Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications
(Full-text capture 2026-09-21; web artifacts lightly stripped; excerpt from the review’s main text.)
Jan Philipp Delling
1Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, Ulm, 89081 Germany
1,✉, Tobias M Boeckers
Tobias M Boeckers
1Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, Ulm, 89081 Germany
2Ulm Site, DZNE, Ulm, Germany
1,2,✉
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1Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, Ulm, 89081 Germany
2Ulm Site, DZNE, Ulm, Germany
✉
Corresponding author.
Received 2021 Jul 15; Accepted 2021 Sep 27; Collection date 2021.
© The Author(s) 2021
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PMCID: PMC8594088 PMID: 34784886
Abstract
Background
Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains ( SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet.
Main text
This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes.
Conclusions
Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.
Keywords: SHANK3, Autism spectrum disorder, ASD, Phelan-McDermid syndrome, PMDS, Therapy
Background
Genes of the SH3 and multiple ankyrin repeat domains ( SHANK) family encode a class of crucial multifunctional scaffolding proteins, whose disruption is highly associated with autism spectrum disorder (ASD) and more specifically the Phelan-McDermid syndrome (PMDS), which results from SHANK3-haploinsufficiency or heterozygous SHANK3 variants that alter function.
Autism spectrum disorder (ASD)
ASD represents a neurodevelopmental disorder that is highly heritable [ 1] and heterogeneous, spanning a wide range of clinical manifestations. Generally, ASD is a subgroup within the diagnostic category of “Neurodevelopmental Disorders” in the fifth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Core symptoms that characterize ASD comprise persistent deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Additionally, sensory anomalies and varying levels of intellectual disability are frequently observed. The symptoms must be present in early childhood and cause clinically significant functional impairment [ 2]. Furthermore, ASD can occur concurrently with other psychiatric or neurological disorders. Among these comorbidities, anxiety, depression, attention-deficit hyperactivity disorder (ADHD), and epilepsy are diagnosed rather frequently in ASD patients [ 3]. The severity of symptoms is influenced by environmental as well as genetic factors and covers a wide range of possible manifestations from subtle social deficits, to intellectual disability or severely affected linguistic skills [ 4, 5].
Commonly ASD is perceived as a rare condition, which is at odds with the estimated prevalence of 1 in 132 in the 2010 Global Burden of Disease study, equating to 52 million cases globally [ 6]. Gender ratios reported in cohorts of ASD patients range from 2:1 to 5:1 [ 7, 8] implying a more frequent occurrence in males.
The abovementioned heterogeneity originates from a wide range of genetic and nongenetic etiologies, which are often unknown. The underlying pathophysiological mechanisms that lead to ASD-associated phenotypes are also not fully understood. The fact that twin and family studies consistently demonstrate high concordance rates and a heritability ranging from 40 to 90% provides convincing evidence for a large genetic contribution to ASD [ 9– 11]. In fact, ASD ranks amongst the most heritable medical diagnoses [ 1]. Fittingly, the number of genes and genomic regions, which are associated with ASD is estimated to be in the hundreds [ 12– 15]. The size of these genetic changes ranges from a single nucleotide to DNA-segments stretching up to millions of bases known as copy number variations (CNV) [ 12, 13, 16– 18]. It has been estimated that 10–20% of ASD patients are affected by rare point mutations or CNVs, most of them de novo [ 14, 16, 19].
