Nonsense-mediated decay

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Canonical NMD pathway (in human) NMD - Nonsense-mediated decay.png
Canonical NMD pathway (in human)

Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. [1] Translation of these aberrant mRNAs could, in some cases, lead to deleterious gain-of-function or dominant-negative activity of the resulting proteins. [2]

Contents

NMD was first described in human cells and in yeast almost simultaneously in 1979. This suggested broad phylogenetic conservation and an important biological role of this intriguing mechanism. [3] NMD was discovered when it was realized that cells often contain unexpectedly low concentrations of mRNAs that are transcribed from alleles carrying nonsense mutations. [4] Nonsense mutations code for a premature stop codon which causes the protein to be shortened. The truncated protein may or may not be functional, depending on the severity of what is not translated. In human genetics, NMD has the possibility to not only limit the translation of abnormal proteins, but it can occasionally cause detrimental effects in specific genetic mutations. [5]

NMD functions to regulate numerous biological functions in a diverse range of cells, including the synaptic plasticity of neurons which may shape adult behavior. [6]

Pathway

While many of the proteins involved in NMD are not conserved between species, in Saccharomyces cerevisiae (yeast), there are three main factors in NMD: UPF1, UPF2 and UPF3 (UPF3A and UPF3B in humans), that make up the conserved core of the NMD pathway. [7] All three of these factors are trans-acting elements called up-frameshift (UPF) proteins. In mammals, UPF2 and UPF3 are part of the exon-exon junction complex (EJC) bound to mRNA after splicing along with other proteins, eIF4AIII, MLN51, and the Y14/MAGOH heterodimer, which also function in NMD. UPF1 phosphorylation is controlled by the proteins SMG-1, SMG-5, SMG-6 and SMG-7.

The process of detecting aberrant transcripts occurs during translation of the mRNA. A popular model for the detection of aberrant transcripts in mammals suggests that during the first round of translation, the ribosome removes the exon-exon junction complexes bound to the mRNA after splicing occurs. If after this first round of translation, any of these proteins remain bound to the mRNA, NMD is activated. Exon-exon junction complexes located downstream of a stop codon are not removed from the transcript because the ribosome is released before reaching them. Termination of translation leads to the assembly of a complex composed of UPF1, SMG1 and the release factors, eRF1 and eRF3, on the mRNA. If an EJC is left on the mRNA because the transcript contains a premature stop codon, then UPF1 comes into contact with UPF2 and UPF3, triggering the phosphorylation of UPF1. In vertebrates, the location of the last exon-junction complex relative to the termination codon usually determines whether the transcript will be subjected to NMD or not. If the termination codon is downstream of or within about 50 nucleotides of the final exon-junction complex then the transcript is translated normally. However, if the termination codon is further than about 50 nucleotides upstream of any exon-junction complexes, then the transcript is down regulated by NMD. [8] The phosphorylated UPF1 then interacts with SMG-5, SMG-6 and SMG-7, which promote the dephosphorylation of UPF1. SMG-7 is thought to be the terminating effector in NMD, as it accumulates in P-bodies, which are cytoplasmic sites for mRNA decay. In both yeast and human cells, the major pathway for mRNA decay is initiated by the removal of the 5’ cap followed by degradation by XRN1, an exoribonuclease enzyme. The other pathway by which mRNA is degraded is by deadenylation from 3’-5'.

