Neurofibromin

Last updated

NF1
PBB Protein NF1 image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NF1 , NFNS, VRNF, WSS, neurofibromin 1
External IDs OMIM: 613113; MGI: 97306; HomoloGene: 141252; GeneCards: NF1; OMA:NF1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4763

18015

Ensembl

ENSG00000196712

ENSMUSG00000020716

UniProt

P21359

Q04690

RefSeq (mRNA)

NM_000267
NM_001042492
NM_001128147

NM_010897

RefSeq (protein)

NP_000258
NP_001035957
NP_001121619

NP_035027

Location (UCSC) Chr 17: 31.09 – 31.38 Mb Chr 11: 79.23 – 79.47 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Neurofibromin (NF-1) is a protein that is encoded in the human by the NF1 gene. [5] NF1 is located on chromosome 17. [6] [7] [8] Neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. [6] [7] [9] NF1 has a high mutation rate and mutations can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1 (NF1, also known as von Recklinghausen syndrome). [6] [7] Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities. [6] [7] [10]

Contents

Gene

NF1 was cloned in 1990 [11] [12] and its product neurofibromin was identified in 1992. [13] [14] [15] [16] Neurofibromin, a GTPase-activating protein, primarily regulates the protein Ras. [17] NF1 is located on the long arm of chromosome 17, position q11.2 [7] NF1 spans over 350-kb of genomic DNA and contains 62 exons. [8] 58 of these exons are constitutive and 4 exhibit alternative splicing ( 9a, 10a-2, 23a, and 28a). [8] The genomic sequence starts 4,951-bp upstream of the transcription start site and 5,334-bp upstream of the translation initiation codon, with the length of the 5' UTR being 484-bp long. [18]

There are three genes that are present within intron 27b of NF1. These genes are EVI2B , EVI2A and OMG, which are encoded on the opposite strand and are transcribed in the opposite direction of NF1. [18] EVI2A and EVI2B are human homologs of the Evi-2A and Evi-2B genes in mice that encode proteins related to leukemia in mice. [19] OMG is a membrane glycoprotein that is expressed in the human central nervous system during myelination of nerve cells. [18]

Promoter

Early studies of the NF1 promoter found that there is great homology between the human and mouse NF1 promoters. [18] The major transcription start site has been confirmed, as well as two minor transcription start sites in both the human and mouse gene. [18]

The major transcription start is 484-bp upstream of the translation initiation site. [20] The open reading frame is 8,520-bp long and begins at the translation initiation site. [20] NF1 exon 1 is 544-bp long, contains the 5' UTR and encodes the first 20 amino acids of neurofibromin. [18] The NF1 promoter lies within a CpG island that is 472-bp long, consisting of 43 CpG dinucleotides, and extends into the start of exon 1. [18] [20] This CpG Island begins 731-bp upstream of the promoter and no core promoter element, such as a TATA or CCATT box, has been found within it. [20] Although no core promoter element has been found, consensus binding sequences have been identified in the 5' UTR for several transcription factors such as Sp1 and AP2. [18]

A methylation map of five regions of the promoter in both mouse and human was published in 1999. This map showed that three of the regions (at approximately – 1000, – 3000, and – 4000) were frequently methylated, but the cytosines near the transcription start site were unmethylated. [18] Methylation has been shown to functionally impact Sp1 sites as well as a CREB binding site. [21] It has been shown that the CREB site must be intact for normal promoter activity to occur and methylation at the Sp1 sites may affect promoter activity. [21]

Proximal NF1 promoter/5' UTR methylation has been analyzed in tissues from NF1 patients, with the idea that reduced transcription as a result of methylation could be a "second hit" mechanism equivalent to a somatic mutation. [18] There are some sites that have been detected to be methylated at a higher frequency in tumor tissues than normal tissues. [18] These sites are mostly within the proximal promoter; however, some are in the 5' UTR as well and there is a lot of interindividual variability in the cytosine methylation in these regions. [18]

3' UTR

A study in 1993 compared the mouse NF1 cDNA to the human transcript and found that both the untranslated regions and coding regions were highly conserved. [18] It was verified that there are two NF1 polyadenylated transcripts that differ in size because of the length of the 3' UTR, which is consistent with what has been found in the mouse gene. [18]

