Alternative titles; symbols
HGNC Approved Gene Symbol: NRAS
Cytogenetic location: 1p13.2 Genomic coordinates (GRCh38): 1:114,704,469-114,716,771 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.2 | ?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic | 614470 | 3 | |
| Colorectal cancer, somatic | 114500 | 3 | ||
| Epidermal nevus, somatic | 162900 | 3 | ||
| Melanocytic nevus syndrome, congenital, somatic | 137550 | 3 | ||
| Neurocutaneous melanosis, somatic | 249400 | 3 | ||
| Noonan syndrome 6 | 613224 | Autosomal dominant | 3 | |
| Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic | 163200 | 3 | ||
| Thyroid carcinoma, follicular, somatic | 188470 | 3 |
Marshall et al. (1982) identified a gene with transforming activity in 2 different human sarcoma cell lines, a fibrosarcoma (HT1080) and an embryonal rhabdomyosarcoma (RD). Hall et al. (1983) identified this gene as a member of the RAS gene family and designated it N-RAS 'after consultation with Wigler and with Weinberg.' They found that NRAS was also activated in a promyelocytic leukemia cell line (HL60) and a neuroblastoma cell line (SK-H-SH). NRAS was present at the same levels in normal fibroblasts and tumor cells. Hall and Brown (1985) identified 2 main NRAS transcripts of 4.3 kb and 2 kb.
Hall and Brown (1985) determined that the NRAS gene contains 7 exons.
By restriction mapping and Southern blot analysis, Hall et al. (1983) mapped the NRAS gene to chromosome 1. By in situ hybridization, Davis et al. (1983) assigned the NRAS gene to the short arm of chromosome 1. A concentration of grains was observed just above the centromere in band 1p13. They commented on the wide dispersion of the oncogenes in the RAS family; each of the 5 mapped to date was on a separate chromosome. Ryan et al. (1983) confirmed assignment of HRAS (190020) to chromosome 11, KRAS2 (190070) to chromosome 12, and NRAS to chromosome 1. Addendum in proof indicated that the same laboratory had assigned NRAS1 to 1p21-cen. De Martinville et al. (1984) assigned NRAS to 1p31-cen. By somatic cell hybrid studies and by in situ hybridization, Rabin et al. (1984) assigned the NRAS gene to 1p13-p11. By in situ hybridization, Popescu et al. (1985) also assigned the NRAS locus to 1p13-p11. Povey et al. (1985) reviewed the conflicting evidence on the site of NRAS on 1p. They found evidence favoring both 1p22 and 1p12-p11. Dracopoli and Meisler (1990) concluded from linkage analysis and pulsed field gel electrophoresis that TSHB (188540), NGFB (162030), and NRAS form a tightly linked gene cluster located in the same chromosomal band. Their location proximal to the AMY2B gene in 1p21 and close linkage to the alpha-satellite centromeric repeat D1Z5 provided strong evidence that the correct assignment for these 3 loci is 1p13 and not 1p22. Mitchell et al. (1995) localized NRAS to 1p13.2 and CD2 (186990) and NGFB to 1p13.1. They concluded that the order is as follows: cen--CD2--NGFB--NRAS--tel.
Using teratomas (see 166950) as a means of 'centromere mapping,' Deka et al. (1989) estimated the NRAS-centromere distance (y) to be 0.30.
Substitution of ser17 with asn (S17N) in any of the RAS proteins produces dominant-inhibitory proteins with higher affinities for exchange factors than normal RAS. These mutants cannot interact with downstream effectors and therefore form unproductive complexes, preventing activation of endogenous RAS. Using experiments in COS-7 cells, mouse fibroblasts, and canine kidney cells, Matallanas et al. (2003) found that the Hras, Kras, and Nras S17N mutants exhibited distinct inhibitory effects that appeared to be due largely to their specific membrane localizations. The authors demonstrated that Hras is present in caveolae, lipid rafts, and bulk disordered membranes, whereas Kras and Nras are present primarily in disordered membranes and lipid rafts, respectively. Thus, the Hras S17N mutant inhibited activation of all 3 wildtype RAS isoforms, the Kras S17N mutant inhibited wildtype Kras and the portion of Hras in disordered membranes, and the Nras S17N mutant inhibited wildtype Nras and the portion of Hras in lipid rafts.
