RESUMEN
Crouzon syndrome is an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis) and maps to chromosome 10q25-q26. We now present evidence that mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause Crouzon syndrome. We found SSCP variations in the B exon of FGFR2 in nine unrelated affected individuals as well as complete cosegregation between SSCP variation and disease in three unrelated multigenerational families. In four sporadic cases, the normal parents did not have SSCP variation. Finally, direct sequencing has revealed specific mutations in the B exon in all nine sporadic and familial cases, including replacement of a cysteine in an immunoglobulin-like domain in five patients.
Asunto(s)
Cromosomas Humanos Par 10 , Disostosis Craneofacial/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento de Fibroblastos/genética , Secuencia de Bases , Exones , Femenino , Humanos , Escala de Lod , Masculino , Datos de Secuencia Molecular , Mutación , Linaje , Polimorfismo Conformacional Retorcido-Simple , Receptor Tipo 2 de Factor de Crecimiento de FibroblastosRESUMEN
Pfeiffer syndrome (PS) is one of the classic autosomal dominant craniosynostosis syndromes with craniofacial anomalies and characteristic broad thumbs and big toes. We have previously mapped one of the genes for PS to the centromeric region of chromosome 8 by linkage analysis. Here we present evidence that mutations in the fibroblast growth factor receptor-1 (FGFR1) gene, which maps to 8p, cause one form of familial Pfeiffer syndrome. A C to G transversion in exon 5, predicting a proline to arginine substitution in the putative extracellular domain, was identified in all affected members of five unrelated PS families but not in any unaffected individuals. FGFR1 therefore becomes the third fibroblast growth factor receptor to be associated with an autosomal dominant skeletal disorder.
Asunto(s)
Anomalías Múltiples/genética , Craneosinostosis/genética , Mutación Puntual , Proteínas Tirosina Quinasas Receptoras , Receptores de Factores de Crecimiento de Fibroblastos/genética , Pulgar/anomalías , Dedos del Pie/anomalías , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 8 , Exones , Femenino , Genes , Humanos , Escala de Lod , Masculino , Datos de Secuencia Molecular , Linaje , Estructura Terciaria de Proteína , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Receptores de Factores de Crecimiento de Fibroblastos/química , SíndromeRESUMEN
Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been identified in Crouzon syndrome, an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis). A mutation in FGFR1 has been established in several families with Pfeiffer syndrome, where craniosynostosis is associated with specific digital abnormalities. We now report point mutations in FGFR2 in seven sporadic Pfeiffer syndrome patients. Six of the seven Pfeiffer syndrome patients share two missense mutations, which have also been reported in Crouzon syndrome. The Crouzon and Pfeiffer phenotypes usually breed true within families and the finding of identical mutations in unrelated individuals giving different phenotypes is a highly unexpected observation.
Asunto(s)
Acrocefalosindactilia/genética , Disostosis Craneofacial/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento de Fibroblastos/genética , Secuencia de Bases , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Fenotipo , Receptor Tipo 2 de Factor de Crecimiento de FibroblastosRESUMEN
Apert syndrome is a distinctive human malformation comprising craniosynostosis and severe syndactyly of the hands and feet. We have identified specific missense substitutions involving adjacent amino acids (Ser252Trp and Pro253Arg) in the linker between the second and third extracellular immunoglobulin (Ig) domains of fibroblast growth factor receptor 2 (FGFR2) in all 40 unrelated cases of Apert syndrome studied. Crouzon syndrome, characterized by craniosynostosis but normal limbs, was previously shown to result from allelic mutations of the third Ig domain of FGFR2. The contrasting effects of these mutations provide a genetic resource for dissecting the complex effects of signal transduction through FGFRs in cranial and limb morphogenesis.
Asunto(s)
Acrocefalosindactilia/genética , Disostosis Craneofacial/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento de Fibroblastos/genética , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , ADN Complementario , Exones , Femenino , Marcadores Genéticos , Genotipo , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Polimorfismo Conformacional Retorcido-Simple , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Mapeo Restrictivo , SindactiliaRESUMEN
We describe a family with non-syndromic sensorineural hearing impairment inherited in a manner consistent with maternal transmission. Affected members were found to have a novel heteroplasmic mtDNA mutation, T7510C, in the tRNA(Ser(UCN)) gene. This mutation was not found in 661 controls, is well conserved between species, and disrupts base pairing in the acceptor stem of the tRNA, making it the probable cause of hearing impairment in this family. Sequencing of the other mitochondrial tRNA genes did not show any other pathogenic mutations. Four other mutations causing hearing impairment have been reported in the tRNA(Ser(UCN)) gene, two having been shown to affect tRNA(Ser(UCN)) levels. With increasing numbers of reports of mtDNA mutations causing hearing impairment, screening for such mutations should be considered in all cases unless mitochondrial inheritance can be excluded for certain.