ASD risk genes are often involved in many functional processes that unfold spatiotemporally across development and various brain regions. Despite the obvious challenges of disentangling the underlying dynamics of such multifunctional genes that might also be sex-dependent, converging pathways have been identified. Proteins encoded by ASD risk genes are mostly involved in processes related to fetal brain development, chromatin modification, and regulation of gene expression in general, as well as the structural and functional integrity of synapses. [ 15, 16, 19– 26]. Among others SHANK1-3 and genes from the NLGN- and NRXN-family encode synaptic proteins that are crucial for the development or functioning of brain circuits, which contribute to ASD etiology [ 27– 29]. Disruption of ASD-associated genes like NLGN1 [ 30], NLGN2 [ 31, 32], NLGN3 [ 33– 37], NLGN4X [ 38, 39], NRXN1 [ 40– 42], or NRXN2 [ 43, 44], but also CACNA1C [ 45], CNTNAP2 [ 46], and GABRB3 [ 47], is often exploited to replicate ASD phenotypes in animal models. Additionally, several studies have identified glutamatergic neurons during cortical development [ 48, 49] and the striatum [ 50] as points of convergence for ASD.
Apart from genetic etiology, environmental factors have been associated with an increased risk of ASD, including hypoxic birth trauma, advanced parental age, maternal obesity, gestational diabetes mellitus, zinc deficiency, and valproate intake during pregnancy [ 51– 54].
SHANK gene family
SHANKs (SHANK1-3), which are also known as proline-rich synapse-associated proteins (ProSAPs), were initially described as proteins that primarily localize to the postsynaptic density (PSD) of excitatory synapses [ 55– 59], which is an electron dense thickening underneath the postsynaptic membrane of glutamatergic synapses. It comprises a great multitude of proteins, which form a wide macromolecular complex that is illustrated in Fig. 1. Among these proteins are other scaffolding and adaptor proteins (e.g., DLGAP1, SHANKs), receptors, channels, and signaling molecules (e.g., NMDAR, AMPAR, GRM, CAMK2), but also cell adhesion proteins like NLGNs or constituents of the cytoskeleton (e.g., actin) [ 60, 61].
Fig. 1.
Macromolecular complexes within the interactome of SHANK3. The multiple layers of the functional units in the central nervous system are shown in succession. In the left lower corner a hippocampal pyramidal neuron is depicted. At the top an overview of a synaptic contact and a detailed illustration of the multiple connections between the different interaction domains of SHANK3 and other synaptic proteins is shown. On the right, putative macromolecular assemblies associated to cellular actin nucleation, which include SHANK3, are shown in the soma. SHANK3 localizes to the postsynaptic density (PSD). The PSD is an electron dense thickening underneath the postsynaptic membrane of glutamatergic synapses. It comprises a great multitude of proteins, which form a wide macromolecular complex. Interaction between SHANK3 and other proteins is mediated by six protein domains, which are depicted by form and color in this image: The SPN-, ANK-, SH3-, PDZ-, PRO-, and SAM-domain. A subset of SHANK3-interacting proteins is illustrated here. DLG4 (or PSD95) is also depicted by its functional domains (PDZ, SH3, GK) to emphasize that different proteins can contribute similar domains to the structural composition of the PSD. Membrane-associated guanylate kinases (MAGUKs) such as DLG4 also serve as major organizers of synapses, by forming a modular interface between the multiple layers of the PSD. For instance, DLG4, DLGAP, SHANK3 and HOMER connect GRM and NMDAR complexes. An additional connection of this complex to the cytoskeleton is mediated by SHANK3’s interaction with CTTN, SHARPIN, SPTAN1, and other proteins. Depending on its configuration, the SPN-domain prevents the binding of SPTAN1 to the ANK-domain. The ARP2/3-complex is crucial for actin nucleation and polymerization. By its interaction with the WAVE regulatory complex (WRC), components of the RAC1-pathway, and ARPC2 itself, SHANK3 might mediate their influence on actin dynamics. PSD: Postsynaptic density, SHANK: SH3 and multiple ankyrin repeat domains, SPN: SHANK/ProSAP/N-terminal, SH3: Src homology 3, PDZ: PSD95/DlgA/Zo-1, PRO: Proline-rich, SAM: Sterile alpha motif, ANK: Ankyrin repeats
As so-called master scaffolding proteins, which are expressed in the central nervous system (CNS) and peripheral nervous system (PNS, somatic and autonomic), SHANKs interact with and thus arrange intermediate scaffolding proteins at the PSD, which profoundly influences synaptic development and function [ 55– 68]. A quaternary complex in the PSD built from DLG4 (also known as PSD95), DLGAP1 (also known as SAPAP1 or GKAP), SHANK, and HOMER proteins connects metabotropic and ionotropic NMDA type glutamate receptor complexes, which might facilitate their interaction [ 55– 57, 59, 64, 65, 67]. Notably, a rather stable pool of SHANK proteins lies closer to the postsynaptic membrane, while another dynamic pool resides more proximally. The stable but not the dynamic pool seems to be able to bind to DLGAP1 [ 69].