Rocks et al. (2005) showed that the specific subcellular distribution of HRAS and NRAS guanosine triphosphate-binding proteins is generated by a constitutive de/reacylation cycle that operates on palmitoylated proteins, driving their rapid exchange between the plasma membrane and the Golgi apparatus. Depalmitoylation redistributes farnesylated Ras in all membranes, followed by repalmitoylation and trapping of Ras at the Golgi, from where it is redirected to the plasma membrane via the secretory pathway. This continuous cycle prevents Ras from nonspecific residence on endomembranes, thereby maintaining the specific intracellular compartmentalization. Rocks et al. (2005) found that the de/reacylation cycle also initiates Ras activation at the Golgi by transport of plasma membrane-localized Ras guanosine triphosphate. Different de/repalmitoylation kinetics account for isoform-specific activation responses to growth factors.
Haigis et al. (2008) used genetically engineered mice to determine whether and how the related oncogenes Kras (190070) and Nras regulate homeostasis and tumorigenesis in the colon. Expression of Kras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek (see 176872)-dependent manner. Nras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc (611731)-mutant colonic tumor, activation of Kras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This Kras tumor phenotype was associated with attenuated signaling through the MAPK pathway (see 176872), and human colon cancer cells expressing mutant Kras were hypersensitive to inhibition of Raf (see 164760) but not Mek. Haigis et al. (2008) concluded that their studies demonstrated clear phenotypic differences between mutant Kras and Nras, and suggested that the oncogenic phenotype of mutant Kras might be mediated by noncanonical signaling through Ras effector pathways.
Nazarian et al. (2010) showed that acquired resistance of BRAF(V600E) (164757.0001)-positive melanomas to PLX4032, a novel class I RAF-selective inhibitor, develops by mutually exclusive PDGFRB (173410) upregulation or NRAS mutations but not through secondary mutations in BRAF(V600E). Nazarian et al. (2010) used PLX4032-resistant sublines artificially derived from BRAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumors and tumor-matched, short-term cultures from clinical trial patients. Induction of PDGFRB RNA, protein, and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sublines, patient-derived biopsies, and short-term cultures. PDGFRB-upregulated tumor cells had low activated RAS levels and, when treated with PLX4032, did not reactivate the MAPK (see 176872) pathway significantly. In another subset, high levels of activated NRAS resulting from mutations led to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRB or NRAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRB or mutated NRAS conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, Nazarian et al. (2010) showed that MAPK reactivation predicts MEK inhibitor sensitivity. Thus, Nazarian et al. (2010) concluded that melanomas escape BRAF(V600E) targeting not through secondary BRAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.
Using a dual pulse-chase strategy comparing palmitate and protein half-lives in transfected COS-7 cells, followed by inhibitor studies, Lin and Conibear (2015) showed that members of the ABHD17 family (see ABHD17A, 617942) were common targets of depalmitoylation inhibitors and could accelerate palmitate turnover on PSD95 (DLG4; 602887) and NRAS in COS-7 cells. ABHD17A relocalized depalmitoylated NRAS from plasma membrane to internal cellular membranes in COS-7 cells. Knockdown studies showed that the endogenous ABHD17 proteins redundantly depalmitoylated NRAS in HEK293T cells. Lin and Conibear (2015) concluded that ABHD17 proteins regulate NRAS palmitate turnover and subcellular localization.
Role in Carcinoma
Vasko et al. (2003) performed a pooled analysis of 269 mutations in HRAS, KRAS, and NRAS found in follicular thyroid tumors (FTC; see 188550) garnered from 39 previous studies. Mutations proved significantly less frequent when detected with than without direct sequencing (12.3% vs 17%). The rates of mutation involving NRAS exon 1 and KRAS exon 2 was less than 1%. Mutations of codon 61 of NRAS were significantly more frequent in follicular tumors (19%) than in papillary cancers (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. HRAS mutations in codons 12/13 were found in 2 to 3% of all types of tumors, but HRAS mutations in codon 61 were observed in only 1.4% of tumors, and almost all of them were malignant. KRAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs 1.6%) and were sometimes correlated with special epidemiologic circumstances. The second part of this study involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). HRAS mutations in codons 12/13 were found in 12.5% of common adenomas and 1 follicular carcinoma (2.9%). Mutations of codon 61 of NRAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively. The authors concluded that their results confirmed the predominance of mutations of codon 61 of NRAS in thyroid follicular tumors and their correlation with malignancy.
Nikiforova et al. (2003) analyzed a series of 88 conventional follicular and Hurthle cell thyroid tumors for RAS (HRAS, NRAS, or KRAS) mutations and PAX8 (167415)-PPARG (601487) rearrangements using molecular methods and for galectin-3 (153619) and mesothelioma antibody HBME-1 expression by immunohistochemistry. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations.