Asunto(s)
ADN Mitocondrial/genética , Pérdida Auditiva Sensorineural/genética , ARN de Transferencia de Serina/genética , Secuencia de Bases , Análisis Mutacional de ADN , ADN Mitocondrial/química , Salud de la Familia , Femenino , Pérdida Auditiva Sensorineural/patología , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Conformación de Ácido Nucleico , Linaje , Mutación Puntual , ARN de Transferencia de Serina/química , Alineación de Secuencia , Homología de Secuencia de Ácido NucleicoRESUMEN
Non-syndromic sensorineural deafness is an extremely genetically heterogeneous condition. We have used autozygosity mapping in a large consanguineous United Arab Emirate family to identify a novel locus for autosomal recessive non-syndromic sensorineural deafness, DFNB27, on chromosome 2q23-q31, with a maximum two-point lod score of 5.18 at theta = 0 for marker D2S2257. The DFNB27 locus extends over a 17 cM region between D2S2157 and D2S2273, and may overlap the DFNA16 locus for dominantly inherited, fluctuating, progressive non-syndromal hearing loss. However, genotype data suggests that the locus is likely to be refined to between D2S326 and D2S2273 and thus distinct from the DFNA16 locus.
Asunto(s)
Cromosomas Humanos Par 2 , Pérdida Auditiva Sensorineural/genética , Mapeo Cromosómico , Consanguinidad , Femenino , Homocigoto , Humanos , Masculino , LinajeRESUMEN
The causative relationship between several of the syndromic forms of craniosynostosis and mutations in the fibroblast growth factor receptor (FGFR) loci is now well established. However, within the group of patients with craniosynostosis, there are several families and sporadic cases whose clinical features differ in variable degrees from the classically described syndromes of craniosynostosis. In this communication we present novel FGFR2 mutations associated with a spectrum of craniosyostosis phenotypes in 4 sporadic cases and in one family in which craniosynostosis segregates. The mutation and phenotype data presented emphasise the clinical variability of mutations at this locus and underline the plasticity of the phenotype-genotype relationship in this important group of congenital malformation syndromes. Mutations found were tyrosine 105 to cysteine, glycine 338 to glutamic acid, serine 351 to cysteine and glycine 384 to arginine. These are the first reported mutations in the first immunoglobulin-like loop (tyrosine 105 to cysteine) and the transmembrane domain (glycine 384 to arginine) of FGFR2, providing further insights into the mechanism of abnormal receptor function in FGFR2 mutations.
Asunto(s)
Craneosinostosis/genética , Mutación Puntual , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento de Fibroblastos/genética , Craneosinostosis/diagnóstico por imagen , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Fenotipo , Radiografía , Receptor Tipo 2 de Factor de Crecimiento de FibroblastosRESUMEN
Transforming growth factor beta1 (TGFbeta1) is a multifunctional cytokine involved in pro- and anti-inflammatory pathways and is expressed in several cell types. Subepithelial fibrosis is one of the principle features of airway remodelling in asthma and is increased in severe patients. TGFbeta1 is implicated in fibrosis, including the deposition of extracellular matrix proteins. TGFbeta1 mRNA levels in eosinophils are increased in severe asthmatics relative to mild asthmatics. Therefore, TGFbeta1 is a promising candidate gene for contributing to asthma severity. Four polymorphisms located in the promoter region and signal peptide (C-509T, 72insC, T869C and G915C) were genotyped in groups of severe asthmatic, mild asthmatic or control individuals defined by steroid usage and pulmonary function. Significant differences ( P=0.016) were found between the groups for the genotype frequencies at C-509T, attributable mainly to a greater relative frequency of homozygosity for the -509T allele in the severe group compared to the mild and control groups. Individuals homozygous for -509T were also homozygous at the other variant sites for the 72C, 869C and 915G alleles (haplotype 1). The T allele creates a putative YY1 transcription factor binding site, but binding between YY1 and the DNA sequence of the T allele was not detected in vitro. In this study, we show that the -509T variant on haplotype 1 is the most informative marker of the TGFbeta1 contribution to asthma severity.
