RESUMO
Keppen-Lubinsky syndrome (KPLBS) is a rare disease mainly characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, a narrow nasal bridge, a tented upper lip, a high palate, an open mouth, tightly adherent skin, an aged appearance, and severe generalized lipodystrophy. We sequenced the exomes of three unrelated individuals affected by KPLBS and found de novo heterozygous mutations in KCNJ6 (GIRK2), which encodes an inwardly rectifying potassium channel and maps to the Down syndrome critical region between DIRK1A and DSCR4. In particular, two individuals shared an in-frame heterozygous deletion of three nucleotides (c.455_457del) leading to the loss of one amino acid (p.Thr152del). The third individual was heterozygous for a missense mutation (c.460G>A) which introduces an amino acid change from glycine to serine (p.Gly154Ser). In agreement with animal models, the present data suggest that these mutations severely impair the correct functioning of this potassium channel. Overall, these results establish KPLBS as a channelopathy and suggest that KCNJ6 (GIRK2) could also be a candidate gene for other lipodystrophies. We hope that these results will prompt investigations in this unexplored class of inwardly rectifying K(+) channels.
Assuntos
Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Deficiência Intelectual/genética , Modelos Moleculares , Anormalidades Múltiplas/patologia , Sequência de Bases , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Primers do DNA/genética , Deficiências do Desenvolvimento/patologia , Exoma/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/química , Humanos , Deficiência Intelectual/patologia , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Linhagem , Análise de Sequência de DNA , Deleção de Sequência/genética , SíndromeRESUMO
Mitochondria-targeting photodynamic therapy (PDT) can block mitochondrial function and trigger the inherent proapoptotic cascade signal of mitochondria, which has been considered to have the potential to amplify the efficiency of PDT. However, the dynamic change of mitochondrial membrane potential (MMP) makes most cationic photosensitizers easily fall off from the mitochondria, which greatly limits the efficiency of PDT. Here, we have developed a smart liposome encapsulation method based on a mitochondria-stapling photosensitizer for efficient theranostic photodynamic therapy. The stapling photosensitizer can be covalently bound inside mitochondria via two reaction sites without a falloff effect, regardless of the change of MMP. As a result, the liposome-based nanophotosensitizer showed a high efficiency of PDT (IC50 = 0.98 µM) under 630 nm light. At the same time, the nanophotosensitizer had fluorescence imaging-guided ability to monitor abnormal mitochondrial morphology during PDT. Importantly, the results of mice experiments also showed that the liposome-based nanophotosensitizer possessed excellent antitumor PDT activity because the released photosensitizer can stay inside mitochondria during the whole process of PDT.