Journal of Neurogenetics

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Possible modifier in the variation of neurofibromatosis type 1 clinical phenotypes

Parisa Sharafi & Sükriye Ayter

To cite this article: Parisa Sharafi & Sükriye Ayter (2018): Possible modifier genes in the variation of neurofibromatosis type 1 clinical phenotypes, Journal of Neurogenetics, DOI: 10.1080/01677063.2018.1456538 To link to this article: https://doi.org/10.1080/01677063.2018.1456538

Published online: 12 Apr 2018.

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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ineg20 JOURNAL OF NEUROGENETICS, 2018 https://doi.org/10.1080/01677063.2018.1456538

REVIEW ARTICLE Possible modifier genes in the variation of neurofibromatosis type 1 clinical phenotypes

Parisa Sharafi and Sukriye€ Ayter Faculty of Medicine, TOBB University of Economics and Technology, Ankara, Turkey

ABSTRACT ARTICLE HISTORY Neurofibromatosis type 1 (NF1) is the most common neurogenetic disorder worldwide, caused by muta- Received 9 October 2017 tions in the (NF1) . Although NF1 is a single-gene disorder with autosomal-dominant inheritance, Accepted 20 March 2018 its clinical expression is highly variable and unpredictable. NF1 patients have the highest known muta- KEYWORDS tion rate among all human disorders, with no clear genotype–phenotype correlations. Therefore, varia- NF1 Neurofibromatosis type 1; tions in mutations may not correlate with the variations in clinical phenotype. Indeed, for the same genotype–phenotype correl- mutation, some NF1 patients may develop severe clinical symptoms whereas others will develop a mild ation; clinical variability; phenotype. Variations in the mutant NF1 allele itself cannot account for all of the disease variability, modifier genes indicating a contribution of modifier genes, environmental factors, or their combination. Considering the gene structure and the interaction of neurofibromin with cellular components, there are many possible candidate modifier genes. This review aims to provide an overview of the potential modifier genes contributing to NF1 clinical variability.

Introduction This region is referred to as the NF1-GAP-related domain (NF1-GRD) and is encoded by the central part of the NF1 Neurofibromatosis type 1 (NF1) (OMIM#162200) is one of gene. The GAP downregulate the activity of the Ras the most common autosomal-dominant disorders, affecting – oncoprotein by stimulating its intrinsic GTPase activity. approximately 1 in 2000 3000 (Koczkowska et al., 2018) Therefore, neurofibromin is part of the Ras-mediated signal individuals in all ethnic groups worldwide. It is clinically transduction mechanism. Several genetic disorders are characterized by cafe-au-lait spots (CLS), Lisch nodules, axil- caused by dysfunction in gene products associated with this lary and inguinal freckling, multiple peripheral nerve tumors, pathway, and owing to their common phenotypes, they have bone lesions, and a predisposition to malignancy. Therefore, been recently classified together and termed as ‘Rasopathies.’ NF1 gene (OMIM# 613113; 17q11.2) is consid- Three genes, EVI2A, EVI2B, and OMGP, are embedded ered to function as a tumor suppressor gene. NF1 gene is within intron 27 b of the NF1 gene. These genes are tran- comprised of 61 exons distributed over 350 kb of genomic scribed in the direction opposite to that of the NF1 gene. DNA (Trovo-Marqui & Tajara, 2006). Initially identified However, little is known about the function of these genes. NF1 gene contained 57 exons (Marchuk et al., 1991). In the A hallmark of the NF1 gene is its high mutation rate; almost next following years four alternatively spliced exons, tempor- half of all NF1 cases result from de novo mutations in NF1 ary numerically assigned as 9a, 10a-2, 23a, and 48a were dis- (Upadhyaya et al., 2003). Detecting mutation causing neuro- covered. Recently, in order to get over inconsistencies and fibromatosis type 1 disease is hindered by lack of mutation confusion which has led by this numbering system in clinical hotspots and a wide mutation spectrum in NF1 gene and scientific publications, this way of exon designations of (Figure 1 (Lower)) (Valero et al., 2011; Zhang et al., 2015; NF1 gene has been updated and named according to their Zhu et al., 2016). However, Koczkowska et al. (2018) showed location, i.e. 11alt12 (formerly 9a), 12alt13 (formerly 10a-2), a hotspot for occurring missense mutation in NF1. However, 30alt31 (formerly 23a), and 56alt57 (formerly 48a) these recurrent missense mutations affect 0.8% of unre- (Anastasaki, Le, Kesterson, & Gutmann, 2017). lated NF1 mutation-positive probands. Neurofibromas, characteristic features of the disease, are NF1 patients have intragenic NF1 mutations with no clear found in cutaneous, subcutaneous, and plexiform types, and genotype–phenotype correlations but there are some excep- although they are benign, they could develop malignancy. tions. It has been shown that patients with 3-bp in-frame NF1 is caused by dominant loss-of-function (LOH) muta- deletion (c0.2970–2972 delAAT) in exon 17 show a mild tions in the NF1 gene, which encodes neurofibromin, a clinical phenotype with no cutaneous neurofibromas or clin- negative regulator of Ras proteins. A 360-amino acid region ically obvious plexiform neurofibromas (PNFs) (Upadhyaya of the gene product shows homology to the catalytic domain et al., 2007). NF1 patients with severe phenotype usually are of the mammalian GTPase-activating protein (GAP). associated mostly with microdeletion (Pasmant et al., 2010).

CONTACT S¸ukriye€ Ayter [email protected] Faculty of Medicine, TOBB University of Economics and Technology, Ankara, Turkey ß 2018 Informa UK Limited, trading as Taylor & Francis Group 2 .SAAIADS AYTER S. AND SHARAFI P.

