Other entities represented in this entry:
HGNC Approved Gene Symbol: NOS1
Cytogenetic location: 12q24.22 Genomic coordinates (GRCh38) : 12:117,208,142-117,361,626 (from NCBI)
Nitric oxide (NO) is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter; it is implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. NO is also responsible for endothelium-derived relaxing factor activity regulating blood pressure. In macrophages, NO mediates tumoricidal and bactericidal actions, as indicated by the fact that inhibitors of NO synthase (NOS) block these effects. Neuronal NOS and macrophage NOS (163730) are distinct isoforms (Lowenstein et al., 1992). Both the neuronal and the macrophage forms are unusual among oxidative enzymes in requiring several electron donors: FAD (see 610595), flavin mononucleotide (FMN), NADPH, and tetrahydrobiopterin.
Bredt et al. (1991) cloned a cDNA for the neuronal form of nitric oxide synthase and studied its expression. The only mammalian protein with close sequence similarity was cytochrome P450 reductase.
Magee et al. (1996) used PCR to clone a novel form of neuronal NOS from rat penile RNA. This NOS cDNA was termed PnNOS for 'penile neuronal NOS.' Sequencing revealed that the PnNOS cDNA was identical to rat cerebellar neuronal NOS1 except for a 102-bp insertion in PnNOS, indicating that PnNOS is a novel isoform. PCR of a human penile cDNA library confirmed that this insert is present in human DNA at the same location. Repetition of RT-PCR showed PnNOS to be the only form of NOS1 expressed in rat penis, urethra, prostate, and skeletal muscle. The PnNOS form was also present in rat cerebellum, liver, and pelvic plexus, although less abundantly than the shorter isoform. The authors postulated that PnNOS may be responsible for the synthesis of nitric oxide during penile erection and may be involved in control of the tone of the urethra, prostate, and bladder.
Wang et al. (1997) identified an nNOS splice variant, expressed in testis, that encodes an N-terminally truncated protein of 1,098 amino acids. Upon expression in CHO-K1 cells, this variant displayed calcium-dependent nitric oxide synthase activity with catalytic activity comparable to that of full-length nNOS.
Newton et al. (2003) identified a variant with an 89-bp insertion within the 5-prime untranslated region. The reading frame was unaffected. This mRNA accounted for 5 to 40% of nNOS transcripts in several tissues and was enriched in testis, brain, skeletal muscle, and lung.
NOS1 cDNA clones contain different 5-prime terminal exons spliced to a common exon 2. By genomic cloning and sequence analysis, Xie et al. (1995) demonstrated that the unique exons are positioned within 300 bp of each other but separated from exon 2 by an intron that is at least 20 kb long. A CpG island engulfs the downstream 5-prime terminal exon. In contrast, most of the upstream exon resides outside of this CpG island. Furthermore, the upstream exon includes a GT dinucleotide repeat. By expressing fusion genes in transfected HeLa cells, Xie et al. (1995) showed that expression of these 2 exons is subject to transcriptional control by separate promoters. However, the proximity of these promoters raises the possibility that complex interactions may be involved in regulating NOS1 gene expression at these sites.
Wang et al. (1997) determined that the promoter region of a splice variant they isolated from testis does not contain canonical TATA and CAAT boxes. It does contain multiple putative cis regulatory elements, including those implicated in testis-specific gene expression.
A common variant described by Newton et al. (2003), which contains an 89-bp insertion in the promoter region, was predicted to form a stem-loop secondary structure.
Using a rat cDNA probe prepared from rat cerebellum RNA, Kishimoto et al. (1992) isolated a human nitric oxide synthase cDNA from a human cerebellum cDNA library. This in turn was used for Southern blot analysis of DNAs from human-rodent hybrid cell lines to map the NOS1 gene to 12q14-qter. Marsden et al. (1993) regionalized the NOS1 gene to 12q24.2 by fluorescence in situ hybridization. Xu et al. (1993) used fluorescence in situ hybridization to map the NOS1 gene to 12q24.2-q24.31. Lee et al. (1995) assigned the homologous gene to mouse chromosome 5 by analysis of interspecific backcrosses.
