RESUMEN
Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.
Asunto(s)
Anomalías Múltiples/genética , Aracnodactilia/genética , Artrogriposis/genética , Blefarofimosis/genética , Fisura del Paladar/genética , Pie Equinovaro/genética , Enfermedades del Tejido Conjuntivo/genética , Contractura/genética , Deformidades Congénitas de la Mano/genética , Canales Iónicos/genética , Oftalmoplejía/genética , Enfermedades de la Retina/genética , Anomalías Múltiples/patología , Aracnodactilia/patología , Artrogriposis/patología , Blefarofimosis/patología , Niño , Preescolar , Fisura del Paladar/patología , Pie Equinovaro/patología , Enfermedades del Tejido Conjuntivo/patología , Contractura/patología , Exoma/genética , Femenino , Deformidades Congénitas de la Mano/patología , Humanos , Masculino , Mutación , Oftalmoplejía/patología , Linaje , Enfermedades de la Retina/patologíaRESUMEN
Currently available methods for interrogating DNA-protein interactions at individual genomic loci have significant limitations, and make it difficult to work with unmodified cells or examine single-copy regions without specific antibodies. In this study, we describe a physiological application of the Hybridization Capture of Chromatin-Associated Proteins for Proteomics (HyCCAPP) methodology we have developed. Both novel and known locus-specific DNA-protein interactions were identified at the ENO2 and GAL1 promoter regions of Saccharomyces cerevisiae, and revealed subgroups of proteins present in significantly different levels at the loci in cells grown on glucose versus galactose as the carbon source. Results were validated using chromatin immunoprecipitation. Overall, our analysis demonstrates that HyCCAPP is an effective and flexible technology that does not require specific antibodies nor prior knowledge of locally occurring DNA-protein interactions and can now be used to identify changes in protein interactions at target regions in the genome in response to physiological challenges.
Asunto(s)
Proteínas de Unión al ADN/genética , Galactoquinasa/genética , Fosfopiruvato Hidratasa/genética , Proteómica/métodos , Proteínas de Saccharomyces cerevisiae/genética , Cromatina/genética , Inmunoprecipitación de Cromatina/métodos , Regiones Promotoras Genéticas , Unión Proteica/genética , Saccharomyces cerevisiae/genéticaRESUMEN
Distal arthrogryposis (DA) syndromes are a group of disorders characterized by multiple congenital contractures. DA type 2A (DA2A or Freeman-Sheldon syndrome), caused by mutations in MYH3, is typically considered the most severe of the DA syndromes. However, there is wide phenotypic variability among individuals with DA2A. We characterized genotype-phenotype relationships in 46 families with DA2A. MYH3 mutations were found in 43/46 (93%) kindreds, with three mutations (p.T178I, p.R672C, and p.R672H) explaining 39/43 (91%) of cases. Phenotypic severity varied significantly by genotype (P=0.0055). Individuals with p.T178I were the most severely affected with both facial contractures and congenital scoliosis. Classification of individuals with DA2A into phenotypic groups of varying severity should facilitate providing families with more accurate information about natural history and suggests that individuals might benefit from personalized medical management motivated by MYH3 genotype.
Asunto(s)
Disostosis Craneofacial/diagnóstico , Disostosis Craneofacial/genética , Estudios de Asociación Genética , Genotipo , Fenotipo , Adolescente , Niño , Preescolar , Proteínas del Citoesqueleto/genética , Análisis Mutacional de ADN , Exones , Facies , Femenino , Humanos , Lactante , Masculino , Mutación , Radiografía , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/patologíaRESUMEN
The distal arthrogryposis (DA) syndromes are a group of disorders characterized by non-progressive congenital contractures of the limbs. Mutations that cause distal arthrogryposis syndromes have been reported in six genes, each of which encodes a component of the contractile apparatus of skeletal myofibers. However, these reports have usually emanated from gene discovery efforts and thus potentially bias estimates of the frequency of pathogenic mutations at each locus. We characterized the spectrum of pathogenic variants in a cohort of 153 cases of DA1 (n = 48) and DA2B (n = 105). Disease-causing mutations in 56/153 (37%) kindreds including 14/48 (29%) with DA1 and 42/105 (40%) with DA2B were distributed nearly equally across TNNI2, TNNT3, TPM2, and MYH3. In TNNI2, TNNT3, and TPM2 the same mutation caused DA1 in some families and DA2B in others. We found no significant differences among the clinical characteristics of DA by locus or between each locus and DA1 or DA2B. Collectively, the substantial overlap between phenotypic characteristics and spectrum of mutations suggests that DA1 and DA2B should be considered phenotypic extremes of the same disorder.