Figure 1. Upper: The location of proteins interacting with neurofibromin protein has been shown. The domains are shown in light blue. Proteins interacting with NF1 are shown in ovals. The color of the ovals is associated with functions ascribed to them. CSRD: cysteine-serine-rich domain; TBD: tubulin-binding domain; GRD: GTPase-activating protein-related domain; PH: pleckstrin homology; CTD: carboxy-terminal domain; SBD: syndecan-bind- ing domain; DDAH1: dimethylarginine dimethylaminohydrolase 1; P: phosphorylation, protein kinase A substrates; APP: amyloid-b precursor protein; DPYSL2: dihydropyrimidinase-related protein 2; FAF2: FAS-associated factor 2; FAK: focal adhesion kinase; LIMK2: LIM domain kinase 2; LRPPRC: leucine-rich pentatricopeptide motif-containing protein; SCF: Skp, Cullin, F-box-containing complex; VCP: valosin-containing protein. Lower: Schematic illus- tration and an overview on general location and the frequency of different types of mutations in NF1 gene. The origin of this data has been taken from histogram of dispersion of NF1 gene mutations in The Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). JOURNAL OF NEUROGENETICS 3

Furthermore, it has been shown that NF1 patients with (Sun et al., 2010) were also studied in mouse models and c0.5425 C > T missense variant (p.Arg1809) are associated Drosophila (Walker & Bernards, 2014). with multiple CALM and considerably low prevalence for It is generally considered that genetic modifiers, distinct NF1-associated benign and malignant tumors (Pinna et al., from the disease itself, play an important role in 2015; Rojnueangnit et al., 2015). On the other hand, it has phenotypic variations of single-gene disorders. Identifying been reported recently that missense mutations at the NF1 these genetic modifiers is very important in terms of both region 844–848 codons are associated with a more severe treatment and genetic counseling. There are several reports phenotype in NF1 patients (Koczkowska et al., 2018). concerning the role of modifier genes in NF1 clinical varia- Although the frequency of NF1 is the same across all eth- tions (Bartelt-Kirbach, Wuepping, Dodrimont-Lattke, & nic groups, and it is considered that the distribution of NF1 Kaufmann, 2009; Pemov et al., 2014; Wiest, Eisenbarth, mutations does not differ among populations, there are Schmegner, Krone, & Assum, 2003). However, the selection some reports from Brazil (Praxedes, 2008), China (Zhang of which phenotype to study is a key challenge in modifier et al., 2015), and Korea (Ko, Sohn, Jeong, Kim, & Messiaen, gene studies. 2013) that challenge this assumption. Moreover, recurrent mutations reported in previous publications are not common in Turkish patients (Terzi, Oguzkan, Anlar, Aysun, & Ayter, Modifier genes in NF1 phenotypic variation 2007; Terzi, Sirin, et al., 2011). In this review, the term ‘modifier gene’ is used to define any Clinical signs are variable and the phenotypic complexity of NF1 is similar to that of multifactorial diseases, including gene that may change several features of the NF1 phenotype, ‘ ’ epigenetic factors and heritable elements such as genetic and the word gene is used for not only protein-coding modifiers. Some NF1 patients with the same mutation may sequences but also for microRNA (miRNA) and long non- develop severe clinical symptoms while others develop a coding RNA genes that may modulate the NF1 phenotype. mild phenotype. As an example, in our previous study, Terzi Considering the gene structure and the interaction of neuro- et al. (Terzi et al., 2007) have identified the same exon 4b fibromin protein with cellular components, there are many mutations, 496delTG and 499delTGTT, in two different NF1 possible candidate modifier genes influencing NF1 as shown families that showed completely different phenotypes. Both in Figure 1. Besides modifier genes, environmental factors of these families have identical mutations that cause a pre- might also contribute to the variable disease phenotype. mature stop codon leading to the same truncated proteins. There are two major strategies to detect the modifier genes These phenotypic variations within and between families in NF1: whole-genome scanning or focusing on specific can- with the same genetic cause may be the effect of modifier didate genes or pathways. In a recent study, Pasmant et al. genes or a second somatic mutation occurring in the tumor (2011) performed whole-genome high-resolution array-com- tissues. The scientific background for this clinical variability parative genomic hybridization of NF1-associated PNF to is not well understood. The allelic heterogeneity of the NF1 identify candidate modifier genes. Neurofibromas are com- mutation may be one of the reasons to explain the pheno- plex benign tumors of the peripheral nerve sheath composed typic variations associated with this disease. The absence of of heterogeneous cell types (Schwann cells, endoneurial cutaneous neurofibromas with a 3-bp NF1 internal deletion fibroblasts, mast cells, and perineurial cells). Although they indicates that the NF1 genotype itself can act as an NF1 are composed of different cell types, neurofibromas arise modifier (Upadhyaya et al., 2007). In addition, patients with from Schwann cells that undergo loss of heterozygosity NF1 microdeletions have increased numbers of early-devel- (LOH) at NF1 through somatic mutations. PNFs may oping dermal neurofibromas (Wu, Liu, Williams, & Ratner, undergo malignant transformation into neurofibrosarcomas, 2017). However, it is also clear that variation in the mutant known as MPNSTs. Therefore, it is very important to iden- NF1 allele itself does not account for all of the disease vari- tify patients at high risk for developing PNF or MPNST in ability observed. This variation could be due to modifier advance. For this reason, detection of modifier genes that genes, environmental factors, or their combination. We have may be important for the development of PNF may help to learned a lot about the biology of NF1 from animal models diagnose and treat these tumors. For this purpose, Pasmant’s including Drosophila (King et al., 2016), Zebrafish (Wolman group used the tissue samples from PNF tumors for gen- et al., 2014), Mouse (Parada, Kwon, & Zhu, 2005), and Swine (Meyerholz et al., 2017). These models are helping to ome-wide array comparative genomic hybridization studies advance our knowledge of disease progression and the iden- to identify the candidate modifier genes involved in PNF tification of biomarkers for the development of suitable development (Pasmant et al., 2011). However, this high- therapies. Research based on preclinical work has already throughput technology is not available for all laboratories, been translated into therapeutic trials for various NF1 fea- and therefore there are several reports dealing with possible tures including PNFs, gliomas, malignant peripheral nerve candidate modifiers. Accumulation of information about sheath tumors (MPNST), and neurocognitive disorders. these modifier genes would have great diagnostic and prog- Especially MPNST models provide benefits beyond evaluat- nostic value. Some of these candidate modifier genes are ing responses to targeted monotherapies and identification listed in Table 1 (the table is a modified from Ratner and of biomarkers’ sensitivity. Some modifier genes like p53 Miller (2015)). The present review discusses these candidate (Wildeman, Sassone-Corsi, Grundstrom, Zenke, & modifier genes and their effect on NF1 clinical phenotypes Chambon, 1984), CXCR4 (Mo et al., 2013), and CXCL12 and potential for future therapies. 4 P. SHARAFI AND S. AYTER