Burnett et al. (1992) localized NO synthase to rat penile neurons innervating the corpora cavernosa and to neuronal plexuses in the adventitial layer of penile arteries. They found, furthermore, that small doses of NO synthase inhibitors abolished electrophysiologically induced penile erections. Thus, they established that nitric oxide is a physiologic mediator of erectile function.
Kharazia et al. (1994) found that all neurons in the striatum were positive for nitric oxide. Synthase staining showed that they were also positive for diaphorase. The 2 activities colocalized in the majority of cortical neurons, but 1% of neurons intensely stained for diaphorase lacked detectable levels of nitric oxide synthase. Kharazia et al. (1994) suggested that these single-labeled neurons (0.01% of cortical neurons) might contain either a splice variant or a novel isoform of NOS.
Deans et al. (1996) found that the OCT2 (164176) transcription factor binds to the downstream 5.1 promoter but not the upstream 5.2 promoter of the neuronal NOS promoter region. OCT2 may activate transcription of neuronal NOS specifically in neuronal cells.
Nitric oxide is synthesized in skeletal muscle by neuronal-type NO synthase, which is localized to sarcolemma of fast-twitch fibers. Synthesis of NO in active muscle opposes contractile force. Brenman et al. (1995) showed that NOS1 partitions with skeletal muscle membranes owing to association of enzyme with dystrophin (300377), the protein mutated in Duchenne muscular dystrophy (DMD; 310200). The dystrophin complex interacts with an N-terminal domain of NOS1 that contains a GLGF motif. Both humans with DMD and mdx mice show a selective loss of NOS1 protein and catalytic activity from muscle membranes, demonstrating a novel role for dystrophin and localizing a signaling enzyme to the myocyte sarcolemma. Brenman et al. (1995) speculated that aberrant regulation of NOS1 may contribute to preferential degeneration of fast-twitch muscle fibers in DMD.
The neuronal isoform of nitric oxide synthase is highly expressed in mammalian skeletal muscle. Since NO had been implicated in the local metabolic regulation of blood flow in contracting skeletal muscle in part by antagonizing sympathetic vasoconstriction, Thomas et al. (1998) hypothesized that NOS1 in skeletal muscle is the source of the NO mediating the inhibition of sympathetic vasoconstriction in contracting muscle. In the mdx mouse, a model of DMD in which dystrophin deficiency results in greatly reduced expression of NOS1 in skeletal muscle, Thomas et al. (1998) found that the normal ability of skeletal muscle contraction to attenuate alpha-adrenergic vasoconstriction is defective. Similar results were obtained in mutant mice that lack the gene encoding NOS1. Together these data suggested a specific role for NOS1 in the local metabolic inhibition of alpha-adrenergic vasoconstriction in active skeletal muscle.
The relevance of the observations in mice to Duchenne muscular dystrophy in children was demonstrated by Sander et al. (2000). They reported that the protective mechanism that NOS1 provides to exercising skeletal muscle by blunting the vasoconstrictor response to alpha-adrenergic receptor activation is defective in children with DMD. Vasoconstrictor response (measured as a decrease in muscle oxygenation) to reflex sympathetic activation was not blunted during exercise of the dystrophic muscles. In contrast, this protective mechanism was intact in healthy children and in those with polymyositis or limb-girdle muscular dystrophy, both muscle diseases that do not result in loss of neuronal nitric oxide synthase. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of the dystrophin-glycoprotein complex. The clinical observations of Sander et al. (2000) suggested that unopposed sympathetic vasoconstriction in exercising human skeletal muscle may constitute a vascular mechanism contributing to the pathogenesis of DMD.