A study conducted in 2000 examined whether the involvement of the 3' UTR in post-transcriptional gene regulation had an effect on the variation of NF1 transcript quantity both spatially and temporally. [18] Five regions of the 3' UTR that appear to bind proteins were found, one of which is HuR, a tumor antigen. [22] HuR binds to AU-rich elements which are scattered throughout the 3' UTR and are thought to be negative regulators of transcript stability. [22] This supports the idea that post-transcriptional mechanisms may influence the levels of NF1 transcript. [22]

Mutations

NF1 has one of the highest mutation rates amongst known human genes, [23] however mutation detection is difficult because of its large size, the presence of pseudogenes, and the variety of possible mutations. [24] The NF1 locus has a high incidence of de novo mutations, meaning that the mutations are not inherited maternally or paternally. [19] Although the mutation rate is high, there are no mutation "hot spot" regions. Mutations tend to be distributed within the gene, although exons 3, 5, and 27 are common sites for mutations. [19]

The Human Gene Mutation Database contains 1,347 NF1 mutations, but none are in the "regulatory" category. [18] There have not been any mutations conclusively identified within the promoter or untranslated regions. This may be because such mutations are rare, or they do not result in a recognizable phenotype. [18]

There have been mutations identified that affect splicing, in fact 286 of the known mutations are identified as splicing mutations. [23] About 78% of splicing mutations directly affect splice sites, which can cause aberrant splicing to occur. [23] Aberrant splicing may also occur due to mutations within a splicing regulatory element. Intronic mutations that fall outside of splice sites also fall under splicing mutations, and approximately 5% of splicing mutations are of this nature. [23] Point mutations that effect splicing are commonly seen and these are often substitutions in the regulatory sequence. Exonic mutations can lead to deletion of an entire exon, or a fragment of an exon if the mutation creates a new splice site. [19] Intronic mutations can result in the insertion of a cryptic exon, or result in exon skipping if the mutation is in the conserved 3' or 5' end. [19]

Protein

NF1 encodes neurofibromin (NF1), which is a 320-kDa protein that contains 2,818 amino acids. [6] [7] [8] Neurofibromin is a GTPase-activating protein (GAP) that negatively regulates Ras pathway activity by accelerating hydrolysis of Ras-bound guanosine triphosphate (GTP). [9] [17] Neurofibromin localizes in the cytoplasm; however, some studies have found neurofibromin or fragments of it in the nucleus. [9] Neurofibromin does contain a nuclear localization signal that is encoded by exon 43, but whether or not neurofibromin plays a role in the nucleus is currently unknown. [8] Neurofibromin is ubiquitously expressed, but expression levels vary depending on the tissue type and developmental stage of the organism. [6] [7] Expression is at its highest level in adult neurons, Schwann cells, astrocytes, leukocytes, and oligodendrocytes. [8] [9]

The catalytic RasGAP activity of neurofibromin is located in a central portion of the protein, that is called the GAP-related domain (GRD). [9] The GRD is closely homologous to RasGAP [9] and represents about 10% (229 amino acids [9] ) of the neurofibromin sequence. [7] The GRD is made up of a central portion called the minimal central catalytic domain (GAPc) as well as an extra domain (GAPex) that is formed through the coiling of about 50 residues from the N- and C- terminus. [9] The Ras-binding region is found in the surface of GAPc and consists of a shallow pocket that is lined by conserved amino acid residues. [9]

In addition to the GRD, neurofibromin also contains a Sec14 homology-like region as well as a pleckstrin homology-like (PH) domain. [9] Sec14 domains are defined by a lipid binding pocket that resembles a cage and is covered by a helical lid portion that is believed to regulate ligand access. [9] The PH-like region displays a protrusion that connects two beta-strands from the PH core that extend to interact with the helical lid found in the Sec14 domain. [9] The function of the interaction between these two regions is presently unclear, but the structure implies a regulatory interaction that influences the helical-lid conformation in order to control ligand access to the lipid binding pocket. [9]