Table 1. List of some modifier genes and proteins that may be important in NF1 patients. This table is modified from Ratner and Miller (2015). Functional category Partner Function Intracellular trafficking LRPPRC Complex in RNA granules, trafficking Kinesin-1 Vesicle transport, APP? APP Melanosome transport? Cytoskeletal interaction LIMK1/LIMK2 Serine-threonine kinase; Rho/ROCK actin cytoskeletal remodeling, Phosphorylate cofilin and prevent the cleavage of F-actin Tubulin Microtubules; inhibits NF1 Ras-GAP activity Neuronal differentiation VCP AAA (ATPase); dendritic spine formation CRMP-2 Neurite outgrowth DPYSL2 Enzyme; interact with collapsin response mediator protein 1(CRMP1) expressed exclusively in the nervous system; have a role in neuronal development and polarity OMGP Downregulate role of neurofibromin on Ras, learning disability? LINGO-1 Leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein-1, expressed in oligodendrocytes and neu- rons, upregulated in CNS disease and injury Cell adhesion Focal adhesion kinase (FAK) Cell adhesion Ubiquitination ETEA (FAF2) UBA/UBX protein SAG/CUL1/FBXW7 (SCF) SCF E3 ubiquitin ligase complex/ubiquitination Cullin 3 E3 ubiquitin ligase complex/Ubiquitination Membrane localization Phospholipids Membrane localization? Caveolin-1 Localization and Ras/FAK/Akt signaling Syndecan Heparan sulfate proteoglycan EVI2B Target of C/EBPa, NFl/leukemia syndromes? Cell signaling DDAH1 NO/NOS regulator 14-3-3 Negatively regulates NF1-GAP activity Ras Signaling Spred1 Downregulation of Ras activity Gender Adenylate cyclase 8 (ADCY8) cAMP polymorphisms, change the optic glioma pathway stereotypically CXCL12 Enhance the growth of astrocytes in females Microdeletions RNF135 Responsible for overgrowth of NF1 patients DNA repair Mismatch; MSH2, MSH6, MSH3, MLH1, PMS2 Constitutional mismatch repair deficiencies (CMMRD), cause rare childhood malignancies Nonallelic homologous recombination (NAHR) Cause microdeletions Mitochondria Succinate dehydrogenase (SDH) Cause gastrointestinal stromal tumor (GISTs) TRAP1 Chaperon, downregulate mitochondrial respiration by reducing the activity of SDH Bone mass Vitamin D Responsible for the regulation of calcium homeostasis Vitamin D receptor (VDR) G/A polymorphism in intron-8 result in a shorter VDR protein and decreased VDR receptor expression which decreases 1.25(OH)2D3 activity MicroRNA’s miR-29c To distinguish malignant from benign tumors miR-34a Direct target of p53 miR-214 Induces cell survival and cisplatin resistance miR-10b Transforming benign NF1-associated neurofibromas to MPNSTs miR-204 Contributes to the growth of MPNSTs miR-21 Important in MPNST progression miR-107 Regulates NF1 in gastric cancer Telomerase TERT mRNA and telomerase activity High-grade malignancy in NF1-associated MPNST Apoptosis Apoptotic protease activating factor-1 (Apaf-1) Tumor development Hepatocellular carcinoma antigen 66 (HCA66) NF1-microdeletion syndrome Others INK4A/ARF and P53 Regulates the cell cycle, underlie the development of MPNSTs in animal models Epidermal growth factor receptor (EGFR) Modify neurofibroma number CXCR4/CXCL12 ligand Cause metastasis and progression of cancer

