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Mirabelli-Badenier M.,Neuropsichiatria Istituto Giannina Gaslini | Severino M.,Neuroradiologia Istituto Giannina Gaslini | Tappino B.,Centro Of Diagnostica Genetica ochimica Delle Malattie Metaboliche Istituto Giannina Gaslini | Tortora D.,University of Chieti Pescara | And 8 more authors.
Metabolic Brain Disease | Year: 2015

Mucolipidosis type IV (MLIV) is a very rare disorder of late endosome/lysosome transport, characterized by neurodevelopmental abnormalities and progressive visual impairment owing to corneal clouding and retinal dystrophy. Greater than 70 % of MLIV patients are of Ashkenazi Jewish ancestry. Here we report a novel MCOLN1double mutant allele [c.395_397delCTG;c.468_474dupTTGGACC] which introduces a premature stop codon [p.Ala132del; p.Asn159LeufsX27] leading to almost complete abrogation of the region coding mucolipin-1, a member of the transient receptor potential (TRP) cation channel family. The genomic lesion was identified in homozygous state, in a non-Jewish Italian MLIV patient, who also presented abnormal serum gastrin levels. Conventional and advanced MRI sequences, including diffusion tensor imaging and tractography, were used for the assessment of white matter involvement in the patient. © 2014, Springer Science+Business Media New York.

Zancan I.,University of Padua | Bellesso S.,University of Padua | Costa R.,University of Padua | Salvalaio M.,University of Padua | And 5 more authors.
Human Molecular Genetics | Year: 2015

Loss of lysosomal glucocerebrosidase (GBA1) function is responsible for several organ defects, including skeletal abnormalities in type 1 Gaucher disease (GD). Enhanced bone resorption by infiltrating macrophages has been proposed to lead to major bone defects. However, while more recent evidences support the hypothesis that osteoblastic bone formation is impaired, a clear pathogenetic mechanism has not been depicted yet. Here, by combining different molecular approaches, we show that Gba1 loss of function in zebrafish is associated with defective canonical Wnt signaling, impaired osteoblast differentiation and reduced bone mineralization. We also provide evidence that increased reactive oxygen species production precedes the Wnt signaling impairment, which can be reversed upon human GBA1 overexpression. Type 1 GD patient fibroblasts similarly exhibit reduced Wnt signaling activity, as a consequence of increased β-catenin degradation. Our results support a novel model in which a primary defect in canonical Wnt signaling antecedes bone defects in type 1 GD. © The Author 2014.

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