Through dynamic changes of their molecular composition and chemical modification of synaptic proteins, neuronal synapses are regulated during development and throughout life, altering their shape, quantity, and overall strength [ 63, 70]. SHANK proteins are crucial in many of these and associated processes. Thus, it is not surprising that mutations leading to dysfunctional synaptic proteins, including SHANKs, result in synaptic and circuitry defects [ 71]. Accordingly, SHANK gene mutations are generally associated with human neuropsychiatric and neurodevelopmental disorders. Defects in SHANK genes, but especially SHANK3, can be causative for idiopathic ASD and ASD-associated syndromes such as the PMDS, but also schizophrenia and intellectual disability [ 27, 28, 72– 77].
SHANK3
The SHANK3 (human) or Shank3 (rodents) gene is located on chromosome 15E3 in mice, on 7q34 in rats, and on 22q13.3 in humans. Shank3 is subject to alternative usage of its 6 promotors and additional mRNA splicing [ 78, 79], resulting in multiple mRNA transcripts and enabling the generation of a great variety of protein isoforms. These findings have led to the prediction of isoform transcripts named Shank3 a-f, of which Shank3 a and e are enriched in the striatum, Shank3 c and d are predominantly expressed in the cerebellum, and Shank3 b is evenly expressed at very low levels across the brain [ 79]. Accordingly, western blot analysis has shown an array of different proteins detected by SHANK3 antibodies also depending on their epitopes [ 80]. However, studies on SHANK3 isoforms have largely focused on mRNA transcripts. Thus, it remains to be clarified how exactly the various transcripts translate into proteins. Nevertheless, this multitude of isoforms enables differential expression patterns across the stages of brain development, brain regions, cell types, and even subcellular structures [ 79, 81– 83], suggesting isoform-specific functions. For example, SHANK3b, which lacks the PRO- and SAM-domain, exhibits nuclear localization, whereas SHANK3a, SHANK3c, and SHANK3e that contain those domains form cytoplasmic clusters [ 79]. SHANK3a and SHANK3c seem to be the isoforms that primarily localize to excitatory synapses [ 79]. With recent advances in the prediction of protein structures in silico, it might be possible to determine how the predicted isoforms of SHANK3 differ on a three-dimensional level [ 84– 86].
Tissue-specific expression of these different isoforms is also regulated by epigenetic mechanisms [ 81, 87, 88]. Notably, DNA methylation within the SHANK3 gene and isoform expression was altered in human brain tissue of ASD patients [ 89].
Shank3 mRNA expression is high in the heart and moderate in the brain and spleen [ 66]. In the nervous system, Shank3 mRNA is enriched in the cortex (especially layers 2–4), hippocampus, amygdala, cerebellum (granule cells), striatum, thalamus, spinal cord, and dorsal root ganglia [ 82, 90– 92]. As opposed to the other SHANKs, SHANK3 is highly enriched at cortico-striatal glutamatergic synapses [ 90].