Paraquat is a pneumotoxicant that produces toxicity by redox cycling with cellular diaphorases, thereby elevating intracellular levels of superoxide. NO synthase participates in paraquat-induced lung injury. It had been theorized that NO reacts with superoxide generated by paraquat to produce the toxin peroxynitrite. Day et al. (1999) asked whether NOS might alternatively function as a paraquat diaphorase and reexamined the question of whether NO/superoxide reactions are toxic or protective. They showed that neuronal NOS had paraquat diaphorase activity that inversely correlates with NO formation; that paraquat-induced endothelial cell toxicity is attenuated by inhibitors of NOS that prevent NADPH oxidation, but is not attenuated by those that do not; that paraquat inhibits endothelium-derived, but not NO-induced, relaxations of aortic rings; and that paraquat-induced cytotoxicity is potentiated in cytokine-activated macrophages in a manner that correlates with its ability to block NO formation. These data indicated that NOS is a paraquat diaphorase and that toxicity of such redox-active compounds involves the loss of NO-related activity.
Using sea urchin gametes, Kuo et al. (2000) showed that nitric oxide synthase is present at high concentration and active in sperm after activation by the acrosome reaction. An increase in nitrostatin within eggs is evident seconds after insemination and precedes the calcium pulse of fertilization. Microinjection of nitric oxide donors or recombinant nitric oxide synthase recapitulates events of egg activation, whereas prior injection of oxyhemoglobin, a physiologic nitric oxide scavenger, prevented egg activation after fertilization. Kuo et al. (2000) concluded that nitric oxide synthase and nitric oxide-related bioactivity satisfied the primary criteria of an egg activator: they are present in an appropriate place, active at an appropriate time, and are necessary and sufficient for successful fertilization. They suggested that nitric oxide may be a universal activator of eggs or oocytes.
Gu et al. (2002) reported activation of matrix metalloproteinase-9 (MMP9; 120361) by Nos1 in a mouse model of cerebral ischemia. Immunochemical analysis of the ischemic cortex following stroke in wildtype animals showed that activated Mmp9 colocalized with Nos1 within neurons. Activation of Mmp9 was abrogated after stroke in Nos1-null mice or in wildtype mice treated with an NOS inhibitor. Biochemical analysis and mass spectrometry revealed that MMP9 activation is initiated by NOS1 through S-nitrosylation of the Zn(2+)-coordinating cysteine within the active site of MMP9. Further oxidation causes irreversible modification of the residue to sulfinic or sulfonic acid. Gu et al. (2002) noted that the regulation of protein function by S-nitrosylation may function as a posttranslational modification analogous to phosphorylation or acetylation.
Raoul et al. (2002) showed that Fas (134637), a member of the death receptor family, triggers cell death specifically in motor neurons by transcriptional upregulation of nNOS mediated by p38 kinase (600289). ASK1 (602448) and Daxx (603186) act upstream of p38 in the Fas signaling pathway. The authors also showed that synergistic activation of the NO pathway and the classic FADD (602457)/caspase-8 (601763) cell death pathway were needed for motor neuron cell death. No evidence for involvement of the Fas/NO pathway was found in other cell types. Motor neurons from transgenic mice expressing amyotrophic lateral sclerosis (ALS; 105400)-linked SOD1 (147450) mutations displayed increased susceptibility to activation of the Fas/NO pathway. Raoul et al. (2002) emphasized that this signaling pathway was unique to motor neurons and suggested that these cell pathways may contribute to motor neuron loss in ALS.
Using a homogenized mouse heart preparation, Khan et al. (2004) demonstrated that xanthine oxidoreductase (XDH; 607633) and Nos1 coimmunoprecipitate and colocalize in the cardiac sarcoplasmic reticulum. Deficiency of Nos1 (but not Nos3; 163729) led to marked increases in Xdh-mediated superoxide production, which in turn depressed myocardial excitation-contraction coupling in a manner reversible by Xdh inhibition. Khan et al. (2004) concluded that NOS1 has a direct antioxidant mechanism via its interaction with XDH.