Function

Through its NF1-GRD domain, neurofibromin increases the rate of GTP hydrolysis of Ras, and acts as a tumor suppressor by reducing Ras activity. [6] [8] When the Ras-Nf1 complex assembles, active Ras binds in a groove that is present in the neurofibromin catalytic domain. [8] This binding occurs through Ras switch regions I and II, and an arginine finger present in neurofibromin. [8] The interaction between Ras and neurofibromin causes GAP-stimulated hydrolysis of GTP to GDP. [8] This process depends on the stabilization of residues in the Ras switch I and switch II regions, which drives Ras into the confirmation required for enzymatic function. [8] This interaction between Ras and neurofibromin also requires the transition state of GDP hydrolysis to be stabilized, which is performed through the insertion of the positively charged arginine finger into the Ras active site. [8] This neutralizes the negative charges that are present on GTP during phosphoryl transfer. [8] By hydrolyzing GTP to GDP, neurofibromin inactivates Ras and therefore negatively regulates the Ras pathway, which controls the expression of genes involved in apoptosis, the cell cycle, cell differentiation or migration. [8]

Neurofibromin is also known to interact with CASK through syndecan, a protein which is involved in the KIF17/ABPA1/CASK/LIN7A complex, which is involved in trafficking GRIN2B to the synapse. This suggests that neurofibromin has a role in the transportation of the NMDA receptor subunits to the synapse and its membrane. Neurofibromin is also believed to be involved in the synaptic ATP-PKA-cAMP pathway, through modulation of adenylyl cyclase. It is also known to bind the caveolin 1, a protein which regulates p21ras, PKC and growth response factors. [8]

Isoforms

There are currently five known isoforms of neurofibromin (II, 3, 4, 9a, and 10a-2) and these isoforms are generated through the inclusion of alternative splicing exons (9a, 10a-2, 23a, and 48a) that do not alter the reading frame. [8] These five isoforms are expressed in distinct tissues and are each detected by specific antibodies. [8]

It has been suggested that the quantitative differences in expression between the different isoforms may be related to the phenotypic variability of neurofibromatosis type 1 patients. [8]

RNA editing

In the NF1 mRNA, there is a site within the first half of the GRD where mRNA editing occurs. [26] Deamination occurs at this site, resulting in the conversion of cytidine into uridine at nucleotide 3916. [26] [27] This deamination changes an arginine codon (CGA) to an in-frame translation stop codon (UGA). [27] If the edited transcript is translated, it produces a protein that cannot function as a tumor suppressor because the N-terminal of the GRD is truncated. [26] The editing site in NF1 mRNA was shown to have high homology to the ApoB editing site, where double stranded mRNA undergoes editing by the ApoB holoenzyme. [27] NF1 mRNA editing was believed to involve the ApoB holoenzyme due to the high homology between the two editing sites, however studies have shown that this is not the case. [26] The editing site in NF1 is longer than the sequence required for ApoB mediated mRNA editing, and the region contains two guanidines which are not present in the ApoB editing site. [27]

Clinical significance

Main symptoms of neurofibromatosis type I Symptoms of neurofibromatosis type 1.png
Main symptoms of neurofibromatosis type I

Mutations in NF1 are primarily associated with neurofibromatosis type 1 (NF1, also known as von Recklinghausen syndrome). [6] [7] NF1 is the most common single gene disorder in humans, occurring in about 1 in 2500–3000 births worldwide. [29] NF1 is an autosomal dominant disorder, but approximately half of NF1 cases arise from de novo mutations. NF1 has high phenotypic variability, with members of the same family with the same mutation displaying different symptoms and symptom intensities. [30] [31] Café-au-lait spots are the most common sign of NF1, but other symptoms include lisch nodules of iris, cutaneous neurofibromas (CNF), plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), attention deficits, learning deficits and other cognitive disabilities. [6] [7] [10]

In addition to neurofibromatosis type I, mutations in NF1 can also lead to juvenile myelomonocytic leukemias (JMML), gastrointestinal stromal tumors (GIST), Watson syndrome, astrocytic neoplasms, phaeochromocytomas and breast cancer. [6]

No effective therapy NF1 yet exists. Instead, people with neurofibromatosis are followed by a team of specialists to manage symptoms or complications. [6] [32] However, in April, 2020, [33] the FDA approved selumetinib (brand name Koselugo) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). [34]