In addition to the well recognized role of NMD in removing aberrant transcripts, there are transcripts that contain introns within their 3' untranslated regions (UTRs). [9] These messages are predicted to be NMD-targets yet they (e.g., activity-regulated cytoskeleton-associated protein, known as Arc) can play crucial biologic functions suggesting that NMD may have physiologically relevant roles. [9]

Molecular rules governing efficiency

NMD is a cellular mechanism that degrades mRNAs containing premature termination codons (PTCs), which can arise from mutations. Comprehensive analyses large scale genetics and gene expression datasets have enabled the systemic identification of the complex rules governing NMD efficiency, and quantification of their relative importance and effect size. [10] This revealed that the efficiency of NMD in recognizing and degrading these faulty transcripts is influenced by several molecular features:

  1. EJC model: The standard EJC model posits that NMD is typically triggered when a PTC is located upstream of the last exon junction complex. If the PTC is downstream of the last EJC, NMD is often inefficient.
  2. Start-proximal effect: PTCs located near the start codon can evade NMD. This evasion is associated with the presence of downstream in-frame stop codons, which can allow the ribosome to bypass the PTC and continue translation.
  3. Exon length and distance to normal stop codon: Long exons and large distances between the PTC and the normal stop codon are associated with inefficient NMD. This suggests that the spatial configuration of the mRNA can influence the accessibility of NMD machinery.
  4. mRNA turnover rate: Transcripts with rapid turnover rates tend to attenuate the effects of NMD. This means that mRNAs that are quickly degraded by other mechanisms may not be efficiently targeted by NMD.
  5. RNA-binding protein motifs: Certain RNA-binding protein motifs near the PTC or within the 3′UTR can modulate NMD efficiency. These motifs can either enhance or inhibit the recognition of PTCs by NMD machinery, depending on their specific interactions with NMD factors.

Mutations

Although nonsense-mediated mRNA decay reduces nonsense codons, mutations can occur that lead to various health problems and diseases in humans. A dominant-negative or deleterious gain-of-function mutation can occur if premature terminating (nonsense) codons are translated. NMD is becoming increasingly evident in the way it modifies phenotypic consequences because of the broad way it controls gene expression. For instance, the blood disorder Beta thalassemia is inherited and caused by mutations within the upstream region of the β-globin gene. [11] An individual carrying only one affected allele will have no or extremely low levels of the mutant β-globin mRNA. An even more severe form of the disease can occur called thalassemia intermedia or ‘inclusion body’ thalassemia. Instead of decreased mRNA levels, a mutant transcript produces truncated β chains, which in turn leads to a clinical phenotype in the heterozygote. [11] Nonsense-mediated decay mutations can also contribute to Marfan syndrome. This disorder is caused by mutations in the fibrillin 1 (FBN1) gene and is resulted from a dominant negative interaction between mutant and wild-type fibrillin-1 gene. [11]

Regulating immunogenic frameshift-derived antigens

NMD plays a role in the regulation of immunogenic frameshift-derived antigens. Frameshift mutations often result in the production of aberrant proteins that can be recognized as neoantigens by the immune system, particularly in cancer cells. [12] However, frameshift mutations often lead to the translation of an out-of-frame PTC that can activate NMD to degrade these mutant mRNAs before they are translated into proteins, thereby reducing the presentation of these potentially immunogenic peptides on the cell surface via HLA class I molecules. This modulation of immunogenicity means that frameshift-derived neoantigens only contribute to the response to immune checkpoint inhibition if they arise from mutations in parts of the genome that are not recognized by NMD. [13]

Research applications

This pathway has a significant effect in the way genes are translated, restricting the amount of gene expression. It is still a new field in genetics, but its role in research has already led scientists to uncover numerous explanations for gene regulation. Studying nonsense-mediated decay has allowed scientists to determine the causes for certain heritable diseases and dosage compensation in mammals.