Following exposure of rats to hypoxic conditions (8% oxygen), Ward et al. (2005) found Nos1 protein increased in aorta, mesenteric arterioles, pulmonary arteries, brain, and diaphragm. NOS1 expression increased in human aortic smooth muscle cells after hypoxic incubation (1% oxygen). Ca(2+)-dependent NOS activity was increased in endothelium-denuded aortic segments from hypoxia-exposed rats. NOS1 inhibition enhanced the contractile responses of endothelium-denuded aortic rings and mesenteric arterioles from hypoxia-exposed rats but not from normoxic rats. The hypoxia-inducible mRNA expressed by human cells contained a novel 5-prime UTR, and transgenic mice possessing a reporter gene under the control of the 5-prime UTR and the immediate 5-prime flanking region demonstrated expression of the reporter after exposure to hypoxia in the aorta, mesenteric arterioles, renal papilla, and brain. Ward et al. (2005) concluded that this hypoxia-responsive NOS1 promoter gives rise to rapid translation and is distinct from NOS1 promoters involved in constitutive and cell-restricted NOS1 expression.
Using mouse models, Kobayashi et al. (2008) demonstrated that the exaggerated exercise-induced fatigue response seen in many neuromuscular disorders is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signaling by nNOS in skeletal muscle is required to maintain activity after mild exercise. Kobayashi et al. (2008) showed that nNOS-null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was relieved only by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signaling response to mild exercise. These findings suggested that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signaling from sarcolemma-localized nNOS, which decreases cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Kobayashi et al. (2008) concluded that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise-induced signaling.
Neuronal NOS localizes to the sarcolemma via direct binding to alpha-1-syntrophin (SNTA1; 601017) and interaction with dystrophin. In a retrospective study of 161 patients with acquired and nondystrophin inherited neuromuscular disorders, Finanger Hedderick et al. (2011) found that 70 (43%) had abnormal sarcolemmal staining of nNOS. These included 42% of those with inherited myopathic conditions, including 59% of those with unspecified congenital myopathy; 25% of those with acquired myopathic conditions, mostly inflammatory myopathy; 57% of those with denervating conditions, mainly spinal muscular atrophy (SMA; 253300); and 93% with hypotonia, most of whom likely had an unidentified single gene disorder. The findings indicated that nNOS mislocalization can be observed in a broad range of neuromuscular conditions independent of the primary cause. There was a significant correlation between abnormal sarcolemmal nNOS staining and compromised mobility status and/or compromised muscle function. Two mouse models of muscle atrophy, those administered high-dose steroids and who underwent short-term starvation, both showed absent or severely reduced sarcolemmal staining of nNOS even without decreased protein levels and in the presence of preserved mobility, suggesting that catabolic stress may be associated with sarcolemmal loss of nNOS. However, muscle tissue from hibernating squirrels, who had no muscle atrophy, showed preservation of sarcolemmal nNOS, indicating complex regulation. The report indicated that nNOS mislocalization plays a role in secondary pathophysiologic processes and suggested that preservation of nNOS may be significant in maintaining muscle homeostasis.
Associations Pending Confirmation
Parkinson disease (PD; 168600) is a neurodegenerative disorder which leads to selective loss of nigral dopaminergic neurons. Inhibition of neuronal NOS (nNOS) and inducible NOS (iNOS) has been shown to result in neuroprotective effects in the model of PD caused by exposure to MPTP, a dopaminergic neurotoxin that is an analog of the pesticide paraquat. Levecque et al. (2003) performed a community-based case-control study of 209 PD patients enrolled in a French health insurance organization for agricultural workers and 488 European controls. Associations were observed with a G-to-A polymorphism in exon 22 of iNOS, designated iNOS 22 (OR for AA carriers, 0.50; 95% CI, 0.29-0.86; p = 0.01) and a T-to-C polymorphism in exon 29 of nNOS, designated nNOS 29 (OR for carriers of the T allele, 1.53; 95% CI, 1.08-2.16; p = 0.02). No association was observed with a T-to-C polymorphism in exon 18 of nNOS, designated nNOS 18. Moreover, a significant interaction of the nNOS polymorphisms with current and/or past cigarette smoking was found (nNOS 18, p = 0.05; nNOS 29, p = 0.04). Levecque et al. (2003) suggested that NOS1 may be a modifier gene in PD.
