Molecular Therapeutics for Heritable Skin Diseases

Uitto, Jouni

doi:10.1038/skinbio.2012.9

Cited by 9 publications

(9 citation statements)

References 48 publications

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“…This observation is consistent with previous demonstrations that mice with β-thalassemia, which have ∼25% level of ABCC6 expression, do not develop mineralization phenotype [20]. These findings have implications for any potential therapy that is aimed to restore ABCC6 expression in the liver of patients with PXE, either through gene therapy, protein replacement, or cell-based therapy approaches [21]. At the same time, it is clear that the expression of Abcc6 in inbred mouse strains can result in varying degrees of mineralization dependent of the diet.…”

Section: Discussionsupporting

confidence: 92%

Mouse Models for Pseudoxanthoma Elasticum: Genetic and Dietary Modulation of the Ectopic Mineralization Phenotypes

Guo

Chou

et al. 2014

PLoS ONE

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Pseudoxanthoma elasticum (PXE), a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene. Null mice (Abcc6−/−) recapitulate the genetic, histopathologic and ultrastructural features of PXE, and they demonstrate early and progressive mineralization of vibrissae dermal sheath, which serves as a biomarker of the overall mineralization process. Recently, as part of a mouse aging study at The Jackson Laboratory, 31 inbred mouse strains were necropsied, and two of them, KK/HlJ and 129S1/SvImJ, were noted to have vibrissae dermal mineralization similar to Abcc6−/− mice. These two strains were shown to harbor a single nucleotide polymorphism (rs32756904) in the Abcc6 gene, which resulted in out-of-frame splicing and marked reduction in ABCC6 protein expression in the liver of these mice. The same polymorphism is present in two additional mouse strains, DBA/2J and C3H/HeJ, with similar reduction in Abcc6 protein levels, yet these mice did not demonstrate tissue mineralization when kept on standard rodent diet. However, all four mouse strains, when placed on experimental diet enriched in phosphate and low in magnesium, developed extensive ectopic mineralization. These results indicate that the genetic background of mice and the mineral composition of their diet can profoundly modulate the ectopic mineralization process predicated on mutations in the Abcc6 gene. These mice provide novel model systems to study the pathomechanisms and the reasons for strain background on phenotypic variability of PXE.

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Section: Discussionsupporting

confidence: 92%

Mouse Models for Pseudoxanthoma Elasticum: Genetic and Dietary Modulation of the Ectopic Mineralization Phenotypes

Guo

Chou

et al. 2014

PLoS ONE

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“…Proteins were separated on a NuPage gel (Life Technologies) and transferred to Hybond nitrocellulose membranes (GE Healthcare). The following primary antibodies were used: β-actin (1:1000; Santa Cruz, sc-47778), IFT27 [1:1000; gift of G. Pazour, University of Massachusetts (Keady et al, 2012)], GLI1 (1:250; clone V812, Cell Signaling, 2534S), GLI3 (1:200; R&D Systems, AF3690), IFT25 (1:1000; Proteintech, 15732-1-AP) and IFT140 [1:500 (Uitto, 2012)]. HRP-conjugated secondary antibodies (BD Biosciences), SuperSignal substrates (Thermo Scientific) and CL-XPosure film (Thermo Scientific) were used for detection.…”

Section: Cell Culture and In Vitro Assaysmentioning

confidence: 99%

Intraflagellar transport 27 is essential for hedgehog signaling but dispensable for ciliogenesis during hair follicle morphogenesis

Yang

Eguether

et al. 2015

Development

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Hair follicle morphogenesis requires precisely controlled reciprocal communications, including hedgehog (Hh) signaling. Activation of the Hh signaling pathway relies on the primary cilium. Disrupting ciliogenesis results in hair follicle morphogenesis defects due to attenuated Hh signaling; however, the loss of cilia makes it impossible to determine whether hair follicle phenotypes in these cilia mutants are caused by the loss of cilia, disruption of Hh signaling, or a combination of these events. In this study, we characterized the function of Ift27, which encodes a subunit of intraflagellar transport (IFT) complex B. Hair follicle morphogenesis of Ift27-null mice was severely impaired, reminiscent of phenotypes observed in cilia and Hh mutants. Furthermore, the Hh signaling pathway was attenuated in Ift27 mutants, which was in association with abnormal ciliary trafficking of SMO and GLI2, and impaired processing of Gli transcription factors; however, formation of the ciliary axoneme was unaffected. The ciliary localization of IFT25 (HSPB11), the binding partner of IFT27, was disrupted in Ift27 mutant cells, and Ift25-null mice displayed hair follicle phenotypes similar to those of Ift27 mutants. These data suggest that Ift27 and Ift25 operate in a genetically and functionally dependent manner during hair follicle morphogenesis. This study suggests that the molecular trafficking machineries underlying ciliogenesis and Hh signaling can be segregated, thereby providing important insights into new avenues of inhibiting Hh signaling, which might be adopted in the development of targeted therapies for Hh-dependent cancers, such as basal cell carcinoma.

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“…In several countries, mutation analysis is now routinely available, every patient having the right to know his/her own mutation. This development expanded the spectrum of disorders encompassed by the term EB and represents the basis for individualized molecular therapeutic approaches (Cho et al, 2012;Uitto, 2012).…”

Section: Clinical Perspectivementioning

confidence: 99%

Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa

Bruckner‐Tuderman

Has

2012

Journal of Investigative Dermatology

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Molecular Therapeutics for Heritable Skin Diseases

Cited by 9 publications

References 48 publications

Mouse Models for Pseudoxanthoma Elasticum: Genetic and Dietary Modulation of the Ectopic Mineralization Phenotypes

Mouse Models for Pseudoxanthoma Elasticum: Genetic and Dietary Modulation of the Ectopic Mineralization Phenotypes

Intraflagellar transport 27 is essential for hedgehog signaling but dispensable for ciliogenesis during hair follicle morphogenesis

Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa

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