Asunto(s)
Acondroplasia/genética , Proteínas de Homeodominio/genética , Síndrome de la Uña-Rótula/genética , Proteínas Tirosina Quinasas , Receptores de Factores de Crecimiento de Fibroblastos/genética , Acondroplasia/patología , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Proteínas con Homeodominio LIM , Masculino , Mutación , Síndrome de la Uña-Rótula/patología , Fenotipo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Factores de TranscripciónRESUMEN
The relationship of delayed membranous cranial ossification to cranium bifidum and parietal foramina syndromes is unclear. We report on a family with delayed cranial membranous ossification (OMIM 155980) that segregates with an apparently balanced reciprocal translocation between chromosomes 2 and 3. The propositus had apparently low-set ears, proptosis, and a soft skull at birth. A radiographic survey of the skeleton showed markedly decreased ossification of the cranial bones and no other skeletal abnormalities. The mother and maternal grandmother of the propositus have brachycephaly, hypertelorism, and a history of a soft skull at birth. Chromosome analysis of peripheral blood from the propositus showed 46,XY,t(2;3)(p15;q12). The propositus, mother, and grandmother carry the same reciprocal translocation, whereas the mother's two phenotypically normal sibs have a normal karyotype. We used an STS-linked BAC resource to define the translocation breakpoint by identifying flanking BAC clones from both chromosomes 2, 1006D24 (D2S2279) and 1060A5 (D2S2231), and chromosome 3, 3D17 (WI8558) and 3D18 [CITB Human BAC Library, J.R.K.]. This represents the second report of a family with delayed membranous ossification of the cranium and the first report of the phenotype segregating with a chromosome rearrangement.
Asunto(s)
Cromosomas Humanos Par 2 , Cromosomas Humanos Par 3 , Osteogénesis/genética , Cráneo/crecimiento & desarrollo , Translocación Genética , Adulto , Femenino , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Masculino , LinajeRESUMEN
Nail patella syndrome (NPS) has been shown to result from loss of function mutations within the transcription factor LMX1B. In a large NPS family a 17 bp intronic deletion encompassing a consensus branchpoint sequence was observed to segregate with the NPS phenotype. RNA analysis demonstrated that deletion of the branchpoint sequence resulted in skipping of the downstream exon. A mechanism to explain this phenomenon is presented.
Asunto(s)
Exones/genética , Proteínas de Homeodominio/genética , Síndrome de la Uña-Rótula/genética , Empalme Alternativo , Secuencia de Aminoácidos , Secuencia de Bases , Células Cultivadas , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Humanos , Proteínas con Homeodominio LIM , Datos de Secuencia Molecular , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Eliminación de Secuencia , Factores de TranscripciónRESUMEN
Nail-patella syndrome (NPS) is a pleiotropic condition characterized by dysplasia of the nails, hypoplasia of the patellae, elbow dysplasia, and progressive kidney disease. The syndrome is inherited in an autosomal dominant manner and has been shown to result from mutations in the LIM-homeodomain encoding LMX1B gene. The LMX1B transcription factor plays a role in defining the development of dorsal-specific structures during limb development. To date, a total of 64 point mutations and small deletions or insertions have been reported, concentrated within either the LIM or homeodomains. No NPS mutations have been observed within the carboxy-terminal third of the coding sequence, suggesting that mutations in this region are not inactivating. These findings support the hypothesis that NPS results from a 50% reduction in LMX1B function via a reduction in synthesis, disruption of secondary structure, or failure to bind DNA.
Asunto(s)
Proteínas de Homeodominio/genética , Mutación , Síndrome de la Uña-Rótula/genética , Femenino , Genes Dominantes , Proteínas de Homeodominio/química , Humanos , Proteínas con Homeodominio LIM , Masculino , Linaje , Fenotipo , Mutación Puntual , Polimorfismo Genético , Eliminación de Secuencia , Factores de Transcripción/química , Factores de Transcripción/genéticaRESUMEN
Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that NPS is the result of haploinsufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations.
Asunto(s)
Proteínas de Homeodominio/genética , Mutación , Síndrome de la Uña-Rótula/genética , Animales , ADN/metabolismo , Análisis Mutacional de ADN , Salud de la Familia , Genes Dominantes , Análisis Heterodúplex , Proteínas de Homeodominio/metabolismo , Humanos , Insulina/genética , Proteínas con Homeodominio LIM , Fenotipo , Regiones Promotoras Genéticas/genética , Ratas , Factores de TranscripciónRESUMEN
Nail-patella syndrome (NPS) is an inherited developmental disorder most commonly involving maldevelopment of the fingernails, kneecaps and elbow joints. NPS exhibits wide variation in phenotypic expression within and among families with respect to these features. Other skeletal abnormalities such as hip dislocation and club foot have also been reported in some individuals with NPS. There is an association between NPS and renal disease, and between NPS and open-angle glaucoma (OAG), but it is not known whether mutations in a single gene cause the observed skeletal, renal and ophthalmic abnormalities. Recently, LMX1B , a transcription factor of the LIM-homeodomain type with homologs that are important for limb development in vertebrates, was mapped to the same general location as NPS at 9q34. We sequenced a large segment of LMX1B from the genomic DNA of probands from four families with NPS and OAG, and identified four mutations: two stop codons, a deletion causing a frameshift and a missense mutation in a functionally important residue. The presence of these putative loss-of-function mutations in the DNA of individuals with NPS indicates that haploinsufficiency of LMX1B underlies this disorder. These findings help to explain the high degree of variability in the NPS phenotype, and suggest that the skeletal defects in NPS are a result of the diminished dorsoventral patterning activity of LMX1B protein during limb development. The results further suggest that the NPS and OAG phenotypes in the families studied result from mutations in a single gene, LMX1B.
Asunto(s)
Genes Homeobox , Proteínas de Homeodominio/genética , Síndrome de la Uña-Rótula/genética , Mutación Puntual/fisiología , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Ligamiento Genético , Glaucoma de Ángulo Abierto/genética , Glaucoma de Ángulo Abierto/fisiopatología , Proteínas de Homeodominio/química , Humanos , Proteínas con Homeodominio LIM , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Síndrome de la Uña-Rótula/fisiopatología , Linaje , Factores de TranscripciónRESUMEN
Nail-patella syndrome (NPS), or onychoosteodysplasia, is an autosomal dominant, pleiotropic disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns, and nephropathy. Previous studies have demonstrated linkage of the nail-patella locus to the ABO and adenylate kinase loci on human chromosome 9q34. As a first step toward isolating the NPS gene, we present linkage analysis with 13 polymorphic markers in five families with a total of 69 affected persons. Two-point linkage analysis with the program MLINK showed tight linkage of NPS and the anonymous markers D9S112 (LOD = 27.0; theta = .00) and D9S315 (LOD = 22.0; theta = .00). Informative recombination events place the NPS locus within a 1-2-cM interval between D9S60 and the adenylate kinase gene (AK1).