Lithium may help treat those with SHANK3 related autism

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The mood-stabilizing drug lithium eases repetitive behaviors seen in mice missing SHANK3, an autism gene, according to a new study.

The findings suggest lithium merits further study as a treatment for some people with autism, even though the drug has troublesome side effects, including tremors and impaired memory.

“Lithium is, of course, a rather difficult, non-ideal treatment,” says lead investigator Gina Turrigiano, professor of vision science at Brandeis University in Waltham, Massachusetts.

“It’s really hard to get people on a lithium regimen that they can tolerate well.” But understanding why lithium works may set the stage for better treatments, she says.

About 1 percent of people with autism have mutations in SHANK3. Deletion or mutation of the gene can also lead to Phelan-McDermid syndrome, which is characterized by intellectual disability, delayed speech and, often, autism.

Case studies of people with Phelan-McDermid syndrome also suggest that lithium eases behavior problems associated with the condition.

Previous work has shown that SHANK3 helps stabilize neuronal circuits by adjusting excitatory and inhibitory signaling like a thermostat.

This process, called homeostatic plasticity, allows neurons to respond to changes in sensory input.

The new study suggests the gene controls this thermostat by regulating how frequently neurons fire and how they adjust the electrical currents flowing through them.

SHANK3 loss or mutation prevents neurons from adapting to changes in sensory input.

“What we’ve shown is there’s this cellular mechanism, and loss of that mechanism is a direct result of a loss of SHANK3,” Turrigiano says.

Firepower

The team first recorded electrical activity in rat neurons in which SHANK3 expression was partially disrupted. They artificially blocked the neurons’ ability to fire. The mutant neurons’ rate of firing did not return to its original range afterward as it did in control cells, the team found.

The neurons also responded with less electrical activity than controls did when the researchers blocked and then restarted electrical currents. This suggests the mutant neurons had lost their ability to adjust the current flowing through them.

Excitatory neurons in the cortex called pyramidal cells are most strongly affected. Lithium restored the cells’ ability to adjust both their firing rates and how much current they carry.

To examine how neurons in mice lacking SHANK3 respond to changes in sensory input, the team implanted electrode arrays into the visual cortex of the mutant mice and controls and glued one eye shut in each mouse.

Over the following three or four days, the neurons in both groups of mice decreased how frequently they fired. But the decrease in the mutant mice was more gradual, suggesting that they take longer to adjust.

Neurons in the control mice returned to their typical firing rate two days after the rate had slowed to its lowest level, presumably because the mice’s brains had adapted to the loss of vision in one eye.

But in the mutant mice, the neurons never returned to their original firing rates, indicating that without the gene, their brains could not adapt.

The mutant mice also groom themselves excessively, a behavior that is thought to align with obsessive or repetitive behaviors in people. To the researchers’ surprise, lithium stopped this behavior entirely. The work appeared in March in Neuron.

Treatment potential

The findings support the idea that lithium may help treat people with SHANK3 mutations, and perhaps those with other forms of autism as well, says Jean Martin Beaulieu, associate professor of psychiatry and neurosciences at the University of Toronto in Canada, who was not involved in the study.

However, he says, the study does not prove that the problems with homeostatic plasticity cause the repetitive behavior. Overgrooming is a complex behavior involving multiple brain areas, he says, whereas the study examined only the visual cortex.

It is also unclear whether lithium acts directly on SHANK3 or on some other target in the circuit, says Thomas Bourgeron, professor of genetics at the Institut Pasteur in Paris, France, who was not involved in the study.

Turrigiano says the loss of SHANK3 may be just the first step in a process that leads to neurons’ inability to adapt to sensory input. Identifying which part of that process lithium corrects may point to new targets for treatment, she says.

Turrigiano’s team is studying how SHANK3 helps balance excitatory and inhibitory activity of neurons, to better understand its role in maintaining homeostatic plasticity.


Phelan-McDermid syndrome (PMS, OMIM 606232) is a rare neurodevelopmental disorder characterized by neonatal hypotonia, global developmental delay, intellectual disability (ID), severely delayed or absent speech, and fre- quent autism spectrum disorder (ASD) [1]. The neurobe- havioral phenotype of PMS is usually severe.