Model organisms

A lot about of our knowledge on the biology of NF1 came from model organisms including the fruit fly Drosophila melanogaster , [35] the zebrafish Danio rerio [36] and the mouse Mus musculus, [37] which all contain an NF1 ortholog in their genome (no NF1 ortholog exists in the nematode Caenorhabditis elegans . [6] ) Research based on these preclinical models has already proven its efficacy as multiple clinical assays have been initiated subsequently regarding neurofibromatosis type 1-related plexiform neurofibromas, gliomas, MPNST and neurocognitive disorders. [6]

Mouse models

In 1994, the first NF1 genetically engineered knockout mice were published: [38] [39] homozygosity for the Nf1 mutation (Nf1-/-) induced severe developmental cardiac abnormalities that led to embryonic lethality at early stages of the development, [38] pointing out that NF1 plays a fundamental role in normal development. On the contrary, Nf1 heterozygous animals (Nf1+/-) were viable but predisposed to form different types of tumors. [39] In some of these tumor cells, genetic events of loss of heterozygosity (LOH) were observed, supporting that NF1 functions as a tumor suppressor gene. [39]

The development of several other NF1 mouse models [40] has also allowed the implementation of preclinical research to test the therapeutic potential of targeted pharmacologic agents, such as sorafenib [41] (VEGFR, PDGFR and RAF kinases inhibitor) and everolimus [41] (mTORC inhibitor) for the treatment of NF1 plexiform neurofibromas, sirolimus (rapamycin) [42] (mTORC inhibitor) for MPNSTs, or lovastatin [43] (HMG-CoA reductase inhibitor), and alectinib [44] (ALK inhibitor) for NF1 cognitive and learning disabilities.

In 2013, two conditional knockout mouse models, called Dhh-Cre;Nf1flox/flox [45] (which develops neurofibromas similar to those found in NF1 patients) and Mx1-Cre;Nf1flox/flox [46] (which develops myeloproliferative neoplasms similar to those found in NF1 juvenile myelomonocytic leukemia/JMML) were used to study the effects of the specific MEK inhibitor PD032590 on tumor progression. [45] [46] The inhibitor demonstrated a remarkable response in tumor regression and in hematologic improvement. [45] [46] Based on these results, phase I [47] and later phase II [48] [49] clinical trials were then conducted in children with inoperable NF1-related plexiform neurofibromas, using Selumetinib, [50] an oral selective MEK inhibitor used previously in several advanced adult neoplasms. The children enrolled in the study [51] benefited from the treatment without suffering from excessive toxic effects, [47] and treatment induced partial responses in 72% of them. [48] These unprecedented and promising results from the phase II SPRINT trial, [48] [49] led, first in 2018, both the Food and Drug Administration (FDA) and the European Medicines Agency to grant selumetinib an Orphan Drug Status for the treatment of neurofibromatosis type 1, and then, a few months later in 2019, FDA to grant a Breakthrough Therapy Designation to the inhibitor. [52]

Drosophila melanogaster

The Drosophila melanogaster ortholog gene [35] of human NF1 (dNF1) has been identified and cloned in 1997. [53] The gene is slightly more compact than its human counterpart but still remains one of the largest genes of the fly genome. It encodes a protein 55% identical and 69% similar to human neurofibromin over its entire 2,802 amino acid length. [53] It comprises an IRA-related central segment containing the catalytic GAP-related domain (GRD), which are both highly similar to their human counterparts. Also, other conserved regions exist both up- and downstream of this domain. [35] [53]

dNF1, like its human counterpart, is mainly expressed in the developing and adult nervous system [54] [55] and primarily controls the MAPK RAS/ERK signaling pathway. [35]

Through the use of several mutant null alleles of dNF1 that have been generated, [53] [54] its role has been progressively elucidated. dNF1 functions to regulate organism growth and whole-body size [53] [54] [55] [56] (first elucidated by the rescue study of The et al. 1997), [57] synaptic growth, [56] neuromuscular junction function, [58] [59] circadian clock and rhythmic behaviors, [60] mitochondrial function, [61] and learning (also found in The) [57] including associative learning and long-term memory. [62] [63] [64] [55] Large scale genetic and functional screens have also led to the identification of dominant modifier genes responsible for the dNF1-associated defects. [56] The et al. 1997 found the size defect to be rescuable by transgenic modification by either a working NF1 or a protein kinase – but this works only during development and not in adulthood. [57]