Heritable diseases

The proopiomelanocortin gene (POMC) is expressed in the hypothalamus, in the pituitary gland. It yields a range of biologically active peptides and hormones and undergoes tissue-specific posttranslational processing to yield a range of biologically active peptides producing adrenocorticotropic hormone (ACTH), b-endorphin, and a-, b- and c-melanocyte-stimulating hormone (MSH).[ citation needed ] These peptides then interact with different melanocortin receptors (MCRs) and are involved in a wide range of processes including the regulation of body weight (MC3R and MC4R), adrenal steroidogenesis (MC2R) and hair pigmentation (MC1R). [14] Published in the British Associations of Dermatologists in 2012, Lack of red hair phenotype in a North-African obese child homozygous for a novel POMC null mutation showed nonsense-mediated decay RNA evaluation in a hair pigment chemical analysis. They found that inactivating the POMC gene mutation results in obesity, adrenal insufficiency, and red hair. This has been seen in both in humans and mice. In this experiment they described a 3-year-old boy from Rome, Italy. He was a source of focus because he had Addison's disease and early onset obesity. They collected his DNA and amplified it using PCR. Sequencing analysis revealed a homozygous single substitution determining a stop codon. This caused an aberrant protein and the corresponding amino acid sequence indicated the exact position of the homozygous nucleotide. The substitution was localized in exon 3 and nonsense mutation at codon 68. The results from this experiment strongly suggest that the absence of red hair in non-European patients with early onset obesity and hormone deficiency does not exclude the occurrence of POMC mutations. [14] By sequencing the patients DNA they found that this novel mutation has a collection of symptoms because of a malfunctioning nonsense-mediated mRNA decay surveillance pathway.

Dosage compensation

There has been evidence that the nonsense-mediated mRNA decay pathway participates in X chromosome dosage compensation in mammals. In higher eukaryotes with dimorphic sex chromosomes, such as humans and fruit flies, males have one X chromosome, whereas females have two. These organisms have evolved a mechanism that compensates not only for the different number of sex chromosomes between the two sexes, but also for the differing X/autosome ratios. [15] In this genome-wide survey, the scientists found that autosomal genes are more likely to undergo nonsense-mediated decay than X-linked genes. This is because NMD fine tunes X chromosomes and it was demonstrated by inhibiting the pathway. The results were that balanced gene expression between X and autosomes gene expression was decreased by 10–15% no matter the method of inhibition. The NMD pathway is skewed towards depressing expression of larger population or autosomal genes than x-linked ones. In conclusion, the data supports the view that the coupling of alternative splicing and NMD is a pervasive means of gene expression regulation. [15]

Designing CRISPR-Cas9 experiments

The implications of NMD are significant when designing CRISPR-Cas9 experiments, particularly those aimed at gene inactivation. [16] CRISPR-Cas9 introduces double-strand breaks that can lead to insertions or deletions (indels), often resulting in frameshift mutations and PTCs. If these PTCs are located in regions that trigger NMD, the resulting mRNAs will be rapidly degraded, leading to effective gene knockdown. However, if the PTCs are in regions that evade NMD, the mutant mRNAs may be translated into truncated proteins, potentially retaining partial function and leading to incomplete gene inactivation. [13] [17] Therefore, understanding and incorporating NMD rules into the design of single guide RNAs (sgRNAs) is essential for achieving desired outcomes in CRISPR-Cas9 experiments. Tools such as NMDetective [13] can predict the likelihood of NMD triggering based on the location of PTCs, thereby aiding in the design of more effective gene-editing strategies.

See also

Related Research Articles

<span class="mw-page-title-main">Frameshift mutation</span> Mutation that shifts codon alignment

A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature of gene expression by codons, the insertion or deletion can change the reading frame, resulting in a completely different translation from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein. A frameshift mutation is not the same as a single-nucleotide polymorphism in which a nucleotide is replaced, rather than inserted or deleted. A frameshift mutation will in general cause the reading of the codons after the mutation to code for different amino acids. The frameshift mutation will also alter the first stop codon encountered in the sequence. The polypeptide being created could be abnormally short or abnormally long, and will most likely not be functional.

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. Nonsense mutations are not always harmful; the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected. As nonsense mutations leads to premature termination of polypeptide chains; they are also called chain termination mutations.

<span class="mw-page-title-main">SR protein</span>

SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respectively. SR proteins are ~200-600 amino acids in length and composed of two domains, the RNA recognition motif (RRM) region and the RS domain. SR proteins are more commonly found in the nucleus than the cytoplasm, but several SR proteins are known to shuttle between the nucleus and the cytoplasm.