Variations according to sex adenylate cyclase 8 (ADCY8) gene in a sex-specific manner. Warrington, Sun, & Rubin (2015) reported that the growth Some specific gene mutations and symptoms are more of human male and female NF1-/- astrocytes varied in prevalent in females. For example, female patients with NF1- response to inhibition of ADCY by dideoxyadenosine; more- associated optic glioma (OPG) require treatment for visual over, CXCL12 enhanced the growth of astrocytes in females decline more often than their male counterparts. Mouse but not in males. models also show similar sex differences in some NF1 symp- This idea was also reinforced by the observation of higher toms. Furthermore, only male NF1 mice showed learning/ incidence of OPG in female children than in male children. deficits, increased Ras activity, and reduced dopa- Riccardi and Lupski (2013) evaluated two different groups mine levels (Diggs-Andrews et al., 2014). for detecting the duplication type of gene mutations in NF1 It has also been shown that adjustment in the level of patients; a total of 21 patients were included in this study, cAMP can change the OPG pathway stereotypically and 18 of them were females. This suggests that there may (Bajenaru et al., 2003; Warrington et al., 2007). NF1-associ- be some modifying factors protecting males from this type ated OPG can be modified by polymorphisms in the of mutation. Collectively, these data suggest that sex is a JOURNAL OF NEUROGENETICS 5 major factor contributing to the extent of the neural dys- predispose cells to myeloid diseases. Therefore, we investi- function in NF1, which should be considered as a modifier gated the expression of EVI2A and EVI2B in NF1 tumors when developing a new therapeutic strategy and planning a and leukemias. Our preliminary results showed the possibil- clinical study (Riccardi & Lupski, 2013). ity of viral integrations in EVI2B in NF1-acute myeloid leu- kemia patients (Ayter, Anlar, Varan, & Cetin, 2017). Another embedded gene in the NF1 structure is OMGP, Variations according to age which encodes the oligodendrocyte myelin glycoprotein Age and the hormonal environment are additional critical (OMGP), expressed only in the oligodendrocytes of the cen- factors contributing to the clinical variation in NF1. Many tral nervous system. To date, no mutations have been disease features are more prevalent in older patients. Some detected in the OMGP gene except for some cases of large clinical features such as dermal neurofibromas begin to deletions of the gene. Specific learning disabilities are the develop around puberty, and the number and size of neuro- most common neurological complication in children with fibromas increase during pregnancy (Theos & Korf, 2006). NF1. The frequency of learning disability is approximately – Indeed, in NF1, many phenotypic features such as the devel- 7 10% in the general population, and is 50% among NF1 opment of neurofibroma are age-dependent. Pemov et al. patients (Kavale & Forness, 2000; Levine, Materek, Abel, ’ (2014) measured a variety of phenotypic features with par- O Donnell, & Cutting, 2006; Moore, 2009). ticular focus on the number of CLS, because these spots are Therefore, the OMGP gene may be a possible candidate easy to quantify and their number tends to reach a max- modifier of NF1-associated learning disability for several rea- sons: (1) it is located within the NF1 gene, (2) is related to imum after early childhood. CLS are ‘tumor-like’ in that axon myelinization, and (3) contains binding sites for the they follow the Knudson’s ‘Two-Hit’ hypothesis: melanocytes transcription factors involved in neuronal development and in these lesions acquire a second somatic mutation in NF1. synaptic plasticity, which are also important for the learning Thus, genes that modify the number of CLS may also pos- process. Neurofibromin and OMGP are both expressed in sibly modify the risk of tumor development. Variations in the same type of cells, and their interaction may help to the number of dermal neurofibromas among NF1 patients, explain the central nervous system findings in NF1 patients even within a family carrying the same NF1 mutation, sup- (Upadhyaya et al., 1998). port the idea of the existence of some modifiers of dermal Neurofibromin and OMGP proteins are regulated by neurofibroma. Second hits almost always require an add- common mechanisms, and both may synergistically inhibit itional time course, and therefore age is likely another Ras activity. Therefore, OMGP might contribute to the important modifier in the variation of CLS counts beside downregulation of Ras by neurofibromin, which is impaired NF1 mutations. in NF1. Another observation of our group is that the unaffected siblings of NF1 patients obtained lower scores in Genes embedded in the NF1 gene certain cognitive tests compared to healthy controls, support- ing the presence of another modifying gene or genes (Terzi, EVI2A, EVI2B, and OMGP are embedded within intron 27b Oguzkan-Balci, Anlar, Erdogan-Bakar, & Ayter, 2011). of the NF1 gene, and Viskochil (2002) proposed that the There have also been some reports of patients with NF1 transcriptional regulation of these embedded genes might and multiple sclerosis. OMGP62 polymorphisms have also play a role in the NF1 clinical phenotype. Both EVI2A and been associated with autism and non-syndromic mental EVI2B encode putative transmembrane proteins. The mouse retardation (Vourc’h et al., 2003). Despite all of these find- homologs (Evi-2a and Evi-2b; ecotropic viral integration ings suggesting a role of OMGP in cognition, Terzi, sites) are associated with viral insertions involved in leuke- Oguzkan-Balci, et al. (2011) did not observe any relationship mia in mice, although their relationships to NF1 symptoms between OMGP gene mutations and learning disability in are unknown (Trovo-Marqui & Tajara, 2006). NF1 patients NF1. Further studies are required with large populations of have a higher risk of developing juvenile chronic myeloge- NF1 patients with learning disability. nous leukemia (OMIM #607785) compared to the general population. There are a limited number of studies in the lit- erature related to NF1-associated leukemia (Buchberg, Microdeletions Bedigian, Jenkins, & Copeland, 1990; Cawthon et al., 1991; Approximately 5–10% of NF1 cases are due to microdele- Kuhn et al., 2012; Largaespada, Shaughnessy, Jenkins, & tions, in which the entire NF1 gene is deleted together with Copeland, 1995; Paulus, Koronowska, & Folster-Holst, 2017). a number of other genes (Kluwe et al., 2004). Patients with It is possible that mutations involving both NF1 and EVI2A NF1-microdeletion syndrome (OMIM#613675) usually have (or EVI2B) may cause NF1/leukemia syndromes more cutaneous, PNFs and a higher risk of developing (OMIM#607785) (Shannon et al., 1994). Indeed, EVI2B