Johnson et al. (2005) found that the 3 human RAS genes, HRAS KRAS, and NRAS, contain multiple let-7 (see 605386) miRNA complementary sites in their 3-prime UTRs that allow let-7 miRNA to regulate their expression. Let-7 expression was lower in lung tumors than in normal lung tissue, whereas expression of the RAS proteins was significantly higher in lung tumors, suggesting a possible mechanism for let-7 in cancer.
Role In Hematologic Malignancies
Using the allele-specific amplification method (ARMS), a highly sensitive 1-stage allele-specific PCR, Bezieau et al. (2001) evaluated the incidence of NRAS- and KRAS2-activating mutations (in codons 12, 13, and 61) in 62 patients with monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), or primary plasma cell leukemia (PPCL), and in human myeloma cell lines (HMCL). Mutations in one or the other gene, or in both, were found in 54.5% of MM patients at diagnosis (but in 81% at the time of relapse), 50% of PPCL patients, and 50% of 16 HMCL patients. In contrast, the occurrence of such mutations was very low in MGUS and indolent MM (12.5%). KRAS2 mutations were always more frequent than NRAS mutations. Bezieau et al. (2001) concluded that these early mutations may play a major role in the oncogenesis of multiple myeloid myeloma and primary plasma cell leukemia.
In white blood cells derived from 8 patients with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified 5 different somatic mutations in the NRAS gene (see, e.g., G12D, 164790.0007 and G13D, 164790.0003). Each patient carried a single somatic mutation. The patients were ascertained from a cohort of 80 children with JMML.
The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo acute myeloid leukemia (AML; 601626), using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The Cancer Genome Atlas Research Network (2013) identified recurrent mutations in the NRAS or KRAS genes in 23 (12%) of 200 samples.
Brewin et al. (2013) noted that the study of the Cancer Genome Atlas Research Network (2013) did not reveal which mutations occurred in the founding clone, as would be expected for an initiator of disease, and which occurred in minor clones, which subsequently drive disease. Miller et al. (2013) responded that NRAS was among several genes in their study whose mutations were often found in subclones, suggesting that they are often cooperating mutations. The authors also identified other genes that contained mutations they considered probable initiators.
RAS-Associated Autoimmune Leukoproliferative Disorder
Oliveira et al. (2007) identified a heterozygous mutation in the NRAS gene (G13D; 164790.0003) in a 49-year-old patient with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470). The patient had a lifelong overexpansion of lymphocytes, childhood leukemia, and early adulthood lymphoma, both successfully treated. He had increased serum CD4-/CD8- alpha/beta T cells and follicular hyperplasia of the lymph nodes. Niemela et al. (2010) stated that the NRAS mutation found by Oliveira et al. (2007) was a somatic mutation.
Noonan Syndrome 6
Cirstea et al. (2010) identified 1 of 2 different heterozygous mutations in the NRAS gene (T50I; 164790.0004 and G60E; 164790.0005) in 5 patients, including a mother and son, with Noonan syndrome-6 (NS6; 613224). The mutations were de novo in 3 patients. In vitro functional expression studies showed that the mutations resulted in enhanced stimulus-dependent MAPK activation. The patients were part of a larger study of 917 affected individuals who were negative for previously known Noonan-associated gene mutations, suggesting that NRAS mutations are a rare cause of Noonan syndrome.
Congenital Melanocytic Nevus Syndrome
Dessars et al. (2009) identified a somatic NRAS mutation in samples from 19 (70%) of 27 patients with congenital melanocytic nevi (CMNS; 137550): 14 nevi carried a Q61K mutation (164790.0008), 4 carried a Q61R mutation (164790.0002), and 1 carried a G13R mutation (164790.0001).
Kinsler et al. (2013) identified somatic oncogenic missense mutations affecting codon 61 of the NRAS gene in affected cutaneous and neurologic tissues from 12 of 15 patients with congenital melanocytic nevus syndrome and/or neurocutaneous melanosis (NCMS; 249400). Affected skin samples from 10 of 13 patients carried a somatic heterozygous mutation, including 8 with Q61K and 2 with Q61R. The same codon 61 mutation was found in each of the anatomically separate melanocytic nevi from the same patient. In addition, all 11 neurologic samples from 5 patients from whom neurologic tissue was available were positive for a somatic Q61K mutation; this included both melanocytic and nonmelanocytic tissue, such as a choroid plexus papilloma and meningioma. In patients with both neurologic and skin samples available, the same mutation was present in both affected tissues. None of the patients carried an NRAS mutation in the blood. Pre- and post-malignant skin tissue was available from a patient with malignant melanoma, which showed a progression from heterozygosity to homozygosity for the Q61K mutation with the onset of malignancy. Mutations at codon 61 in the NRAS gene affect the guanosine triphosphate-binding site and result in constitutive activation of NRAS. Kinsler et al. (2013) concluded that multiple congenital melanocytic nevi and neuromelanosis, as well as nonmelanocytic CNS lesions, result from somatic mosaicism, and that the mutation probably occurs in a progenitor cell in the developing neural crest or neuroectoderm. The findings also suggested that these mutations may be lethal in the germline. Three of the original 15 patients with CMNS did not have NRAS mutations.
