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Human Molecular Genetics Pages 1707-1712  
RNA processing and clinical variability in neurofibromatosis type I (NF1)
Introduction
clinical Features Of NF1
Genetic Features Of NF1
Alternative Transcript Expression
Unequal Allelic Expression
NF1 mRNA Editing
Conclusion
The Future
Acknowledgements
References
Table

RNA processing and clinical variability in neurofibromatosis type I (NF1)

RNA processing and clinical variability in neurofibromatosis type I (NF1)

Gary R. Skuse1,2,*, Amedeo J. Cappione2

Departments of 1,2Medicine and 1Radiation Oncology, 1,2Division of Genetics, and 1Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA

Received May 16, 1997

Neurofibromatosis type 1 (NF1) is a common genetic disorder which predisposes affected individuals to a variety of clinical features including tumors of the central and peripheral nervous systems. The product of the NF1 gene, neurofibromin, is a tumor suppressor which most likely acts through the interaction of its GTPase activating protein (GAP) related domain (GRD) with RAS to regulate cellular growth. Two intriguing features of NF1 are the wide range of potentially affected tissues and the great variation in expressivity of disease traits across those affected. To date, the underlying source of this variation remains somewhat unclear, but evidence suggests that aberrations in normal NF1 RNA processing may be involved. This evidence includes: (i) differences in the relative ratios of the type I and type II splice variants in NF1 tumors compared with nontumor tissues; (ii) unequal expression of mutant and normal NF1 alleles in cultured cells derived from NF1 patients; (iii) the existence of NF1 tumors which display NF1 mRNA editing levels that are greater than that seen in non-NF1 tumors; and (iv) tissue-specific and developmental stage-specific expression of particular alternative NF1 transcripts. These findings suggest that the classical 2-hit model for tumor suppressor inactivation used to explain NF1 tumorigenesis can be expanded to include the post-transcriptional mechanisms which regulate NF1 gene expression. Aberrations in these mechanisms may lead to the pathogenesis of NF1 and may play a role in the observed clinical variability.

INTRODUCTION

Neurofibromatosis type 1 (NF1) is a complex hereditary syndrome displaying a vast array of clinical features, which affects tissues derived primarily from the embryonic neural crest. The disease is fully penetrant; however, there is a high degree of phenotypic variability among affected individuals (1). Statistical analyses of common NF1 disease markers within affected families suggest that trait-specific modifying genes may contribute to the expression of particular NF1 clinical features (2). Interestingly, NF1 gene expression is also quite complex, being modulated post-transcriptionally by a number of alternative splicing events and RNA editing in response to a myriad of intrinsic and extrinsic factors. Thus, to better understand the complexity of NF1 disease expression we must first define the factors responsible for the normal regulation of NF1 gene expression and then determine what goes awry in the pathogenesis of this relatively common genetic disorder.

CLINICAL FEATURES OF NF1

Neurofibromatosis type I (NF1) or von Recklinghausen neurofibromatosis is a complex disease in terms of the vast array of associated clinical features and genetics (3,4). Clinically, this disease results in a number of abnormalities which affect tissues derived from the embryonic neural crest (5). The more common manifestations include café au lait spots (hyperpigmented macules), cutaneous and subcutaneous neurofibromas (benign tumors), and malignancies of the central and peripheral nervous systems. The less common abnormalities observed in NF1 patients include learning disabilities (although frank mental retardation is rare) and skeletal abnormalities such as scoliosis and pseudoarthrosis (6). NF1 affects [sim]1 in 3500 live births with no apparent bias for sex or ethnicity (7,8).

A hallmark of this disease is the extreme variability in expression between patients, even among affected members of the same family (9). For example, one would expect affected siblings, who inherited the disease allele from an affected parent, to display the same clinical phenotype, yet this is not always true. It is difficult to reconcile this clinical variability simply in terms of mutations in a single gene. One study which focused on the quantifiable features of NF1 supported the likelihood that other loci were involved in modulating expression of the disease phenotype (10). In this context it is likely that aberrant RNA processing events, which normally affect NF1 gene expression, may play a role in the pathogenesis of this disease and may lead to the variable clinical phenotype.