was MPNST compared to patients with NF1 (Ning et al., 2016). identified as a direct target gene of C/EBPa, a transcription Three typical and seven atypical forms of these microdele- factor critical for myeloid differentiation (Zjablovskaja et al., tions have been detected: type-1 (1.4 Mb long, resulting in 2017). It is possible that these genes are related to leukemia 14 deleted protein-coding genes and NF1), type-2 (1.2 Mb observed in NF1 patients, although there are no data con- long, resulting in 13 deleted protein-coding genes and NF1), firming this association in the literature. Expression of this and type 3 (1.0 Mb long, with 8 deleted protein-coding genes gene may be altered by viral integration, which could and NF1) microdeletions (Pasmant et al., 2009). Pasmant 6 P. SHARAFI AND S. AYTER et al. (2010) showed that learning disabilities and facial dys- Indeed, some hotspots of meiotic NAHR have been identi- morphism were significantly associated with NF1-microdele- fied in both types of microdeletions (Raedt et al., 2006; Vogt tion syndrome. Spiegel et al. (2005) proposed that et al., 2012). overgrowth was in fact a distinctive phenotype of patients with NF1-microdeletion syndrome. Alternatively, Douglas et al. (2007) suggested that RNF135 haploinsufficiency was The role of mitochondria responsible for the overgrowth of individuals with NF1 Mitochondrial DNA (mtDNA) microdeletions. The results of Pasmant et al. (2010) con- firmed this suggestion, because four patients with NF1- mtDNA does not contain any protective histone molecules microdeletion syndrome presented childhood overgrowth, in its structure and thus has a limited capacity to repair although the RNF135 gene was not included in the microde- damage, making it particularly sensitive to damage from letion interval (no whole gene deletions of RNF135). Ning reactive oxygen species (ROS) and accumulation of muta- et al. (2016) conducted the largest study to date on the tions (Penta, Johnson, Wachsman, & Copeland, 2001). growth of NF1 patients with microdeletions. They measured Recent reports have shown that these accumulated somatic the weight, length, and head circumference of 56 patients mtDNA mutations have an important role in the develop- with NF1 microdeletions and 226 NF1 patients with other ment of tumors in the brain, ovary, esophagus, breast, and kinds of mutations. They detected that children with micro- colon (Alonso et al., 1997; Fliss et al., 2000; Hibi et al., 2001; deletions were taller and heavier than the non-deletion NF1 Liu et al., 2001; Polyak et al., 1998; Tan, Bai, & Wong, patients; however, they noted that no differences were 2002). Analysis of mtDNA mutations and comparison of the observed in early infancy. The head circumference measure- presence of somatic mtDNA mutations in NF1 tumor and ments and age at puberty were similar in both groups of non-tumor cells (Kurtz et al., 2004) showed that all mtDNA NF1 patients, those with and without microdeletions (Ning mutations occurred in the hypervariable D-loop region of et al., 2016). the mitochondrial genome, which is unique because the mutations detected in tumors related to other organs are mostly located in coding regions (Alonso et al., 1997; Fliss DNA repair system et al., 2000; Hibi et al., 2001; Liu et al., 2001; Polyak et al., DNA repair is a series of mechanisms that protect the cells’ 1998; Tan et al., 2002; Wong, Lueth, Li, Lau, & DNA from developing detriments due to environmental fac- Vogel, 2003). tors and normal metabolic processes inside the cell, and try According to Kurtz et al. (2004), cutaneous neurofibro- to correct such damage in DNA molecules (Albert et al., mas could be formed from cells already carrying somatic 2008). One of these mechanisms is mismatch repair (MMR), mtDNA mutations. which is present in all cells to correct errors that are not otherwise corrected by the proofreading mechanism (Jiricny, Succinate dehydrogenase (SDH) and TRAP1 2006). Any functional abnormality of this system results in replication errors that remain uncorrected, leading to a Succinate dehydrogenase subunit B (SDHB) is one of the mutator phenotype and sporadic mutation formation. ubiquitously expressed proteins in the mitochondria. The According to the existing information, the association lack of SDHB expression was observed in cases of Carney between constitutional mismatch repair deficiencies triad and Carney Stratakis syndrome-associated gastrointes- (CMMRD) and NF1 seems to be incorrect, because some tinal stromal tumors (GISTs) (OMIM#606864) (Pasini et al., CMMRD patients with rare childhood malignancies have 2008; Price, Zielenska, Chilton-MacNeill, Smith, & Pappo, been erroneously included in presumed NF1 cohorts. 2005). GISTs arise in NF1 patients 150-times more often Therefore, to re-evaluate the likely association between NF1 than they do in the general population (Bajor, 2009). Similar and childhood malignancies such as central nervous system to the majority of adult GISTs, NF1-associated GISTs tumors and rhabdomyosarcomas, all prospective and retro- express SDHB; however, unlike the majority of GISTs, they spective studies should be repeated to exclude cases of do not respond well to imatinib treatment (Wang, Lasota, & CMMRD. It should also be pointed out that the incidence of Miettinen, 2011). This observation raised the possibility that postzygotic NF1 mutations in some CMMRD patients can be SDHB could be a candidate modifier of the phenotypic vari- responsible for the observed NF1 features (Wimmer, ation in NF1. Sciacovelli et al. (2013) proposed that inhib- Rosenbaum, & Messiaen, 2017). ition of SDH with the mitochondrial chaperone TRAP1 Another DNA repair mechanism that is speculated to could promote neoplastic growth. TRAP1 expression is affect NF1 is nonallelic homologous recombination (NAHR) restricted to the mitochondria and has a protective role in (Messiaen et al., 2011). As mentioned above, different types oxidative stress. TRAP1 is highly expressed in many tumors, of microdeletions have been identified in NF1 depending on and therefore, may also be a crucial factor in NF1 tumors. the size of the deleted region. It has been shown that the Cancer cells require a high amount of oxygen so that they majority of type-1 NF1 microdeletions (1.4 Mb) occur in the can expand their own blood supply rapidly (Gilkes, germline through a NAHR mechanism (Messiaen et al., Semenza, & Wirtz, 2014). Yet, because their growth rate is 2011). Type-2 NF1 deletions (1.2 Mb) have also been so high, cancer cells have acquired a mechanism, known as reported to occur predominantly because of intrachromoso- the Warburg effect, which decreases the rate of mitochon- mal mitotic (post-zygotic) NAHR (Roehl et al., 2012). drial respiration (Frezza & Gottlieb, 2009) to allow the JOURNAL OF NEUROGENETICS 7

