetic, Recombination, Genetic, Spain, Chromosomes, Human, Pair 5, DNA, Satellite genetics, Genetic Linkage, Muscular Atrophy, Spinal genetics
- Abstract
A locus responsible for autosomal recessive spinal muscular atrophy (SMA) on chromosome 5q11.2-q13.3 has been mapped to a critical interval delimited by markers D5S435 and D5S557. By a modification of the Vectorette-(GT)n method, we have isolated three polymorphic CA repeats from two YACs of the SMA region. Two of them (D5S1417 and D5S1416) map within the SMA critical region, and the other (D5S1415) is centromeric to D5S435. Linkage analysis in Spanish SMA families with eleven markers showed that in our families the disease is linked to this region and confirmed that the novel markers are tightly linked to the SMA locus. The most likely order of markers was 5cen-(D5S63/D5S1356)-(D5S125/D5S465)- (D5S435/D5S1417/D5S1416/D5S557)-D5S610- D5S112-D5S127-5qter, with odds against alternative orders > 1,000:1. Genetic distances are in agreement with those previously published. However, the recombination fraction between D5S610 and D5S112 is remarkably greater than expected from the physical distance, suggesting a hot spot for recombination in this region. Our results from haplotype and multipoint analyses show that the SMA locus must lie between D5S465 and D5S112, and lend further support to the current location of the SMA locus.
- Published
- 1995
- Full Text
- View/download PDF
49. Microcins.
- Author
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Moreno F, San Millán JL, Hernández-Chico C, and Kolter R
- Subjects
- Amino Acid Sequence, Anti-Bacterial Agents pharmacology, Bacteriocins pharmacology, Colicins chemistry, DNA Replication drug effects, Enterobacteriaceae genetics, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression Regulation, Bacterial, Molecular Sequence Data, Anti-Bacterial Agents biosynthesis, Anti-Bacterial Agents chemistry, Bacteriocins biosynthesis, Bacteriocins chemistry, Colicins biosynthesis, Enterobacteriaceae metabolism, Genes, Bacterial
- Published
- 1995
- Full Text
- View/download PDF
50. Characterization of four mutations in the neurofibromatosis type 1 gene by denaturing gradient gel electrophoresis (DGGE).
- Author
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Valero MC, Velasco E, Moreno F, and Hernández-Chico C
- Subjects
- Amino Acid Sequence, Base Sequence, Codon, DNA Mutational Analysis, Electrophoresis, Polyacrylamide Gel, Exons, Female, Humans, Male, Molecular Sequence Data, Pedigree, Transcription, Genetic, Genes, Neurofibromatosis 1, Neurofibromatosis 1 genetics, Point Mutation, Sequence Deletion
- Abstract
Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders. The gene responsible for the disease has a very high mutation rate, approximately fifty per cent of NF1 patients appear to have a de novo mutation. The search for mutations is hampered by the large size of the NF1 gene and up to date, relatively few mutations have been characterized. In the present work, we report the results of screening seventy unrelated NF1 patients for mutations in NF1 exons 29 and 31 by using an experimental approach that combines the polymerase chain reaction (PCR) with denaturing gradient gel electrophoresis (DGGE). Four mutations were identified and characterized. Three of them consist of C-T transitions resulting in nonsense mutations, two in exon 29, C5242T and C5260T, and one in exon 31, C5839T. The fourth mutation consists of a two-base pair deletion in exon 31, 5843delAA, also resulting in a premature stop codon. The finding in our patients of mutation C5839T, previously reported in three independent studies, supports that this position is a hotspot within the NF1 gene.
- Published
- 1994
- Full Text
- View/download PDF
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