GENETIC FEATURES OF NF1

NF1 is also complex at the genetic level (for reviews see 4,10). The NF1 gene itself, located at 17q11.2, encompasses >300 kb of human chromosome 17 (11). The 60 exons which constitute the human NF1 gene give rise to several alternatively spliced transcripts. The first one discovered, termed type I, contains an open reading frame of nearly 8.5 kb which encodes a protein of 2818 amino acids (12). Within the central portion of the NF1 encoded protein, neurofibromin, lies a region with homology with the mammalian GTPase activating proteins (GAP) (13,14) and the yeast inhibitor of RAS proteins 1 and 2 (15,16) termed the GAP related domain (GRD). The tumor suppressor activity of neurofibromin is thought to arise from its interaction with and consequent inactivation of RAS (17,18). The location of the NF1 GRD and the site of RNA processing events are shown in Figure 1.

ALTERNATIVE TRANSCRIPT EXPRESSION

Multiple alternative transcripts have been detected which arise from the NF1 gene (Table 1). The two best characterized of these transcripts differ by the inclusion or exclusion of an additional exon located within the NF1 GRD. The type II transcript includes the 63 bp exon 23a which introduces an additional 21 amino acids into neurofibromin while the type I transcript excludes this exon (19). Expression of the type II transcript appears to be regulated in a tissue- and developmental stage-specific manner (20-24).


Figure 1 Sites of NF1 mRNA processing. The horizontal line represents the NF1 mRNA with nucleotide positions indicated below. Alternatively spliced exons and other landmarks are shown above the line. The GAP related domain is represented by the shaded rectangle labeled GRD.

Expression of the type I and type II transcripts also appears to respond to extracellular factors, thereby suggesting that modulation of NF1 gene expression through the expression of these two alternative transcripts is regulated by some epigenetic mechanism. Changes in the levels of NF1 gene expression have been observed in response to environmental factors such as cerebral ischemia in the rat (25). A study of the rat pheochromocytoma cell line PC12 revealed that the relative levels of the type I transcript compared with type II changed in response to treatment with a variety of factors, including nerve growth factor (NGF) and dexamethasone among others (26). That same study detected expression of a third alternative transcript, termed type III, which includes an additional exon within the NF1 GRD, upon treatment of PC12 cells with the protein synthesis inhibitor cycloheximide. The type III transcript includes the 41 bp exon 23b which causes a frame shift and consequently introduces a stop codon within the NF1 GRD (Table 1) (27). A similar transcript cannot be detected in the human cell lines NGP, a neuroblastoma line, or A172, a glioblastoma line (unpublished data).


A fourth murine NF1 transcript isoform, type IV, has been identified which includes exon 23b but not 23a (28). This transcript is present in both mouse and rat. The frame shift resulting from inclusion of exon 23b leads to a termination signal at codon number 1384 of the NF1 gene. Expression levels of both the type III and type IV transcripts are substantially lower than that of types I and II. Levels of the type III transcript are highest in mouse adrenal glands while type IV levels are highest in testis. Interestingly, while the type III and type IV NF1 transcript isoforms encode proteins which lack the majority of their GRDs, their ability to bind to RAS is similar to that of the full length neurofibromin (28). This observation suggests that truncated forms of neurofibromin resulting from translation of the types III and IV transcripts may somehow compete with full length neurofibromin for RAS binding, thereby acting in a dominant negative fashion to regulate the conversion of RAS from its active GTP bound form to its inactive GDP bound form. Several NF1 transcripts have been identified which retain the ability to bind to microtubules yet have reduced or absent GAP activity (Table 2).

Table 1. NF1 alternative transcripts
Transcript name

 Alternative exon
included

 Tissues in which
it is expressed

 Consequence in
neurofibromin

 Does it affect
the GRD?		 Species

 

 Reference

 
9br

 

 9br

 

 CNS only, reduced expression in brain tumors Addition of 10 amino acids

 

 no

 

 human, mouse

 (29)

 
Type II

 

 23a

 

 all, increased expression in brain tumors Addition of 21 amino acids

 

 yes

 

 human, mouse, rat

 (12,20)

 
Type III (rodent) 23a and 23b

 Adrenal glands, kidney, ovaries Introduction of frame shift

 yes

 mouse, rat

 (27,28)
Type IV (rodent) 23b

testis

 Introduction of frame shift

 yes

 mouse

 (28)
Type 3

 

 48a

 

 fetal and adult cardiac and skeletal muscle Addition of 18 amino acids

 

 no

 

 human, mouse, rat

 (34)

 
Type 4

 

