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Osimani S.,Robert Debre University Hospital | Osimani S.,University of Pavia | Husson I.,Robert Debre University Hospital | Passemard S.,Robert Debre University Hospital | And 9 more authors.
European Journal of Medical Genetics | Year: 2010

Uncommon features of rare genetic disorders are often poorly known, as the likelihood of having them reported is low. We describe a 7-year-old boy with clinical and radiological diagnosis of pycnodysostosis, and c.436G>C (p.G146R) mutation in CSTK). He developed intracranial hypertension that required surgical decompression. Despite patent fontanels, the cause of the intracranial hypertension was identified to be a combination of coronal and metopic craniosynostoses. Intracranial hypertension and craniosynostosis have only been reported once in pycnodysostosis, which is on the contrary characterized by delayed closure of the sutures and persistence of open fontanels. Our observation confirms that intracranial hypertension represents a rare but life-threatening complication of pycnodysostosis. We strongly suggest including systematic examination of fundus oculi and monitoring of OFC in the systematic clinical follow-up of these patients. © 2009 Elsevier Masson SAS. All rights reserved.

Bachetti T.,CNR Institute of Molecular Genetics | DiZanni E.,CNR Institute of Molecular Genetics | Lantieri F.,CNR Institute of Molecular Genetics | Lantieri F.,University of Genoa | And 13 more authors.
Annals of Human Genetics | Year: 2010

The Glial Fibrillary Acidic Protein (GFAP) gene encodes a cytoskeletal protein belonging to the intermediate filament family whose expression is considered as a marker of astrocytes differentiation. GFAP expression, shown to be upregulated as a consequence of brain gliosis, depends on hormones, growth factors, cytokine, and transcription factors and, among these latters, activator protein 1 (AP-1) has been demonstrated to play a crucial role. In this study, we have focused on a 2.2 kb sequence of the regulatory region located upstream of the GFAP gene, searching in a panel of control individuals for single-nucleotide polymorphisms (SNPs) that could modulate GFAP transcription. Among four SNPs of the GFAP promoter whose alleles have been predicted by in silico analysis to induce differences in the pattern of binding transcription factors, we have identified a new AP-1 binding site lying at -250 bp upstream from the GFAP transcriptional start site. The two alleles of this polymorphic locus have shown to bind the AP-1 complex to different extents, thus promoting variable transcriptional activities of the GFAP promoter. Therefore, these SNP alleles may, among others, mediate the effects of GFAP mutations, thus explaining the phenotypic heterogeneity of Alexander disease. © 2010 The Authors Annals of Human Genetics © 2010 Blackwell Publishing Ltd/University College London.

Biancheri R.,Child Neurology and Psychiatry Unit | Rosano C.,SS Biopolimeri e Proteomica | Denegri L.,Child Neurology and Psychiatry Unit | Lamantea E.,C Besta Neurological Institute | And 4 more authors.
European Journal of Human Genetics | Year: 2013

Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus-Merzbacher-like disease (PMLD1, MIM 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus-Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra-and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G>A) mutation, occurring in a highly conserved motif (SRPTEK) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a 'salt bridge network', crucial for a proper connexin-connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein. © 2013 Macmillan Publishers Limited. All rights reserved.

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