Figure 2. A summary of mitochondrial-mediated pathways which affect the neurofibromin protein functions. cells to grow in a hypoxic condition (Hsu & Sabatini, 2008). SDH through TRAP1. Specifically, Masgras et al. (2017) This effect is initiated by the induction of hypoxia-inducible demonstrated that a fraction of the active ERK located in the transcription factor-1 (HIF1), which is activated by hypoxia mitochondrial matrix of cells with a neurofibromin deficit together with the accumulation of succinate and fumarate, phosphorylated TRAP1, which in turn inhibited SDH and the Krebs cycle metabolites (Selak et al., 2005). HIF1 promoted tumor growth. This suggests that any detriment in decreases the influx of pyruvate to the Krebs cycle and acti- the RAS/ERK Signaling pathway that could affect its activity vates glycolysis (Semenza, 2010). Specifically, TRAP1, an in cells lacking neurofibromin can lead to inhibition of mito- evolutionarily conserved chaperone of the heat-shock protein chondrial respiration. 90 family (Altieri, Stein, Lian, & Languino, 2012), downregu- lates mitochondrial respiration by reducing the activity of SDH, which in turn stabilizes HIF1 by increasing succinate Vitamin D and bone mass levels (Sciacovelli et al., 2013). It has been proposed that the inhibition of SDH by Vitamin D is a fat-soluble secosteroid whose function is to TRAP1 has both anti-oxidant and anti-apoptotic effects on increase the absorption of calcium, iron, magnesium, phos- tumor cells. The conditions of the tumor microenvironment, phate, and zinc from the intestine. The most important such as abnormal activation of signal transduction pathways, forms of vitamin D are vitamin D2 (cholecalciferol) and increase the accumulation of ROS in cancer cells vitamin D3 (ergocalciferol). Both forms can be ingested (Holmstrom & Finkel, 2014). To prohibit the harmful effect from foods and supplements, but cholecalciferol can also be of ROS, a scavenging program that can protect tumor cells synthesized naturally in the skin from cholesterol under sun from cell death is elicited (Trachootham, Alexandre, & exposure (Calvo, Whiting, & Barton, 2005; Holick, 2004). Huang, 2009). The inhibition of SDH, which is the main site The precursor of vitamin D in the skin is 7-dehydrocholes- of ROS generation, with TRAP1 can have an anti-apoptotic terol, which is synthesized upon exposure to ultraviolet effect (Grimm, 2013). Notably, mutations in the SDH gene irradiation. Next, vitamin D is hydroxylated to 25-hydroxyvi- resulting in LOH are extremely rare. Nevertheless, TRAP1 tamin D3 (25(OH)D3) in the liver, and further has many post-translational modifications (Rasola, Neckers, hydroxylation takes place in the kidney to form the biologic- & Picard, 2014; Yoshida et al., 2013), and any defect in these ally active form of vitamin D, 1,25-dihydroxyvitamin D3 modifications can affect SDH enzymatic activity (Guzzo, (1,25(OH)2D3) (Heaney, Horst, Cullen, & Armas, 2009). Sciacovelli, Bernardi, & Rasola, 2014). Some of these interac- Vitamin D is responsible for the regulation of calcium tions are summarized in Figure 2. homeostasis, which plays a critical role in bone metabolism Moreover, a recent report showed that activation of the (Holick, 2004). Approximately 10% of NF1 patients show RAS/extracellular signal-related kinase (ERK) signaling path- focal bony abnormalities (Illes, Halmai, de Jonge, & way in neurofibromin-deficient cells in the pro-tumorigenic Dubousset, 2001), severe osteomalacia (Brunetti-Pierri et al., stage boosted the glycolysis reaction and downregulated 2008), and reduction in bone mass (Dulai et al., 2007), sug- mitochondrial oxidative phosphorylation by inhibition of gesting a link to vitamin D deficiency. 8 P. SHARAFI AND S. AYTER