 23a and 48a

 

 fetal and adult cardiac and skeletal muscle Addition of 21 amino acids in GRD and 18 amino acids at carboxy terminus yes

 

 human, mouse, rat

 (35)

 
N-Isoform

 Excludes exons 11-most of 49 normal brain and brain tumors Excludes amino acids 548-2815 yes

 human

 (23,37)

Table 2 . Effects of alternative splicing on the NF1 microtubule binding domain and GAP activity
TranscriptMicrotubule binding domainGAP activitya
9brYesNormal
Type IYesNormal
Type IIYesReduced
Type III (rodent)YesNo
Type IV (rodent)YesNo
Type 3YesYes
Type 4YesYes
N-IsoformNoNo
Edited NF1 mRNAYesNob
aGAP activity has been measured for the human type I and type II transcript isoforms, information for the other isoforms is based on the location of an introduced stop codon relative to the GRD.
bIf a protein is translated from the edited NF1 mRNA it would lack the complete GRD.

In addition to the transcript isoforms which differ within their GRDs, several have been identified which differ elsewhere within the coding region. One such transcript contains an additional exon between exons 9 and 10a that is only expressed in brain (29). The additional exon, termed 9br to reflect its tissue-specific expression, encodes 10 amino acids inserted between residues 420 and 421. Expression of the 9br-containing transcript is conserved in mouse thereby supporting the notion that its function, which has yet to be determined, is important. The tissue-specific developmental pattern of expression of murine transcripts containing this alternatively spliced exon suggests that it plays a role in nervous system differentiation and development (30).

While expression of the 9br-containing transcript appears to be localized to the brain, it was not observed in a series of pilocytic astrocytomas of the optic nerve studied by Platten and coworkers (31). They observed a predominance of the NF1 type II transcript isoform lacking exon 9br in those tumors accompanied by an overabundance of NF1 expression, up to 4-fold higher than normal brain. This last observation is somewhat puzzling since neurofibromin is thought to be a tumor suppressor. Overexpression of neurofibromin in a tumor contradicts our common understanding of neurofibromin function but supports an additional role(s) for the NF1 encoded protein.

The same group of investigators that identified the exon 9br-containing NF1 transcript isoform also found a 3[prime] splice variant that includes an additional 54 bp exon inserted 4203 bp downstream of the site of exon 23a inclusion in the NF1 type II transcript isoform (32). The isoform containing that additional exon has been found in skeletal muscle and brain and represents at least 10% of the total NF1 transcript content in those cell types. Its function and temporal expression profile are currently unknown.

While the vast majority of NF1 research in recent years has focused on the GAP related domain, there is some inferential evidence for other functional domains within neurofibromin based on alternative splicing events. An alternative splicing event occurs at the 3[prime] end of the NF1 transcript to produce a transcript containing exon 48a which is observed in developing and adult skeletal and cardiac muscle (33-35). Transcripts containing exon 48a but not 23a are termed type 3 and those with both 48a and 23a are type 4. This observed tissue specificity is, at first glance, unexpected due to the lack of muscle pathology in NF1 patients. However, findings of cardiac abnormalities in transgenic mice homozygously deficient for NF1 suggest that NF1 gene expression is necessary for proper muscle development (36). In this light it is conceivable that exon 48a-containing NF1 transcript expression in particular is necessary.

One particularly interesting NF1 transcript isoform has been identified which lacks the region encoding the GRD. Termed the N-isoform, this transcript includes the region encoding the 547 amino-terminal amino acid residues common to other NF1 transcripts, lacks the GRD, and includes an additional four amino acids normally found in the carboxy terminus (37). Expression of this centrally truncated transcript has been observed in both normal brain and brain tumors, yet its function and any role it may play in regulating neurofibromin expression remain unclear (23).

UNEQUAL ALLELIC EXPRESSION

In addition to regulation of NF1 gene expression through alternative splicing, there is evidence for unequal expression of NF1 alleles. RNA from cultured fibroblasts derived from 15 NF1 patients and from white blood cells from another patient was analyzed for NF1 allele expression (38). Those studies revealed variable levels of allelic expression, expressed as ratios of one allele to the other, ranging from 0.1 to 26.8. Similar analyses of RNA from non-NF1 individuals revealed a more consistent allelic ratio ranging from 1.0 to 1.4. Since these findings were based on analyses of total cellular RNA, the investigators also looked at allelic expression of NF1 transcripts in nuclear RNA. It is interesting that those ratios were consistently [sim]1.0 (0.8-1.6) in the NF1 patients with unequal expression detected in total RNA. These intriguing results suggest that the detected unequal NF1 allelic expression arises either from different stability or differential transport to the cytoplasm. In either case these findings represent yet another level of regulation of NF1 gene expression.