<span class="mw-page-title-main">Insertion (genetics)</span> Type of mutation

In genetics, an insertion is the addition of one or more nucleotide base pairs into a DNA sequence. This can often happen in microsatellite regions due to the DNA polymerase slipping. Insertions can be anywhere in size from one base pair incorrectly inserted into a DNA sequence to a section of one chromosome inserted into another. The mechanism of the smallest single base insertion mutations is believed to be through base-pair separation between the template and primer strands followed by non-neighbor base stacking, which can occur locally within the DNA polymerase active site. On a chromosome level, an insertion refers to the insertion of a larger sequence into a chromosome. This can happen due to unequal crossover during meiosis.

<span class="mw-page-title-main">Eukaryotic translation termination factor 1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation termination factor1 (eRF1), also referred to as TB3-1 or SUP45L1, is a protein that is encoded by the ERF1 gene. In Eukaryotes, eRF1 is an essential protein involved in stop codon recognition in translation, termination of translation, and nonsense mediated mRNA decay via the SURF complex.

<span class="mw-page-title-main">Nuclear cap-binding protein complex</span> RNA-binding protein

Nuclear cap-binding protein complex is a RNA-binding protein which binds to the 5' cap of pre-mRNA. The cap and nuclear cap-binding protein have many functions in mRNA biogenesis including splicing, 3'-end formation by stabilizing the interaction of the 3'-end processing machinery, nuclear export and protection of the transcripts from nuclease degradation. During mRNA export, the nuclear cap-binding protein complex recruits ribosomes to begin the pioneer round of translation. When RNA is exported to the cytoplasm the nuclear cap-binding protein complex is replaced by cytoplasmic cap binding complex. The nuclear cap-binding complex is a functional heterodimer and composed of Cbc1/Cbc2 in yeast and CBP20/CBP80 in multicellular eukaryotes. Human nuclear cap-binding protein complex shows the large subunit, CBP80 consists of 757 amino acid residues. Its secondary structure contains approximately sixty percent of helical and one percent of beta sheet in the strand. The small subunit, CBP20 has 98 amino acid residues. Its secondary structure contains approximately twenty percent of helical and twenty-four percent of beta sheet in the strand. Human nuclear cap-binding protein complex plays important role in the maturation of pre-mRNA and in uracil-rich small nuclear RNA.

<span class="mw-page-title-main">Non-stop decay</span>

Non-stop decay (NSD) is a cellular mechanism of mRNA surveillance to detect mRNA molecules lacking a stop codon and prevent these mRNAs from translation. The non-stop decay pathway releases ribosomes that have reached the far 3' end of an mRNA and guides the mRNA to the exosome complex, or to RNase R in bacteria for selective degradation. In contrast to nonsense-mediated decay (NMD), polypeptides do not release from the ribosome, and thus, NSD seems to involve mRNA decay factors distinct from NMD.

<span class="mw-page-title-main">UPF1</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 1 is a protein that in humans is encoded by the UPF1 gene.

Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can be programmed by the nucleotide sequence of the mRNA and is sometimes affected by the secondary, 3-dimensional mRNA structure. It has been described mainly in viruses, retrotransposons and bacterial insertion elements, and also in some cellular genes.

<span class="mw-page-title-main">UPF2</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 2 is a protein that in humans is encoded by the UPF2 gene.

<span class="mw-page-title-main">UPF3B</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 3B is a protein that in humans is encoded by the UPF3B gene.

<span class="mw-page-title-main">SMG1</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase SMG1 is an enzyme that in humans is encoded by the SMG1 gene. SMG1 belongs to the phosphatidylinositol 3-kinase-related kinase protein family.

<span class="mw-page-title-main">CASC3</span> Protein-coding gene in the species Homo sapiens

Protein CASC3 is a protein that in humans is encoded by the CASC3 gene.

<span class="mw-page-title-main">UPF3A</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 3A is a protein that in humans is encoded by the UPF3A gene.

