Abstract | BACKGROUND:
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. 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. RESULTS: Here 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. CONCLUSIONS: The 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.
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Authors | Antonia Assunto, Ursula Ferrara, Alessandro De Luca, Claudia Pivonello, Lisa Lombardo, Annapina Piscitelli, Cristina Tortora, Valentina Pinna, Paola Daniele, Rosario Pivonello, Maria Giovanna Russo, Giuseppe Limongelli, Annamaria Colao, Marco Tartaglia, Pietro Strisciuglio, Daniela Melis |
Journal | Orphanet journal of rare diseases
(Orphanet J Rare Dis)
Vol. 14
Issue 1
Pg. 261
(11 15 2019)
ISSN: 1750-1172 [Electronic] England |
PMID | 31730495
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- NF1 protein, human
- Neurofibromin 1
- Protein Isoforms
- RNA, Messenger
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Topics |
- Adolescent
- Adult
- Case-Control Studies
- Cerebrovascular Disorders
(genetics, metabolism, pathology)
- Child
- Child, Preschool
- Cognitive Dysfunction
(genetics, metabolism, pathology)
- Female
- Humans
- Infant
- Male
- Middle Aged
- Neoplasms
(genetics, metabolism, pathology)
- Neurofibromatosis 1
(genetics, metabolism, pathology)
- Neurofibromin 1
(genetics, metabolism)
- Optic Nerve Glioma
(genetics, metabolism, pathology)
- Protein Biosynthesis
- Protein Isoforms
(genetics, metabolism)
- RNA, Messenger
(genetics, metabolism)
- Young Adult
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