NF1 mRNA EDITING

In addition to the expression of several alternative transcripts, the NF1 mRNA is a substrate for a somewhat uncommon form of RNA processing, namely RNA editing. Editing is a form of post-transcriptional processing by which the coding sequence of the RNA is changed from that which is prescribed by the encoding DNA. RNA editing thus provides another level by which gene expression can be regulated and protein diversity expanded. Several examples of mRNA editing have been identified to date, all of which can be categorized mechanistically as either base substitution or base modification editing (39,40). Base substitution mRNA editing involves the addition, deletion, or replacement of specific nucleotides within the target transcript. Base modification mRNA editing involves the chemical modification of existing nucleotides within the transcript to convert them into different ones. The latter mechanism acts on the NF1 mRNA so that a cytidine at position 3916 is deaminated to become a uracil (41).

The consequence of NF1 mRNA editing is that an in frame stop codon is introduced in the 5[prime] portion of the NF1 GRD. This may result in expression of a truncated form of neurofibromin, lacking the complete GRD, or may lead to an unstable mRNA through nonsense mediated decay (42,43). Which of these two alternatives applies to the edited NF1 mRNA remains to be determined. In either case there is the potential to inactivate NF1 tumor suppressor activity without involving mutations to the NF1 gene itself. This scenario is consistent with the 2-hit hypothesis originally proposed by Knudson (44) and demonstrated to be applicable to malignant NF1 tumors by loss of heterozygosity (LOH) studies in our laboratory (45) and to some benign neurofibromas (46). It is possible that a shortened form of neurofibromin is expressed which either has a unique function compared with the full length protein or somehow interacts with the full length protein to regulate its function.

Interestingly the N-terminal portion of neurofibromin has a demonstrated ability to bind to microtubules (47,48). Immunocytochemical studies localized neurofibromin to the perinuclear region of NIH 3T3 cells coincident with cytoplasmic microtubules (47). These findings are not consistent with the interaction of neurofibromin with RAS at the inner surface of the cell membrane. Since the microtubule binding region would be included in a truncated neurofibromin encoded by an edited mRNA, it is conceivable that such a protein, if expressed, may function to displace microtubule bound full-length neurofibromin thereby liberating it to interact with RAS. This notion has yet to be explored.

Whether or not NF1 mRNA editing plays a role in the pathogenesis of NF1 or NF1 tumors has not been proven definitively. A study of 23 tumors resected from NF1 and non-NF1 patients demonstrated a trend for higher levels of NF1 mRNA editing in tumors compared with nontumor tissues (49). New data have come to light since completing that study which suggest that NF1 mRNA editing in NF1 tumors may not be a consistent event. To date an additional 10 tumors have been analyzed with levels of editing at or below the levels observed in nontumor tissue. The significance of these data remains unclear due to the inherent heterogeneity of the tumor samples analyzed both in terms of the proportion of infiltrating nontumor tissue and the integrity of their RNA. However, the failure to detect LOH in benign neurofibromas analyzed in our laboratory (50) suggests that another mechanism, distinct from mutations at the NF1 locus, may be responsible for the development of these lesions. Though there are several explanations for the failure to detect LOH, namely the difficulty in analyzing a large gene and the availability of informative probes, it is plausible that NF1 tumors may occasionally arise due to inappropriate expression of the edited or alternatively spliced isoforms of NF1. It is conceivable, particularly in light of the already recognized complex mechanisms which regulate NF1 gene expression, that a class of tumors exists in which NF1 mRNA is edited at levels below that observed in nontumor tissue. This possibility is currently under investigation.