Mutations in the RB1 gene (614041) predispose humans and mice to tumor development. Takahashi et al. (2006) assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of 1 or 2 Nras alleles significantly reduced the severity of pituitary tumors arising in Rb1 +/- animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1 +/- mice progressed to metastatic medullary carcinomas after loss of Nras. In Rb1/Nras doubly heterozygous mice, distant medullary thyroid carcinoma metastases were associated with loss of the remaining wildtype Nras allele. Loss of Nras in Rb1-deficient C cells resulted in elevated Ras homolog family A (RhoA) activity, and this was causally linked to the invasiveness and metastatic behavior of these cells. These findings suggested that the loss of the protooncogene Nras in certain cellular contexts can promote malignant tumor progression.
Nitta et al. (1987) found a G-to-C point mutation at the first letter of codon 13 in the NRAS gene as the presumed basis for activation of the gene in a case of rectal cancer (see 114500). The point mutation resulted in the substitution of arginine for glycine.
Dessars et al. (2009) identified a heterozygous somatic G13R mutation in 1 of 27 congenital melanocytic nevi (137550).
Nikiforova et al. (2003) found that the CAA-CGA mutation of NRAS codon 61, resulting in a gln-to-arg change (Q61R), was present in 70% (12) of follicular carcinomas (see 188550) and 55% (6) of follicular adenomas studied.
Hafner et al. (2012) identified a somatic Q61R mutation in 1 of 72 keratinocytic epidermal nevi (162900).
Dessars et al. (2009) identified a somatic Q61R mutation in 4 of 27 congenital melanocytic nevi (137550).
In affected skin samples from 2 of 13 patients with congenital melanocytic nevus syndrome (CMNS; 137550), Kinsler et al. (2013) identified a somatic heterozygous c.182C-A transversion in the NRAS gene, resulting in the Q61R mutation. The substitution occurred in the guanosine triphosphate-binding site and was predicted to result in constitutive activation of NRAS. One of the samples from 1 of the patients showed homozygosity for the Q61R mutation: this patient later developed fatal leptomeningeal melanocytic disease (NCMS; 249400) that was indistinguishable from malignant melanoma.
Lim et al. (2014) identified a Caucasian female who presented at birth with linear epidermal nevi (SFM; 163200) restricted to the left side of her body and distributed from neck to calf. Histopathology showed acanthosis and papillomatosis. A femur radiograph taken when the patient was 7 years of age revealed dysplastic bone with a sclerotic appearance. At a younger age, she had lesions that were more lytic in nature. In a second patient with this mutation who had congenital melanocytic nevus syndrome (137550), Lim et al. (2014) showed that elevated serum FGF23 (605380) originated from dysplastic bone with the Q61R mutation. The mutation was absent from normal bone.
In white blood cells derived from 2 unrelated children with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G-to-A transition in the NRAS gene, resulting in a gly13-to-asp (G13D) substitution.
Oliveira et al. (2007) identified a heterozygous G-to-A transition in the NRAS gene, resulting in a gly13-to-asp (G13D) substitution, in a 49-year-old patient with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470). The patient had a lifelong overexpansion of lymphocytes and a history of childhood leukemia, and early adulthood lymphoma, both successfully treated. There were no developmental defects. Laboratory studies showed increased serum alpha/beta CD4-/CD8- T cells and lymph node follicular hyperplasia. There was no evidence of CD95 (134637)-mediated apoptosis, but the patient's lymphocytes resisted death by IL2 (147680) withdrawal, indicating a specific defect in lymphocyte apoptosis. Further studies of the patient's cells indicated a decrease of the proapoptotic protein BIM (BCL2L11; 603827), which is critical for withdrawal-induced mitochondrial apoptosis. The mutation was found in the patient's lymphoblasts, peripheral blood mononuclear cells, monocytes, EBV-transformed B cells, and buccal epithelial cells. It was not present in the patient's unaffected relatives, suggesting de novo occurrence. The patient had no developmental abnormalities or features of Noonan syndrome. Oliveira et al. (2007) noted that the same mutation had been identified somatically in myeloid and lymphoid malignancies (Bos et al., 1985; Lubbert et al., 1990). Niemela et al. (2010) stated that the NRAS mutation found by Oliveira et al. (2007) was a somatic mutation.
