RESUMO
Robinow syndrome (RS) is a phenotypically and genetically heterogeneous condition that can be caused by mutations in genes encoding components of the non-canonical Wnt signaling pathway. In contrast, germline mutations that act to increase canonical Wnt signaling lead to distinctive osteosclerotic phenotypes. Here, we identified de novo frameshift mutations in DVL1, a mediator of both canonical and non-canonical Wnt signaling, as the cause of RS-OS, an RS subtype involving osteosclerosis, in three unrelated individuals. The mutations all delete the DVL1 C terminus and replace it, in each instance, with a novel, highly basic sequence. We showed the presence of mutant transcript in fibroblasts from one individual with RS-OS and demonstrated unimpaired protein stability with transfected GFP-tagged constructs bearing a frameshift mutation. In vitro TOPFlash assays, in apparent contradiction to the osteosclerotic phenotype, revealed that the mutant allele was less active than the wild-type allele in the canonical Wnt signaling pathway. However, when the mutant and wild-type alleles were co-expressed, canonical Wnt activity was 2-fold higher than that in the wild-type construct alone. This work establishes that DVL1 mutations cause a specific RS subtype, RS-OS, and that the osteosclerosis associated with this subtype might be the result of an interaction between the wild-type and mutant alleles and thus lead to elevated canonical Wnt signaling.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Nanismo/genética , Nanismo/patologia , Mutação da Fase de Leitura/genética , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Osteosclerose/genética , Fosfoproteínas/genética , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/patologia , Via de Sinalização Wnt/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Desgrenhadas , Proteínas de Fluorescência Verde/metabolismo , Humanos , Fosfoproteínas/metabolismo , FosforilaçãoRESUMO
Robinow syndrome (RS) is a clinically and genetically heterogenous condition primarily characterized by short stature, mesomelia, genital hypoplasia, oral abnormalities, and a facial gestalt that includes hypertelorism, a short nose, and a broad mouth. The disorder exists in both a dominant and a more severe recessive form. Here two unrelated cases of sporadic RS are described with the additional finding of axial and appendicular osteosclerosis. These two patients, coupled with three additional patients previously described in the literature, may represent a distinct sub-phenotype of this condition.