The interactome of SHANK3 covers a wide variety of proteins, which are involved in many cellular processes [ 93, 94]. Aside from interactors, which represent a common core interactome involved in scaffolding, processes of the PSD in general, or regulation of the actin cytoskeleton, the majority of interacting proteins varies depending on the brain region. This might enable the functional diversity of SHANK3. Common interactors include the HOMER and DLGAP family, but also actin-associated proteins. Interactors, which are related to the cytoskeleton include subunits of the ARP2/3-complex as major mediator of actin nucleation and constituents of the associated WAVE regulatory complex, such as ABI1, WASF1, and CYFIP2 [ 93– 96]. Interestingly, these common interaction profiles also seem to encompass proteins related to myelin- and mitochondrion-associated processes [ 96]. Other exemplary categories, which fit the brain-region-dependent SHANK3 interactome, include GTP binding, gluconeogenesis, cell-cell adhesion, or endocytosis [ 93, 96]. Apart from unbiased proteomic approaches to characterize the interactome of SHANK3, single proteins have been identified, which directly bind to SHANK3. Among these are proteins, which are crucial for dendritic spine formation, synaptic transmission and plasticity, cytoskeleton regulation, and the localization of SHANK3 to the PSD [ 56, 58, 59, 65, 94, 97– 103].
The abovementioned highly complex protein-protein interactions of SHANK3 are mediated by its domains. The longest isoform of SHANK3 in mice comprises six highly conserved domains: SHANK/ProSAP/N-terminal (SPN), ankyrin repeats (ANK), Src homology 3 (SH3), PSD95/DlgA/Zo-1 (PDZ), proline-rich (PRO), and sterile alpha motif (SAM). For instance, the ANK-domain binds to SHARPIN [ 98], SPTAN1 (also known as α-fodrin) [ 99], and CTNND2 [ 104], while the PDZ-domain interacts with DLGAP1 (which binds to DLG4) [ 59], GRIA1 (also known as GluA1 or GluR1 subunit of ionotropic AMPA type glutamate receptors) [ 100], and CTNNB1 as crucial constituent of the Wnt signaling pathway [ 105]. A SPN-domain at the N-terminus binds to the ANK-domain and limits its ability to interact with SHARPIN or SPTAN1 [ 97]. The PRO-region encompasses the binding motifs for HOMER [ 65, 101] and CTTN [ 59]. SHANK3’s ability to self-multimerize in a zinc-dependent manner depends on the SAM-domain [ 59, 102]. Synaptic targeting of SHANK3 is mediated by a conserved C-terminal region that includes the SAM-domain [ 58], while several nuclear localization signals are responsible for its translocation to the nucleus [ 105].
Among the remaining interaction partners of SHANK3 are kinases like MAPK1 (also known as ERK2), PRKACA, GSK3B, CSNK2, or RPS6KA2/3 [ 106, 107]. Notably, murine SHANK3 is phosphorylated by MAPK1 at 18 residues, 3 of which have also been observed in vivo and shown to increase SHANK3 turnover and degradation if phosphorylated. Accordingly, activation of constituents belonging to the MAPK/ERK-pathway, like IGF1R, KIT, PKA, RAF1, MAP2K1, or MAPK1, lead to destabilization of SHANK3. Other proteins like TRIO, TAF1, and SIK1 were shown to stabilize SHANK3 [ 106]. In addition phosphorylation of a serine at position 685 by PKA facilitates the interaction of SHANK3 with ABI1 [ 94], while interaction with CTTN is prevented by RPS6KA3-mediated phosphorylation [ 107].
Generally, it has been shown that SHANK-proteins undergo degradation upon activity-dependent ubiquitination [ 108], which is influenced by DLGAP1 [ 109] and regulates their abundance at the synapse.
Aside from its role in postsynapses, SHANK3 also localizes to presynaptic specializations in hippocampal neurons [ 110], afferent nerve terminals in the spinal cord and peripheral terminals of the skin [ 92], the neuromuscular junction and the Z-disc of skeletal muscle tissue, where it binds to ACTN2 [ 111]. Additionally, SHANK3 translocates from synapses to the nucleus in an activity-dependent manner [ 112] and mediates Ca-dependent signaling to the nucleus via interaction with CAMK2A and L-type calcium channels [ 113]. Recently, it has also been observed that SHANK3 is involved in TRPV1-mediated pain processing in the dorsal root ganglia and spinal cord [ 92].