De Filippi et al. (2009) identified a de novo germline heterozygous G13D substitution in the NRAS gene in a male infant who presented at age 2 months with juvenile myelomonocytic leukemia (JMML; 607785) and was later noted to have dysmorphic features suggestive of, but not diagnostic of, Noonan syndrome (NS6; 613224). Features included short stature, relative macrocephaly, high forehead, epicanthal folds, long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and low scores on performance tasks. Cardiac studies were normal. There were no hematologic abnormalities related to RALD in this patient.
In 2 unrelated boys with Noonan syndrome-6 (NS6; 613224), Cirstea et al. (2010) identified a de novo heterozygous 149C-T transition in exon 3 of the NRAS gene, resulting in a thr50-to-ile (T50I) substitution in a conserved residue located in the beta-2-beta-3 loop connecting the 2 switch regions. In vitro functional expression studies showed that the mutant protein resulted in enhanced downstream phosphorylation in the presence of serum, but did not substantially affect intrinsic GTPase activity. Molecular modeling indicated that thr50 interacts with the polar heads of membrane phospholipids and is an integral part of a region that controls RAS membrane orientation. Cirstea et al. (2010) hypothesized that the T50I substitution might alter RAS orientation, increase the interaction of GTP-bound RAS with its effectors, and enhance a downstream signal flow consistent with a gain of function.
In 3 patients from 2 unrelated families with Noonan syndrome-6 (NS6; 613224), Cirstea et al. (2010) identified a heterozygous 179G-A transition in exon 3 of the NRAS gene, resulting in a gly60-to-glu (G60E) substitution in a conserved residue in the switch 2 region. One proband had a de novo mutation, whereas the other inherited it from his affected mother. In vitro functional expression studies showed that the mutant protein resulted in enhanced downstream phosphorylation in the presence of serum, and that the G60E mutant NRAS protein accumulated constitutively in the active GTP-bound form, although it appeared to be resistant to GAP stimulation.
By targeted next-generation sequencing in a father and daughter with Noonan syndrome, Ekvall et al. (2015) identified heterozygosity for the G60E mutation in the NRAS gene.
Hafner et al. (2012) identified a somatic pro34-to-leu (P34L) mutation in the NRAS gene in 1 of 72 keratinocytic epidermal nevi (162900).
Hafner et al. (2012) identified a somatic gly12-to-asp (G12D) mutation in the NRAS gene in 1 of 72 keratinocytic epidermal nevi (162900).
In white blood cells derived from 2 unrelated children with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G-to-A transition in the NRAS gene, resulting in a gly12-to-asp (G12D) substitution.
Li et al. (2013) showed that a single allele of oncogenic Nras(G12D) increases hematopoietic stem cell (HSC) proliferation and also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all prior to leukemia initiation. Nras(G12D) also confers long-term self-renewal potential to multipotent progenitors. Li et al. (2013) found that Nras(G12D) had a bimodal effect on HSCs, increasing the frequency with which some HSCs divide and reducing the frequency with which others divide. This mirrored bimodal effects on reconstituting potential, as rarely dividing Nras(G12D) HSCs outcompeted wildtype HSCs, whereas frequently dividing Nras(G12D) HSCs did not. Nras(G12D) caused these effects by promoting STAT5 (601511) signaling, inducing different transcriptional responses in different subsets of HSCs. Li et al. (2013) concluded that 1 signal can therefore increase HSC proliferation, competitiveness, and self-renewal through bimodal effects on HSC gene expression, cycling, and reconstituting potential.
Dessars et al. (2009) identified a somatic gln61-to-lys (Q61K) mutation in the NRAS gene in 14 of 27 congenital melanocytic nevi (137550).
In affected skin samples from 8 of 13 patients with congenital melanocytic nevus syndrome (CMNS; 137550), including 4 with neurocutaneous melanosis (NCMS; 249400), Kinsler et al. (2013) identified a somatic heterozygous c.181C-A transversion in the NRAS gene, resulting in a gln61-to-lys (Q61K) substitution in the guanosine triphosphate-binding domain. The mutation was predicted to result in constitutive activation of NRAS. Neurologic samples from 5 patients from whom tissue was available were positive for a somatic Q61K mutation, and the same mutation was present in both neurologic and skin samples when available. Kinsler et al. (2013) concluded that multiple congenital melanocytic nevi and neuromelanosis, as well as associated nonmelanocytic CNS lesions, result from somatic mosaicism, and that the mutation probably occurs in a progenitor cell in the developing neural crest or neuroectoderm. The findings also suggested that the mutation may be lethal in the germline.
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