Abstract
BackgroundNeurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability.ResultsHere we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment.ConclusionsThe present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.
Highlights
Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations
Design and setting of the study One hundred and thirty eight individuals diagnosed with NF1 according to National Institutes of Health criteria were enrolled into the study at the Department of Translational Medicine, Federico II University of Naples, Pediatric Section, after the study protocol was discussed with each patient and an informed consent was signed
Expression levels of NF1 mRNA isoforms I and II were examined in peripheral blood leukocytes of 138 NF1 patients and compared with those of 138 population, ageand sex-matched healthy controls
Summary
Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. As many as 92–94% of multiexon genes are predicted to undergo alternative splicing [4]. This process is important in the control of developmental programs and cell physiology, as well as in the pathogenesis. 1:2000–3000 live births) [7, 8] It is transmitted as an autosomal dominant trait, and is caused by germline loss-of-function mutations in the NF1 gene, which encodes neurofibromin, a GTPase negatively controlling RAS signaling [9]. The neoplastic risk is related to functional loss of the GTPase activity of neurofibromin due to somatic hits involving NF1, according to the Knudson’s model, causing cell autonomous, and sustained activation of the Ras-mitogen-activated protein kinases (MAPK) pathway
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