<span class="mw-page-title-main">SMG6</span> Protein-coding gene in the species Homo sapiens

Telomerase-binding protein EST1A is an enzyme that in humans is encoded by the SMG6 gene on chromosome 17. It is ubiquitously expressed in many tissues and cell types. The C-terminus of the EST1A protein contains a PilT N-terminus (PIN) domain. This structure for this domain has been determined by X-ray crystallography. SMG6 functions to bind single-stranded DNA in telomere maintenance and single-stranded RNA in nonsense-mediated mRNA decay (NMD). The SMG6 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Decapping complex</span> Eukaryotic protein complex that removes the 5 cap on mRNA

The mRNA decapping complex is a protein complex in eukaryotic cells responsible for removal of the 5' cap. The active enzyme of the decapping complex is the bilobed Nudix family enzyme Dcp2, which hydrolyzes 5' cap and releases 7mGDP and a 5'-monophosphorylated mRNA. This decapped mRNA is inhibited for translation and will be degraded by exonucleases. The core decapping complex is conserved in eukaryotes. Dcp2 is activated by Decapping Protein 1 (Dcp1) and in higher eukaryotes joined by the scaffold protein VCS. Together with many other accessory proteins, the decapping complex assembles in P-bodies in the cytoplasm.

mRNA surveillance mechanisms are pathways utilized by organisms to ensure fidelity and quality of messenger RNA (mRNA) molecules. There are a number of surveillance mechanisms present within cells. These mechanisms function at various steps of the mRNA biogenesis pathway to detect and degrade transcripts that have not properly been processed.

<span class="mw-page-title-main">Exon junction complex</span> Protein complex assembled on mRNA

An exon junction complex (EJC) is a protein complex which forms on a pre-messenger RNA strand at the junction of two exons which have been joined together during RNA splicing. The EJC has major influences on translation, surveillance, localization of the spliced mRNA, and m6A methylation. It is first deposited onto mRNA during splicing and is then transported into the cytoplasm. There it plays a major role in post-transcriptional regulation of mRNA. It is believed that exon junction complexes provide a position-specific memory of the splicing event. The EJC consists of a stable heterotetramer core, which serves as a binding platform for other factors necessary for the mRNA pathway. The core of the EJC contains the protein eukaryotic initiation factor 4A-III bound to an adenosine triphosphate (ATP) analog, as well as the additional proteins Magoh and Y14. The binding of these proteins to nuclear speckled domains has been measured recently and it may be regulated by PI3K/AKT/mTOR signaling pathways. In order for the binding of the complex to the mRNA to occur, the eIF4AIII factor is inhibited, stopping the hydrolysis of ATP. This recognizes EJC as an ATP dependent complex. EJC also interacts with a large number of additional proteins; most notably SR proteins. These interactions are suggested to be important for mRNA compaction. The role of EJC in mRNA export is controversial.

The Consensus Coding Sequence (CCDS) Project is a collaborative effort to maintain a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assemblies. The CCDS project tracks identical protein annotations on the reference mouse and human genomes with a stable identifier, and ensures that they are consistently represented by the National Center for Biotechnology Information (NCBI), Ensembl, and UCSC Genome Browser. The integrity of the CCDS dataset is maintained through stringent quality assurance testing and on-going manual curation.

<span class="mw-page-title-main">C14orf102</span> Protein-coding gene in the species Homo sapiens

Chromosome 14 open reading frame 102 is a 3810bp protein-encoding gene that is highly conserved among its non-distant orthologs. It contains 20 introns and 8 different RNAs - 7 splice variants and 1 unspliced form - and is located on the reverse strand of chromosome 14 (14q32.11). The protein encoded by this gene belongs to the UPF0614 family of Up-frameshift proteins and has a molecular weight of 132.417 kDa and isoelectric point of 7.88. It is expected to have a protein binding function and localization in the cytoplasm.