SHANK-associated ASD and Phelan McDermid syndrome (PMDS)
A connection between SHANK-mutations and ASD has been established in several human genetic studies [ 27, 28, 72– 74, 76, 77] and was further validated in animal models targeting Shank1 [ 114– 117], Shank2 [ 118– 121], or Shank3 [ 78, 80, 82, 83, 90, 92, 94, 118, 122– 140]. Behavioral phenotypes, like increased repetitive routines, abnormal social behavior, elevated anxiety levels, impaired neuronal physiology, and altered PSD levels of HOMER, DLGAPs, NMDARs, AMPARs and other proteins, typify SHANK3-deficient murine animal models [ 78, 83, 90, 94, 118, 122, 124– 128, 130, 132]. These resemble some neuropsychiatric disorders in humans. It was estimated in a meta-analysis that approximately 1% of all ASD-cases are accounted for by truncating mutations in the SHANK gene family [ 73]. This is a surprisingly high percentage, considering the etiological diversity of ASD. Notably, no truncating SHANK1/2/3-mutations, but mutations, which were predicted to be damaging (PolyPhen-2) were found in 4.7% of the healthy controls [ 73]. Additionally, SHANK3 mutations have been observed in both asymptomatic parents and their ASD-diagnosed children [ 28]. Thus, such non-truncating SHANK mutations might not be causative for ASD by themselves, but rather contribute to its development in a susceptible genetic and environmental setting.
The PMDS was the first heterozygous neurodevelopmental disorder associated with SHANK mutation [ 27]. Genetically PMDS is caused by a 22q13.3 deletion and clinically presents with hypotonia, impaired language skills, ASD, and various other symptoms [ 27, 141, 142]. Apart from classical deletions, the PMDS can be caused by ring chromosomes and unbalanced translocations, but also by SHANK3 point mutations [ 73, 143– 145]. In nearly all PMDS patients, SHANK3 is affected, and it is assumed that SHANK3 haploinsufficiency is the major causative factor of their neurodevelopmental and behavioral deficits, although deletions that do not include SHANK3 also result in certain subphenotypes of PMDS [ 142, 146– 149]. Genetic screening of patients with ASD, which was not due to a heterozygous loss of the gene, also found SHANK3 mutations [ 28, 73, 74, 76, 150]. Many SHANK3 mutations in humans affect exon 21 and are associated with intellectual disability [ 73]. Although SHANK1 and SHANK2 mutations are also associated with ASD [ 73, 77], cognitive deficits are more severe in patients with SHANK3 mutations [ 73]. Clinical screening for SHANK mutations might thus be reasonable, since they represent a potential monogenic and syndromic etiology of ASD [ 73].
Main text
Phenotypes and pathophysiology in animal models of SHANK3 deficiency
Various strategies targeting Shank3 to mimick pathologies that are observed in PMDS patients have been applied in rodent and non-human primate models. These include the constitutive knockout (KO) models of Shank3 that affect different exons and thus also a different number its six promotors. These KO strategies result in isoform-specific deletion patterns, leaving some isoforms intact, which might even lead to their compensatory overexpression [ 125, 151]. Conditional KO-models (cKO) have been used to study the effects of promotor-driven cell-type-specific SHANK3 deficiency, which has connected certain neuron populations or brain regions to subphenotypes of mutant animals. Alternatively, mutations that have previously been associated to ASD in human patients are studied using knock in (KI) strategies. A conditional KI (cKI) model has also been used to reexpress SHANK3 at later stages of development. In this review, all models, which are covered, were assigned a code. The nomenclature used for this code was defined according to the abovementioned strategies of genetic intervention and consists of two parts, which are separated by a vertical bar. The first part of the nomenclature depicts the targeted exons of Shank3, and the second represents the affected domain and an associated mutation or a promotor-driven Cre-expression, if present.