Infantile hypertrophic pyloric stenosis (IHPS; 179010), characterized by enlarged pyloric musculature and gastric outlet obstruction, is associated with altered expression of NOS1. Saur et al. (2004) studied molecular mechanisms by which NOS1 gene expression was altered in pyloric tissues of 16 German infants with IHPS and 9 German controls. In IHPS patients, quantitative RT-PCR after normalization against glyceraldehyde-3-phosphate dehydrogenase (GAPD; 138400) showed significantly decreased expression of total NOS1 mRNA, which affected predominantly exon 1c. Expression of exon 1f was increased significantly, indicating a compensatory upregulation of this NOS1 mRNA variant. DNA samples of 16 IHPS patients and 81 controls were analyzed for NOS1 exon 1c promoter mutations and SNPs. Sequencing of the 5-prime flanking region of exon 1c revealed mutations in 3 of 16 IHPS tissues, whereas 81 controls showed the wildtype sequence exclusively. Carriers of the A allele of a -84G-A SNP (rs41279104) in the exon 1c promoter region (163731.0001) had increased risk for development of IHPS (odds ratio, 8.0; 95% CI, 2.5 to 25.6). Reporter gene assays revealed an unchanged promoter activity for mutations but an approximately 30% decrease for the A allele of the -84G-A SNP (p less than 0.001). Saur et al. (2004) interpreted their findings as indicating that genetic alterations in the NOS1 exon 1c regulatory region influence expression of the gene and contribute to the pathogenesis of IHPS. In contrast, Lagerstedt-Robinson et al. (2009) found no association between rs41279104 and infantile hypertrophic pyloric stenosis among 82 Swedish patients and 80 controls. The frequency of the A allele in the control group was 29%.
Reif et al. (2006) studied NOS1 as a candidate gene for schizophrenia (see 181500) and bipolar disorder (125480) because the gene is located in a major linkage hotspot for both disorders and because nitric oxide is a promising candidate molecule in the pathogenesis of endogenous psychosis. Reif et al. (2006) examined 5 NOS1 polymorphisms as well as a haplotype consisting of 2 functional polymorphisms located in the transcriptional control region of the gene (G-84A and a VNTR) in 195 chronic schizophrenia patients, 72 bipolar I patients, and 286 controls. Single-marker association analyses showed that the exon 1c promoter polymorphism (G-84A) was linked to schizophrenia, whereas synonymous coding region polymorphisms were not associated with disease. Long promoter alleles of the repeat polymorphism were associated with less severe psychopathology. The haplotype was also shown to be significantly associated with schizophrenia. Reif et al. (2006) suggested that regulatory polymorphisms of NOS1 contribute to the genetic risk for schizophrenia.
See 163731.0002 for discussion of a possible association between variation in the NOS1 gene and achalasia (see 200400).
Mice with targeted disruption of neuronal NO synthase display grossly normal appearance, locomotor activity, breeding, long-term potentiation, and long-term depression. NOS1-deficient mice are resistant to neural stroke damage following middle cerebral artery ligation. Nelson et al. (1995) reported a large increase in aggressive behavior and excessive, inappropriate sexual behavior in NOS1 'knockout' mice. Initial observations indicated that male NOS1-deficient mice engaged in chronic aggressive behavior, not apparent among NOS1-deficient female mice or wildtype male or female mice housed together. Relevance of the observations to human behavior was suggested.