References

  1. ↑ Baker KE, Parker R (June 2004). "Nonsense-mediated mRNA decay: terminating erroneous gene expression". Current Opinion in Cell Biology. 16 (3): 293–299. doi:10.1016/j.ceb.2004.03.003. PMID   15145354.
  2. ↑ Chang YF, Imam JS, Wilkinson MF (2007). "The nonsense-mediated decay RNA surveillance pathway". Annual Review of Biochemistry. 76: 51–74. doi:10.1146/annurev.biochem.76.050106.093909. PMID   17352659. S2CID   2624255.
  3. ↑ Kulozik A. "Research Focus 1: Nonsense Mediated Decay (NMD)". Molecular Medicine Partnership Unit. University of Heidelberg. Archived from the original on 2016-11-17. Retrieved 2014-11-17.
  4. ↑ Sharma J, Keeling KM, Rowe SM (August 2020). "Pharmacological approaches for targeting cystic fibrosis nonsense mutations". European Journal of Medicinal Chemistry. 200: 112436. doi:10.1016/j.ejmech.2020.112436. PMC   7384597 . PMID   32512483.
  5. ↑ Holbrook JA, Neu-Yilik G, Hentze MW, Kulozik AE (August 2004). "Nonsense-mediated decay approaches the clinic". Nature Genetics. 36 (8): 801–808. doi:10.1038/ng1403. PMID   15284851. S2CID   23188275.
  6. ↑ Notaras M, Allen M, Longo F, Volk N, Toth M, Li Jeon N, et al. (December 2020). "UPF2 leads to degradation of dendritically targeted mRNAs to regulate synaptic plasticity and cognitive function". Molecular Psychiatry. 25 (12): 3360–3379. doi: 10.1038/s41380-019-0547-5 . PMC   7566522 . PMID   31636381. S2CID   204812259.
  7. ↑ Behm-Ansmant I, Izaurralde E (February 2006). "Quality control of gene expression: a stepwise assembly pathway for the surveillance complex that triggers nonsense-mediated mRNA decay". Genes & Development. 20 (4): 391–398. doi: 10.1101/gad.1407606 . PMID   16481468.
  8. ↑ Lewis BP, Green RE, Brenner SE. 2003. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proceedings of the National Academy of Sciences of the United States of America 100:189-192. doi:10.1016/j.bbrc.2009.04.021
  9. 1 2 Bicknell AA, Cenik C, Chua HN, Roth FP, Moore MJ (December 2012). "Introns in UTRs: why we should stop ignoring them". BioEssays. 34 (12): 1025–1034. doi: 10.1002/bies.201200073 . PMID   23108796. S2CID   5808466.
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  12. ↑ Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N, Reading JL, et al. (August 2017). "Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis". The Lancet. Oncology. 18 (8): 1009–1021. doi:10.1016/S1470-2045(17)30516-8. PMID   28694034.
  13. 1 2 3 Lindeboom RG, Vermeulen M, Lehner B, Supek F (November 2019). "The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy". Nature Genetics. 51 (11): 1645–1651. doi:10.1038/s41588-019-0517-5. PMC   6858879 . PMID   31659324.
  14. 1 2 Cirillo G, Marini R, Ito S, Wakamatsu K, Scianguetta S, Bizzarri C, et al. (December 2012). "Lack of red hair phenotype in a North-African obese child homozygous for a novel POMC null mutation: nonsense-mediated decay RNA evaluation and hair pigment chemical analysis". The British Journal of Dermatology. 167 (6): 1393–5. doi:10.1111/j.1365-2133.2012.11060.x. PMID   22612534.
  15. 1 2 Yin S, Deng W, Zheng H, Zhang Z, Hu L, Kong X (June 2009). "Evidence that the nonsense-mediated mRNA decay pathway participates in X chromosome dosage compensation in mammals". Biochemical and Biophysical Research Communications. 383 (3): 378–82. doi:10.1016/j.bbrc.2009.04.021. PMID   19364502.
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