Indeed, more than 60% of patients with NF1 displayed a altered expression can contribute to human diseases such as severely low vitamin D level (20 ng/ml) (Lammert et al., lung cancer (Chen et al., 2012). Weng, Chen, Chen, Liu, and 2005). Nakayama et al. (1999) observed some significant Bao (2013) reported the significant upregulation of serum reduction in the pigmentations of the CLS in response to miRNA-24 levels only in NF1-MPNST patients, and sug- vitamin D treatment besides bone abnormalities. Therefore, gested that this miRNA could be a biomarker for NF1- vitamin D can be another factor affecting the phenotype of MPNST detection. NF1 patients. Correspondingly, the level of 25(OH)D3 was Although the role of miRNA in the NF1 phenotypic vari- measured in NF1 patients and compared to that in healthy ation can be considered as a new subject of study, several people. There are some conflicting data in the literature con- miRNAs have already been detected in NF1 tumorigenesis to cerning the seasonal effect of vitamin D levels (Lammert date, including miR-29c (used to distinguish malignant from et al., 2006; Tucker et al., 2009). However, Schnabel et al. benign tumors (Wang et al., 2011), miR-34a (a direct target (2014) observed a low level of 25(OH)D3 in adults with NF1 of p53 (Subramanian et al., 2010), miR-214 (induces cell sur- both in summer and winter. They also emphasized that der- vival and cisplatin resistance (Yang et al., 2008), miR-10 b mal neurofibromas did not block the dermal synthesis of 7- (transforms benign NF1-associated neurofibromas to dehydrocholesterol. MPNSTs (Subramanian et al., 2010), miR-204 (contributes Vitamin D receptor (VDR) is another factor that is con- to the growth of MPNSTs (Gong et al., 2012), miR-21 sidered to affect the vitamin D levels and bone mass in NF1 (important in MPNST progression (Itani et al., 2012), and patients. VDR, also known as calcitriol receptor, is encoded miR-107 (regulates NF1 in gastric cancer (Wang et al., by genes located on chromosome 12 (12q12–14) (Miyamoto 2016). Nevertheless, there is still much work to be done to et al., 1997). Different series of polymorphisms have been gain a detailed understanding of the actual function and reported in the VDR genes, which alter the biological proc- pathway of miRNAs in NF1 (Sedani et al., 2012). esses of this receptor (Morrison, Yeoman, Kelly, & Eisman, 1992). Two of these polymorphisms were identified as a T/C transition located in a start codon (ATG) (Uitterlinden, Additional gene mutations in NF1-associated tumors Fang, Van Meurs, Pols, & Van Leeuwen, 2004) and a G/A For the development of malignant transformation, especially polymorphism located on intron-8, which were detected in NF1-related MPNSTs, besides the NF1 mutations, add- using the FokI and BsmI restriction enzymes, respectively itional mutations in several genes, including INK4A/ARF (Ingles et al., 1997). These two polymorphisms result in a and P53, are required. A mouse model was developed for shorter VDR protein with decreased expression. Bueno et al. MPNSTs by generating mice with mutations in both the hypothesized that the reduced VDR expression might NF1 and p53 genes (Cichowski et al., 1999). The loss of the decrease 1.25(OH)2D3 activity, even when vitamin D levels P53 gene is responsible for the abnormalities in DNA dam- are normal, which would in turn decrease the bone turnover age-dependent cell cycle arrest and apoptosis. Mutations in rate in NF1 patients due to the lack of calcium absorption in p53 underlie the development of MPNSTs in animal models, the duodenum (Souza Mario Bueno et al., 2015). However, but there are controversies remaining related to the role of Souza Mario Bueno et al. (2015) did not detect correlations P53 mutations in human MPNSTs (Gottfried, Viskochil, & between low vitamin D levels and VDR gene polymorphisms Couldwell, 2010; Legius et al., 1994). and deregulation of osteoblast and osteoclast activity of Changes in growth factor expression create secondary NF1 patients. genetic events contributing to malignant transformation. Growth factors help to suppress cell death in Schwann cell MicroRNA’s (miRNA’s) precursors. Abnormal growth factor receptor expression also plays a role in tumor development, progression, and malig- Approximately 20 years ago, miRNAs were discovered as nant transformation. Wu et al. (2017) found that epidermal new regulatory factors of the genome. This mechanism has growth factor receptor (EGFR) levels modified the neuro- greatly contributed to gain a better understanding of the fibroma number. Neurofibroma development requires bial- pathogenesis of many cancers at the molecular level. lelic NF1 mutations in Schwann cells and/or Schwann cell miRNAs function in RNA silencing and negatively regulate precursors. In mouse models, when NF1 was mutated in at the post-transcriptional level Schwann cells and Schwann cell precursors, all animals (Bartel, 2004). formed neurofibromas, and the number of tumors increased It is now well established that miRNAs play a critical role in proportion to the expression level of EGFR. These data in cancer development, given their involvement in cell differ- demonstrate that neurofibroma formation increases when entiation, developmental control, neural development, cell EGFR is overexpressed and NF1 is mutated. Amplification of proliferation, and apoptosis. The miRNAs also have a crucial the receptor and disturbed Ras signaling both contribute to function in tumor progression such as in cancer invasion benign tumor formation. and metastasis (Sedani, Cooper, & Upadhyaya, 2012). Studies of different tumor types have demonstrated that There are several hundred types of miRNAs, which have the expression levels of chemokine receptors such as CXCR4 several hundred-target genes, making them useful bio- are increased in tumor tissues, which are linked to the markers in cancer diagnosis, prognoses, as well as candidate metastasis and progression of cancer. Karaosmanoglu et al. therapeutic targets. In addition, certain types of stable (2018), in her thesis studies, analyzed the gene expression of miRNAs have also been found in human serum, whose CXCR4 and its ligand CXCL12 in human neurofibromas. JOURNAL OF NEUROGENETICS 9

