RESUMO
Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.
Assuntos
Fibronectinas/genética , Fraturas Ósseas/genética , Mutação/genética , Osteocondrodisplasias/genética , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/genética , Osso e Ossos/patologia , Cartilagem/patologia , Criança , Pré-Escolar , Exoma/genética , Feminino , Humanos , Masculino , Fenótipo , Escoliose/genéticaRESUMO
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.
Assuntos
Anormalidades Múltiplas/genética , Aracnodactilia/genética , Artrogripose/genética , Blefarofimose/genética , Fissura Palatina/genética , Pé Torto Equinovaro/genética , Doenças do Tecido Conjuntivo/genética , Contratura/genética , Deformidades Congênitas da Mão/genética , Canais Iônicos/genética , Oftalmoplegia/genética , Doenças Retinianas/genética , Anormalidades Múltiplas/patologia , Aracnodactilia/patologia , Artrogripose/patologia , Blefarofimose/patologia , Criança , Pré-Escolar , Fissura Palatina/patologia , Pé Torto Equinovaro/patologia , Doenças do Tecido Conjuntivo/patologia , Contratura/patologia , Exoma/genética , Feminino , Deformidades Congênitas da Mão/patologia , Humanos , Masculino , Mutação , Oftalmoplegia/patologia , Linhagem , Doenças Retinianas/patologiaRESUMO
The combination of Dandy-Walker malformation, other central nervous system anomalies, and postaxial polydactyly has been reported previously in two pairs of siblings. We propose the name 'Pierquin syndrome' for this combination and we report a new patient with this disorder.