Mental retardation and cardiovascular malformations in NF1 microdeleted patients point to candidate genes in 17q11.2

University of Milan, Milano, Lombardy, Italy
Journal of Medical Genetics (Impact Factor: 6.34). 02/2004; 41(1):35-41. DOI: 10.1136/jmg.2003.014761
Source: PubMed
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    • "microdeletion patients showing severe intellectual disability [11], and for non syndromic intellectual disability [12]. Given the key role played by CDK5R1 in central nervous system (CNS) development and maintenance, the regulation of its expression is crucial. "
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    ABSTRACT: Cyclin-Dependent Kinase 5 Regulatory subunit 1 (CDK5R1) encodes p35, a specific activator of Cyclin-Dependent Kinase 5 (CDK5). CDK5 and p35 have a fundamental role in neuronal migration and differentiation during CNS development. Both the CDK5R1 3'-UTR's remarkable size and its conservation during evolution strongly indicate an important role in post-transcriptional regulation. We previously validated different regulatory elements in the 3'-UTR of CDK5R1, which affect transcript stability, p35 levels and cellular migration through the binding with nELAV proteins and miR-103/7 miRNAs. Interestingly, a 138bp-long region, named C2.1, was identified as the most mRNA destabilizing portion within CDK5R1 3'-UTR. This feature was maintained by a shorter region of 73bp, characterized by two poly-U stretches. UV-CL experiments showed that this region interacts with protein factors. UV-CLIP assays and pull-down experiments followed by mass spectrometry analysis demonstrated that nELAV and hnRNPA2/B1 proteins bind to the same U-rich element. These RNA-binding proteins (RBPs) were shown to oppositely control CDK5R1 mRNA stability and p35 protein content at post-trascriptional level. While nELAV proteins have a positive regulatory effect, hnRNPA2/B1 has a negative action that is responsible for the mRNA destabilizing activity both of the C2.1 region and of the full-length 3'-UTR. In co-expression experiments of hnRNPA2/B1 and nELAV RBPs we observed an overall decrease of p35 content. We also demonstrated that hnRNPA2/B1 can downregulate nELAV protein content but not viceversa. This study, by providing new insights on the combined action of different regulatory factors, contributes to clarify the complex post-transcriptional control of CDK5R1 gene expression.
    Full-text · Article · May 2014 · Biochimica et Biophysica Acta
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    • "The high allelic heterogeneity of the constitutional NF1 mutation may explain some of this variability. A more severe phenotype has indeed been described in patients with large deletions of the NF1 gene region, particularly in respect to the presence of learning disabilities, facial dysmorphic features, and cardiovascular malformations, as compared with patients carrying intragenic NF1 mutations [Mautner et al., 2010; Pasmant et al., 2010; Venturin et al., 2004]. However, in the case of intragenic NF1 mutations, no clearcut allele–phenotype correlations have been established so far, with the exception of a 3-bp in-frame deletion (c.2970–2972 delAAT) in exon 17 of the NF1 gene, which was associated with a particular clinical phenotype characterized by the absence of cutaneous neurofibromas [Upadhyaya et al., 2007]. "
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    ABSTRACT: Neurofibromatosis type 1 (NF1) affects about one in 3,500 people in all ethnic groups. Most NF1 patients have private loss-of-function mutations scattered along the NF1 gene. Here, we present an original NF1 investigation strategy and report a comprehensive mutation analysis of 565 unrelated patients from the NF-France Network. A NF1 mutation was identified in 546 of the 565 patients, giving a mutation detection rate of 97%. The combined cDNA/DNA approach showed that a significant proportion of NF1 missense mutations (30%) were deleterious by affecting pre-mRNA splicing. Multiplex ligation-dependent probe amplification allowed the identification of restricted rearrangements that would have been missed if only sequencing or microsatellite analysis had been performed. In four unrelated families, we identified two distinct NF1 mutations within the same family. This fortuitous association points out the need to perform an exhaustive NF1 screening in the case of molecular discordant related patients. A genotype-phenotype study was performed in patients harboring a truncating (N=368), in-frame splicing (N=36), or missense (N=35) mutation. The association analysis of these mutation types with 12 common NF1 clinical features confirmed a weak contribution of the allelic heterogeneity of the NF1 mutation to the NF1 variable expressivity. This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2013 · Human Mutation
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    • "Indeed, the clinical diagnosis of NF1 does not allow the formulation of a definite prognosis. Moreover, NF1 gene mutations do not correlate with the clinical picture, except for two remarkable exceptions neither of which include TO: the whole NF1 gene deletion [Upadhyaya et al., 1998; Riva et al., 2000; Venturin et al., 2004; Spiegel et al., 2005; Mensink et al., 2006], and the 3-bp in-frame deletion of exon 17 (c.2970-2972 delAAT) [Upadhyaya et al., 2007]. "
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    ABSTRACT: Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disorder characterized by high penetrance, widely variable expressivity and occurrence of specific skeletal changes such as tibial osteopathy (TO). We collected data on patients referred to the Italian Neurofibromatosis Study Group in order to compare clinical features between 49 NF1 patients with TO, and 98 age-matched NF1 patients without TO, and to determine whether the presence of TO is associated with a different risk of developing the typical NF1 complications. We assessed both groups for: age at diagnosis of NF1, gender distribution, family history, gender inheritance, presence of scoliosis, sphenoid wing osteopathy, other skeletal abnormalities, macrocrania, hydrocephalus, plexiform neurofibromas, tumors, optic pathway gliomas, T2H (high-signal intensity areas on T2 weighted brain MRI), epilepsy, headache, mental retardation, cardiovascular malformations, and Noonan phenotype. Patients of both groups were subdivided by gender and re-evaluated for these items. Statistical comparison was carried out between the two groups of patients for each feature. We collected data on type of treatment and on the clinical conditions of NF1-TO patients after follow-up. Patient's age at NF1 diagnosis was significantly younger in NF1-TO subjects compared with NF1 subjects without TO, and the incidence of T2H was significantly reduced in NF1-TO males compared with NF1 males without TO. The presence of TO does not imply that there is an increased risk of developing typical complications of NF1 (e.g., optic pathway glioma, plexiform neurofibroma, etc.), however, it does allow us to make an earlier diagnosis of NF1. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · May 2013 · American Journal of Medical Genetics Part A
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