The results of this experiment showed that the CXCR4 gene understand the clinical complexity of certain single-gene dis- expression level was increased up to 120-fold and the orders such as NF1, it is not possible to explain all of the CXCL12 gene expression level was increased up to 512-fold phenotypic variations of the genes by the allelic heterogen- in all tumors relative to normal human Schwann cells. eity alone. Indeed, NF1 patients have a large number of NF1 Telomerase can also be considered as a potential modifier mutations with no clear genotype–phenotype correlations of NF1. Owing to the shortening of telomeres beyond a cer- with some exceptions as mentioned before (Koczkowska tain level, cells are arrested and enter cellular senescence et al., 2018; Pasmant et al., 2010; Pinna et al., 2015; (Greider, 1998). The enzyme telomerase comprises two subu- Rojnueangnit et al., 2015; Upadhyaya et al., 2007). nits: telomerase RNA and the telomerase reverse transcript- Variations in NF1 mutations may not correlate with the var- ase (TERT) (Kilian et al., 1997). However, it has been iations observed in the clinical phenotype. Therefore, detec- reported that the TERT mRNA expression and telomerase tion of mutations is not a big help in a clinical setting in activity can be detected in most cancer cells, and this prop- terms of genetic counseling, since it is not possible to accur- erty can be used as a biomarker for cancer screening (Kim ately predict the severity of disease simply by identification et al., 1994). A recent study demonstrated a correlation of the specific causal mutation. Clinical signs are variable between the high-fold expression of TERT, telomerase activ- and the phenotypic complexity of NF1 is similar to that of ity, and high-grade malignancy in NF1-associated MPNST. multifactorial diseases, including epigenetic factors and herit- These data can provide a new approach for the modifying able elements. Some NF1 patients with the same mutation effect of telomerase and the treatment of NF1-associated may develop severe clinical signs while others develop a malignant tumors (Jones, Grimstead, Sedani, Baird, & mild phenotype. Moreover, some patients carrying two dif- Upadhyaya, 2017; Mantripragada et al., 2008). ferent pathological mutations will still have a mild phenotype Apoptosis can be initiated in the intrinsic and extrinsic (Terzi et al., 2012). The most important issue to consider in pathways. Both pathways induce cell death by activating cas- the search for modifier genes is to select a specific clinical pases. One of the important proteins in the intrinsic pathway phenotype and a relevant study population. Besides the is apoptotic protease activating factor-1 (Apaf-1), and any loss of expression of this protein can result in tumor devel- selection of modifier genes, there are some other problems opment (Igney & Krammer, 2002). Hepatocellular carcinoma associated with the collection and biobanking of samples, antigen 66 (HCA66) is one of the proteins that interacts since any variations in the collection and conservation tech- with Apaf-1 and can regulate apoptosis. The HCA66 gene, niques may change the results. Therefore, conflicting data located on chromosome 17q11.2, is one of the genes that is exist in the literature. Considering the gene structure and deleted in NF1-microdeletion syndrome (De Raedt et al., the interaction of neurofibromin protein with cellular com- 2004). Patients with NF1-microdeletion syndrome have a ponents, there are many possible candidate modifier genes. distinct phenotype with a poor prognosis characterized by a In addition, environmental factors might also contribute to low IQ, dysmorphic features, and numerous neurofibromas the diverse phenotype observed clinically. Most of the studies (Leppig et al., 1997). Piddubnyak et al. (2007) examined the dealing with modifier genes have thus far concentrated on effect of the modulated expression of HCA66 on the apop- tumors, which indeed show sub-phenotypic variations in tosis of cell lines derived from NF1-microdeleted patients. terms of type, size, location, and the age of development. In this study, they showed that HCA66 seems to regulate Several candidate modifier genes have already been studied apoptosis at the level of the Apaf-1-induced activation of and supporting data exist in the literature. Studies that can caspase-9 in the apoptosome following cytochrome c/dATP accurately mimic the effects of naturally occurring genetic stimulation. Likewise, they presumed that the binding of modifiers might lead to the development of new therapeu- HCA66 can also induce a conformational change that would tics. Gaining a deeper understanding of the molecular basis increase the recruitment of caspase-9. Therefore, the reduced of variable phenotypes may improve the prediction, treat- expression of HCA66 could make cell lines derived from ment, and prevention of several NF1-related complications. NF1-microdeleted patients less susceptible to apoptosis. These new findings will be crucial in providing more accur- Accordingly, not only the HCA66 gene but also all of the ate genetic counseling. proteins involved in the apoptotic pathway should be consid- ered as possible modifiers in NF1 tumors. Disclosure statement

Conclusion The authors declare that they have no conflict of interest. The borders between single-gene disorders and multiple- References gene disorders are becoming less clear. In other words, there is no obvious clear distinction between simple Mendelian Albert, B., Dennis, A., Lewis, J., Raff, M., Ropberts, K., & Walter, P. and complex traits (Dipple & McCabe, 2000). In reality, (2008). Molecular biology of the cell (5th ed.). Milton Park, UK: even if there is generally one gene that is primarily respon- Taylor & Francis Group. sible for the pathogenesis, one or more independently inher- Alonso, A., Martin, P., Albarran, C., Aquilera, B., Garcia, O., Guzman, A., … Sancho, M. (1997). Detection of somatic mutations in the ited modifier genes will ultimately influence the phenotype. mitochondrial DNA control region of colorectal and gastric tumors The term ‘modifier gene’ is thus used to define any gene by heteroduplex and single-strand conformation analysis. that may change the disease phenotype. When we try to Electrophoresis, 18, 682–685. doi:10.1002/elps.1150180504 10 P. SHARAFI AND S. AYTER

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