In the heart, nitric oxide inhibits L-type calcium channels but stimulates sarcoplasmic reticulum calcium release, leading to variable effects on myocardial contractility. Barouch et al. (2002) demonstrated that spatial confinement of specific nitric oxide synthase isoforms regulates this process. Endothelial nitric oxide synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type calcium channels allows nitric oxide to inhibit beta-adrenergic-induced inotropy. Neuronal nitric oxide synthase (NOS1), however, is targeted to cardiac sarcoplasmic reticulum. NO stimulation of sarcoplasmic reticulum calcium release via the ryanodine receptor (RYR2; 180902) in vitro suggests that NOS1 has an opposite, facilitative effect on contractility. Barouch et al. (2002) demonstrated that Nos1-deficient mice have suppressed inotropic response, whereas Nos3-deficient mice have enhanced contractility, owing to corresponding changes in sarcoplasmic reticulum calcium release. Both Nos1 -/- and Nos3 -/- mice developed age-related hypertrophy, although only Nos3 -/- mice were hypertensive. Nos1/3 -/- double knockout mice had suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodeling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function.
Wehling-Henricks et al. (2005) produced dystrophin (300377)-deficient mdx mice in which there was myocardial expression of a NOS1 transgene. Expression of the transgene prevented the progressive ventricular fibrosis of mdx mice and greatly reduced myocarditis. Electrocardiographs (ECG) of ambulatory mdx mice showed cardiac abnormalities that were characteristic of DMD patients. All of these ECG abnormalities in mdx mice were improved or corrected by NOS1 transgene expression. In addition, defects in mdx cardiac autonomic function, which were reflected by decreased heart rate variability, were significantly reduced by NOS1 transgene expression. Wehling-Henricks et al. (2005) concluded that their findings indicate that increasing NO production by dystrophic hearts may have therapeutic value.
Hurt et al. (2006) noted that, in addition to the predominant nNos-alpha isoform, alternative splicing produces catalytically active nNos-beta and catalytically inactive nNos-gamma. They found that nNos-beta preserved normal erectile function in mice lacking nNos-alpha, despite a decrease in stimulus-response characteristics and increased sensitivity to a NOS inhibitor.
This variant, formerly titled PYLORIC STENOSIS, INFANTILE HYPERTROPHIC, SUSCEPTIBILITY TO, has been reclassified based on the findings of Lagerstedt-Robinson et al. (2009).
In a study of 16 German patients with infantile hypertrophic pyloric stenosis (179010) and 81 German controls, Saur et al. (2004) found that carriers of the A allele of a -84G-A SNP in the exon 1c promoter of the NOS1 gene had increased risk for development of IHPS (odds ratio, 8.0; 95% CI, 2.5 to 25.6). Reporter gene assays revealed an approximately 30% decrease for the A allele of the -84G-A SNP (P less than 0.001).
In contrast, Lagerstedt-Robinson et al. (2009) found no association between rs41279104 and infantile hypertrophic pyloric stenosis among 82 Swedish patients and 80 controls. The frequency of the A allele in the control group was 29%.
This variant is classified as a variant of unknown significance because its contribution to achalasia (see 200400) has not been confirmed.
Shteyer et al. (2015) reported 2 sibs, a 6-year-old girl and a 2.5-year-old boy, with infantile-onset achalasia and autism. The children were born to first-cousin parents of Arab origin. By whole-exome sequencing in the sister, Shteyer et al. (2015) identified a homozygous c.3606C-G transversion (chr12.117,665,246G-C, GRCh37) in the NOS1 gene, resulting in a tyr1202-to-ter (Y1202X) substitution in the C-terminal electron-supplying reductase domain (NOSred). By Sanger sequencing, the mutation was found in homozygous state in her affected brother and in heterozygous state in her unaffected parents and unaffected brother. The variant was not present in the dbSNP (build 138) or Exome Variant Server databases.
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