Interestingly, whole-body size deficits, learning defects and aberrant RAS/ERK signaling are also key features of the NF1 condition in humans, [6] [35] and are all due to a deregulation of the anaplastic lymphoma kinase ALK-NF1-RAS/ERK signaling pathway in flies. [55] [56] Pharmacological treatment using a highly-specific ALK inhibitor corrected all these defects in flies [55] and this therapeutic approach was later successfully validated in a preclinical mouse model of NF1 [65] [44] by treating mice with Alectinib, suggesting it represents a promising therapeutic target. [32]

See also

Related Research Articles

<span class="mw-page-title-main">Exon</span> A region of a transcribed gene present in the final functional mRNA molecule

An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term exon refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts. In RNA splicing, introns are removed and exons are covalently joined to one another as part of generating the mature RNA. Just as the entire set of genes for a species constitutes the genome, the entire set of exons constitutes the exome.

<span class="mw-page-title-main">Neurofibromatosis</span> Medical condition

Neurofibromatosis (NF) refers to a group of three distinct genetic conditions in which tumors grow in the nervous system. The tumors are non-cancerous (benign) and often involve the skin or surrounding bone. Although symptoms are often mild, each condition presents differently. Neurofibromatosis type I (NF1) is typically characterized by café au lait spots, neurofibromas, scoliosis, and headaches. Neurofibromatosis type II (NF2), on the other hand, may present with early-onset hearing loss, cataracts, tinnitus, difficulty walking or maintain balance, and muscle atrophy. The third type is called schwannomatosis and often presents in early adulthood with widespread pain, numbness, or tingling due to nerve compression.

The coding region of a gene, also known as the coding sequence (CDS), is the portion of a gene's DNA or RNA that codes for a protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compared to non-coding regions over different species and time periods can provide a significant amount of important information regarding gene organization and evolution of prokaryotes and eukaryotes. This can further assist in mapping the human genome and developing gene therapy.

<span class="mw-page-title-main">Alternative splicing</span> Process by which a gene can code for multiple proteins

Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included within or excluded from the final RNA product of the gene. This means the exons are joined in different combinations, leading to different splice variants. In the case of protein-coding genes, the proteins translated from these splice variants may contain differences in their amino acid sequence and in their biological functions.

<span class="mw-page-title-main">Neurofibromatosis type I</span> Type of neurofibromatosis disease

Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system human disorder caused by the mutation of neurofibromin 1 (NF-1), a gene on chromosome 17 that is responsible for production of a protein (neurofibromin) which is needed for normal function in many human cell types. NF-1 causes tumors along the nervous system which can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any person's race or sex. NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1.

<span class="mw-page-title-main">Neurofibromatosis type II</span> Type of neurofibromatosis disease

Neurofibromatosis type II is a genetic condition that may be inherited or may arise spontaneously, and causes benign tumors of the brain, spinal cord, and peripheral nerves. The types of tumors frequently associated with NF2 include vestibular schwannomas, meningiomas, and ependymomas. The main manifestation of the condition is the development of bilateral benign brain tumors in the nerve sheath of the cranial nerve VIII, which is the "auditory-vestibular nerve" that transmits sensory information from the inner ear to the brain. Besides, other benign brain and spinal tumors occur. Symptoms depend on the presence, localisation and growth of the tumor(s). Many people with this condition also experience vision problems. Neurofibromatosis type II is caused by mutations of the "Merlin" gene, which seems to influence the form and movement of cells. The principal treatments consist of neurosurgical removal of the tumors and surgical treatment of the eye lesions. Historically the underlying disorder has not had any therapy due to the cell function caused by the genetic mutation.

<span class="mw-page-title-main">Neurofibroma</span> Benign nerve-sheath tumor in the peripheral nervous system

A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In 90% of cases, they are found as stand-alone tumors, while the remainder are found in persons with neurofibromatosis type I (NF1), an autosomal-dominant genetically inherited disease. They can result in a range of symptoms from physical disfiguration and pain to cognitive disability.

Phakomatoses, also known as neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes. The majority of phakomatoses are single-gene disorders that may be inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Presentations may vary dramatically between patients with the same particular syndrome due to mosaicism, variable expressivity, and penetrance.

