Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1 | Orphanet Journal of Rare Diseases | Full Text

Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1 | Orphanet Journal of Rare Diseases | Full Text

Orphanet Journal of Rare Diseases

Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1

• 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 

Orphanet Journal of Rare Diseases volume 14, Article number: 261 (2019) Cite this article

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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.