An alternative nomenclature would additionally refer to the remaining SHANK3 protein isoforms, since whole exon deletions or point mutations affecting similar regions were reported to result in markedly different isoform compositions. For example, in ex21|PRO mice, the absence of major high-molecular isoforms, increased low-molecular isoforms, and the appearance of a new low-molecular band were observed [ 125]. Models mimicking point mutations within the same exon presented with different isoform patterns. Mice of the model ex21|PRO-InsG3680 showed an almost complete loss of SHANK3 [ 127], whereas ex21|PRO-InsG3728 introducing the same mutation described in human patients [ 28] and a Neo-stop cassette resulted in the loss of major high-molecular isoforms, increased low-molecular isoforms, and the appearance of a new low-molecular band [ 126], comparable to ex21|PRO-mice. ex21|PRO-R1117X resulted in the loss of major isoforms and the expression of a predicted truncated high-molecular protein [ 127]. Notably, some missense point mutations, as established in the model ex17|PRM-S685I, do not alter the isoform pattern [ 94]. An isoform-based nomenclature would be in need of a standardized report on isoform composition across all models investigated, also using antibodies targeting different regions of the protein to cover all of its putative isoforms. This information is currently not available for all models covered in this review. Although it is not feasible to generate a detailed and consistent nomenclature based on protein-isoforms of SHANK3, the models which were summarized under the same term in the nomenclature described above, generally present with similar isoform patterns.
It is important to note that many behavioral studies aim to correlate aberrant behavioral patterns in mutant mice or other model organisms with symptoms in human patients. The interpretation of such behaviors is at least to some extent subjective and sometimes even questionable. Nevertheless, behavioral abnormalities in the animal models covered in this review are categorized according to symptoms and comorbidities, which are frequently observed in ASD or the PMDS. This serves to establish a common ground, which enables comparability between the different animal models and human behavior. Due to the abovementioned subjectiveness, the reader is encouraged to treat those interpretations with caution as one could also argue that rodent behavior should not be humanized.
Behavioral traits
Social behavior
Among other symptoms, ASD is defined by an impairment of social interacion, which often manifests as difficulties in the approach to social situations, reciprocal social interaction, and verbal but also nonverbal communication. Although PMDS patients often meet the criteria of ASD and display severe impairments of language and communication [ 152], neural responses to communicative vocal sounds and orienting to social stimuli were less affected in PMDS patients when compared to patients with idiopathic ASD [ 153]. These differential findings and the fact that an ASD diagnosis is not present in all PMDS patients suggest that SHANK3-deficient animals should not necessarily present with profound social behavioral deficits. Accordingly, such deficits have been reported, however with variability, in SHANK3-deficient animals. Rodent social behavior is highly influenced by experimental conditions and handling. Slight differences in protocols of the most commonly used test, the three-chambered social approach test could also be explanatory for the differences observed between cohorts of animals with identical or similar alterations of the Shank3 gene.
Here, social behavior was categorized in three subdomains: social motivation/interaction, social recognition, and social communication. For instance, the frequently measured social preference in three-chamber tests or free interaction in social dyads were included in social motivation/interaction, while social novelty preference tasks were categorized as tests of social recognition. Analysis of socially induced ultrasonic vocalizations or social olfactory preference tasks in rodents were regarded as tests of social communication.
Abnormal behavioral patterns concerning social motivation or interaction have been consistently observed in the murine models ex4-22|ALL [ 128, 130], ex4-9|ANK [ 78, 80, 124, 154– 156], ex11|SH3 [ 123, 157], ex13-16|PDZ [ 83, 90, 155, 158– 166], and ex14-16|PDZ [ 131], although deficits were not recapitulated for some of these models in single studies [ 129, 167, [168](https://pmc.ncbi.nlm.nih.gov/article
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