<span class="mw-page-title-main">Merlin (protein)</span> Mammalian protein found in Homo sapiens

Merlin is a cytoskeletal protein. In humans, it is a tumor suppressor protein involved in neurofibromatosis type II. Sequence data reveal its similarity to the ERM protein family.

<span class="mw-page-title-main">Schwannomatosis</span> Rare genetic disorder

Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). Originally described in Japanese patients, it consists of multiple cutaneous schwannomas, central nervous system tumors, and other neurological complications, excluding hallmark signs of NF. The exact frequency of schwannomatosis cases is unknown, although some populations have noted frequencies as few as 1 case per 1.7 million people.

<span class="mw-page-title-main">PAX6</span> Protein-coding gene in humans

Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the PAX6 gene.

<span class="mw-page-title-main">Ultrabithorax</span> Protein-coding gene found in Drosophila melanogaster

Ultrabithorax (Ubx) is a homeobox gene found in insects, and is used in the regulation of patterning in morphogenesis. There are many possible products of this gene, which function as transcription factors. Ubx is used in the specification of serially homologous structures, and is used at many levels of developmental hierarchies. In Drosophila melanogaster it is expressed in the third thoracic (T3) and first abdominal (A1) segments and represses wing formation. The Ubx gene regulates the decisions regarding the number of wings and legs the adult flies will have. The developmental role of the Ubx gene is determined by the splicing of its product, which takes place after translation of the gene. The specific splice factors of a particular cell allow the specific regulation of the developmental fate of that cell, by making different splice variants of transcription factors. In D. melanogaster, at least six different isoforms of Ubx exist.

<span class="mw-page-title-main">Splice site mutation</span> Mutation at a location where intron splicing takes place

A splice site mutation is a genetic mutation that inserts, deletes or changes a number of nucleotides in the specific site at which splicing takes place during the processing of precursor messenger RNA into mature messenger RNA. Splice site consensus sequences that drive exon recognition are located at the very termini of introns. The deletion of the splicing site results in one or more introns remaining in mature mRNA and may lead to the production of abnormal proteins. When a splice site mutation occurs, the mRNA transcript possesses information from these introns that normally should not be included. Introns are supposed to be removed, while the exons are expressed.

A nerve sheath tumor is a type of tumor of the nervous system which is made up primarily of the myelin surrounding nerves. From benign tumors like schwannoma to high grade malignant neoplasms known as malignant peripheral nerve sheath tumors, peripheral nerve sheath tumors include a range of clearly characterized clinicopathologic entities. A peripheral nerve sheath tumor (PNST) is a nerve sheath tumor in the peripheral nervous system. Benign peripheral nerve sheath tumors include schwannomas and neurofibromas.

<span class="mw-page-title-main">RBM4</span> Protein-coding gene in the species Homo sapiens

RNA-binding protein 4 is a protein that in humans is encoded by the RBM4 gene.

<span class="mw-page-title-main">EVI2B</span> Protein-coding gene in the species Homo sapiens

Protein EVI2B is a protein that in humans is encoded by the EVI2B gene.

<span class="mw-page-title-main">Legius syndrome</span> Medical condition

Legius syndrome (LS) is an autosomal dominant condition characterized by cafe au lait spots. It was first described in 2007 and is often mistaken for neurofibromatosis type I. It is caused by mutations in the SPRED1 gene. It is also known as neurofibromatosis type 1-like syndrome.

<span class="mw-page-title-main">SPRED1</span> Protein-coding gene in the species Homo sapiens

Sprouty-related, EVH1 domain-containing protein 1 (Spread-1) is a protein that in humans is encoded by the SPRED1 gene located on chromosome 15q13.2 and has seven coding exons.

Amita Sehgal is a molecular biologist and chronobiologist in the Department of Neuroscience at the Perelman School of Medicine at the University of Pennsylvania. Sehgal was involved in the discovery of Drosophila TIM and many other important components of the Drosophila clock mechanism. Sehgal also played a pivotal role in the development of Drosophila as a model for the study of sleep. Her research continues to be focused on understanding the genetic basis of sleep and also how circadian systems relate to other aspects of physiology.

<span class="mw-page-title-main">Shapiro–Senapathy algorithm</span>

The Shapiro—Senapathy algorithm (S&S) is an algorithm for predicting splice junctions in genes of animals and plants. This algorithm has been used to discover disease-causing splice site mutations and cryptic splice sites.

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