Asunto(s)
Asma/genética , Factor de Crecimiento Transformador beta/genética , Corticoesteroides/administración & dosificación , Adulto , Alelos , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Mutación Puntual , Polimorfismo Genético , Regiones Promotoras Genéticas , Señales de Clasificación de Proteína/genética , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Factor de Crecimiento Transformador beta1RESUMEN
Craniofrontonasal dysplasia (CFND) is a rare X-linked disorder that maps to a 13-cM region on Xp22. Phenotypic features include craniosynostosis, hypertelorism and a broad nasal root with or without a bifid nasal tip. Multiple examples have been reported of males having a less severe phenotype than females. We report haplotype analyses in two CFND families over the critical region to which the gene has been mapped. In pedigree 1, a clinically unaffected male inherited the affected marker haplotype spanning the critical region. We suggest that this individual does have the CFND mutation, but has an extremely mild phenotype that is not detectable with clinical examination. Under the assumption that he is an unknown phenotype, a combined two-point LOD score of 1.68 at zero recombination was obtained, increasing the previously reported total to 5.61 (DXS8022). The data do not narrow down the critical region. This result stresses the importance of subjecting fathers of apparently sporadic cases to a highly critical medical examination and may also explain the unequal ratio of reported female-to-male cases.
Asunto(s)
Anomalías Craneofaciales/genética , Cromosoma X , Craneosinostosis/etiología , Femenino , Humanos , Hipertelorismo/etiología , Hipertelorismo/genética , Masculino , Repeticiones de Microsatélite , LinajeRESUMEN
Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have previously been identified in Crouzon syndrome, an autosomal dominant condition involving premature fusion of the cranial sutures. Several different missense and other mutations have been identified in Crouzon syndrome patients, clustering around the third immunoglobulin-like domain. We report here the identification of a mutation in the transmembrane region of FGFR3, common to three unrelated patients with classical Crouzon syndrome and acanthosis nigricans, a dermatological condition associated with thickening and abnormal pigmentation of the skin. The mutation within the FGFR3 transcript was determined by direct sequencing as a specific gcg to gag transversion, resulting in an amino acid substitution ala391glu within the transmembrane region.
Asunto(s)
Acantosis Nigricans/genética , Disostosis Craneofacial/genética , Factores de Crecimiento de Fibroblastos/genética , Proteínas Tirosina Quinasas , Receptores de Factores de Crecimiento de Fibroblastos/genética , Acantosis Nigricans/complicaciones , Adolescente , Niño , Disostosis Craneofacial/complicaciones , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Puntual , Reacción en Cadena de la Polimerasa , Proteínas Tirosina Quinasas Receptoras/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Receptor Tipo 3 de Factor de Crecimiento de FibroblastosRESUMEN
Several mutations involving the fibroblast growth factor receptor (FGFR) gene family have been identified in association with phenotypically distinct forms of craniosynostosis. One such point mutation, resulting in the substitution of proline by arginine in a critical region of the linker region between the first and second immunoglobulin-like domains, is associated with highly specific phenotypic consequences in that mutation at this point in FGFR1 results in Pfeiffer syndrome and analogous mutation in FGFR2 results in Apert syndrome. We now show that a much more variable clinical presentation accompanies analogous mutation in the FGFR3 gene. Specifically, mental retardation, apparently unrelated to the management of the craniosynostosis, appears to be a variable clinical consequence of this FGFR3 mutation.
Asunto(s)
Arginina/genética , Craneosinostosis/genética , Factores de Crecimiento de Fibroblastos/genética , Mutación , Prolina/genética , Proteínas Tirosina Quinasas , Receptores de Factores de Crecimiento de Fibroblastos/genética , Acrocefalosindactilia/genética , Adulto , Niño , Preescolar , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Receptor Tipo 3 de Factor de Crecimiento de FibroblastosRESUMEN
Craniosynostosis, which affects approximately 1 in 2000 children, is the result of the abnormal development and/or premature fusion of the cranial sutures. Studies of mutations in patients with craniosynostosis have shown that the family of fibroblast growth factor receptor genes are extremely important in the correct formation of the skull, and digits. Mutations in the third immunoglobulin domain of fibroblast growth factor receptor 2 (FGFR2), in part of the molecule corresponding to a tissue specific isoform (IIIc), can cause both Crouzon and Pfeiffer syndromes. Two specific mutations in the linking region between the second and third immunoglobulin domains of FGFR2 occur in Apert syndrome. We present here mutations associated with the Crouzon syndrome, also in the third immunoglobulin domain but in an upstream exon. This exon is expressed in both tissue isoforms. Five different mutations were detected in 11 unrelated individuals. A cysteine to phenylalanine change was found in six individuals. This cysteine forms half of the disulphide bridge maintaining the secondary structure of the immunoglobulin domain. The first deletion within an FGFR gene is reported. Together with mutations in exon IIIc these account for 25 mutations out of 40 Crouzon patients studied in our combined series (5).