Another intriguing observation which supports the notion that the introduction of a stop codon at the NF1 editing site is pathogenic comes from the identification of an NF1 patient at the University of Tennessee at Memphis who is heterozygous for a C to U transition at base number 3916 (V. Park and E. Pivnick, personal communication). The mutation in that patient, an 8 year old female with an apparently negative family history of NF1, was detected during the course of routine screening of NF1 patient cDNA with a protein truncation test (PTT). Sequence analysis of this patient's genomic DNA confirmed that the mutation is present in the DNA and therefore does not arise from aberrantly high levels of mRNA editing. Whether this mutation is pathogenic and whether it is the patient's sole NF1 mutation has not been demonstrated. It is important to note, however, that analysis of this patient's entire NF1 coding region by PTT did not detect any other truncating mutations. Work is underway in our laboratory to determine whether a polypeptide expressed in cultured cells from a cDNA fragment derived from this patient can act in a dominant negative fashion to affect the product of the endogenous NF1 gene.

Interestingly, neither mouse nor rat NF1 mRNAs undergo RNA editing. This is most likely due to sequence divergence between the human and murine species at the editing site (41). However, murine species do express the alternatively spliced type III and type IV isoforms which, to date, have not been identified in any human cells analyzed (unpublished data). It is thus tempting to speculate that human NF1 mRNA editing and alternative splicing of the murine exon 23b are divergent mechanisms which have evolved to conserve the introduction of a stop codon at the 5[prime] end of the NF1 GRD. Analysis of RNA isolated from the aforementioned NF1 patient demonstrated that the two NF1 alleles were expressed equally, thereby demonstrating the stability of an NF1 mRNA carrying a nonsense mutation at position 3916. It can therefore be inferred that production of the same stop codon, by RNA editing, should not confer instability upon the NF1 transcript but may allow for the creation of a truncated form of neurofibromin.


Figure 2 Regulation of neurofibromin expression. Three mechanisms are illustrated which may regulate intracellular neurofibromin levels. The top horizontal line represents normal NF1 gene expression. The middle horizontal line represents both NF1 mRNA editing or biallelic DNA mutations which result in the absence of neurofibromin or the expression of an abnormal protein. The bottom horizontal line represents unequal allelic expression resulting from a single DNA mutation in the NF1 gene.

Site-specific editing of the NF1 transcript was identified through sequence homology to the tripartite motif responsible for apolipoprotein B (apoB) mRNA editing (41,51). The trans-acting factors responsible for the chemical conversion in apoB mRNA editing assemble at the editing site as a large complex termed the editosome. The editosome is composed of a number of undefined auxiliary factors, two RNA binding proteins (p66 and p44) and a cytidine deaminase (APOBEC-1) which gains catalytic specificity through complex assembly (52,53). Unlike apoB, NF1 editing does not demonstrate dependence on rate-limiting quantities of APOBEC-1 (41). However, inhibition of APOBEC-1 expression by the expression of stably transfected antisense transcripts reduces the efficiency of both NF1 and apoB editing (unpublished data). These results suggest that both mRNAs are substrates for APOBEC-1 but that auxiliary factors which comprise their respective editosomes, and confer substrate specificity, may be distinct.

CONCLUSION

Many mechanisms have been identified which modulate NF1 gene expression. Taken together they may function to regulate intracellular neurofibromin levels, express or inhibit the tumor suppressor activity of neurofibromin, or to selectively express other forms of neurofibromin with functions currently not understood (Fig. 2). Clearly the roles of the NF1 gene products in regulating cellular proliferation and differentiation have yet to be fully revealed.

THE FUTURE

NF1 is interesting from both a clinical and a biological perspective. While there is not yet a clearly understood association between aberrations in the myriad mechanisms involved with NF1 mRNA processing and observed clinical phenotype, it is likely that one exists. Once such an understanding is attained there will be opportunities for presymptomatic and prognostic genetic testing as well as for developing gene therapies which are directed at correcting abnormalities of RNA processing. On the one hand the complexity inherent in NF1 gene expression may appear daunting. On the other hand it provides a challenge to molecular geneticists with the potential reward of gaining insight into mechanisms which likely play a role in regulating the expression of other disease-related genes as well.

ACKNOWLEDGEMENTS

Work in the authors' laboratory is supported by grants awarded to G.R.S. from the National Institutes of Health (CA55173), the Charlotte Geyer Foundation, and the Buffalo Rochester Syracuse Neurooncology Research Group. A.J.C is supported in part by a predoctoral award from the Interdepartmental Training Grant in Genetics and Regulation (GM07102).

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*To whom correspondence should be addressed. Tel: +1 716 275 3463; Fax: +1 716 273 1034; Email: gary_skuse@medicine.rochester.edu

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