In a prospective study of 32 PMS individuals, 77% manifested severe-to-profound ID and 84% met criteria for ASD using gold standard diagnostic tools [2]. Dysmorphic features are usually mild and include long eyelashes, large or prominent ears, bulbous nose, pointed chin, fleshy hands, and dysplastic toenails [1]. Additional features include gastrointestinal problems, seizures, motor deficits, struc- tural brain abnormalities, renal malformations, lymph- edema, and recurrent infections [1].

The major neurodevelopmental features of PMS are caused by deletions or mutations of the SHANK3 gene, which encodes a scaffolding protein of the postsynaptic density of glutamatergic synapses. Most reported cases of PMS are caused by 22q13.3 deletions, which usually encompass many genes and can extend up to 9.2 Mb [2–4].

Genotype-phenotype analyses indicate that the size of the deletion and the number and/or severity of clinical manifestations are positively correlated [2, 4–7]. Specifically, correlations have been reported between dele- tion size and hypotonia [5–7], developmental delay [5–7], dysmorphic features [2, 7], speech abilities [4], social com- munication deficits related to ASD [2], and other medical conditions [2]. Furthermore, individuals with small ter- minal deletions may have more favorable developmental trajectories than those with larger deletions [8].

De novo truncating and missense mutations in SHANK3 have been identified in cohorts ascertained for ASD [9–16] or ID [17–21]. In addition, there is a single report of two families ascertained for schizophrenia with mutations in SHANK3; affected individuals also had ID [22].

Despite the increasing number of mutations in SHANK3, their prevalence in PMS and more broadly in ASD is underestimated because clinical sequencing is still uncommon compared to chromosomal microarray. In addition, SHANK3 has been poorly covered by whole exome sequencing due to high GC content [13, 23], and there is little in the PMS phenotype that would prompt a clinician to specifically target SHANK3 for optimized Sanger sequencing. We and others estimate that SHANK3 haploinsufficiency might account for up to 1% of more severely affected ASD cases [13, 23].

Given the dearth of identified cases with SHANK3 mutations, analyses of PMS cohorts have largely focused on individuals with 22q13.3 deletions [2–8, 24]. Only two studies on PMS have included a few individuals carrying SHANK3 mutations [2, 24].

These observations have been complemented by the description of a small number of individuals identified through SHANK3 targeted sequencing in ASD cohorts [9–13]. Large-scale sequencing studies have been instrumental in revealing additional SHANK3 mutations but have not provided detailed phenotypic information [14–16, 19–21].
The limited number of subjects with SHANK3 muta- tions e

xamined thus far, and the lack of systematic clin- ical evaluation have hindered the characterization of the phenotypic spectrum associated with SHANK3 mutations. Here, we aimed to delineate the genetic spectrum of SHANK3 mutations and their associated phenotype in relationship to PMS features.

Results

SHANK3 mutations

We report 17 individuals (including two monozygotic twins) with SHANK3 mutations identified through WES or panel sequencing. The variants were distributed throughout the protein and included 13 frameshift, two nonsense, and one missense mutation (Table 1, Fig. 1a). Notably, we observed an identical frameshift mutation, c.3679dupG (p.Ala1227Glyfs*69), in three unrelated in- dividuals.

Mutations were confirmed to be de novo in 15 individuals and non-paternal or non-maternal in two (no DNA was available from the other two parents). In addition to a nonsense mutation, individual S13 carries a missense variant (p.Ser1291Leu) absent in the mother but present in the unaffected sister and in four individ- uals in the Genome Aggregation Database (gnomAD), suggesting it is likely benign, despite being predicted as damaging by several in silico tools (Additional file 1: Table S3). All other mutations are absent from the Exome Variant Server (EVS) and gnomAD.

The missense mutation in S14 (p.Asp1672Tyr) affects a highly conserved residue and is predicted to be dam- aging by all algorithms used, including Polyphen-2, SIFT, PANTHER, MutPred2, Condel2, CADD, and M-CAP (Additional file 1: Table S3).

We also searched the literature and ClinVar for SHANK3 mutations and assessed their pathogenicity. Variants listed in Additional file 1: Table S1 meet the following criteria: (1) loss-of-function variants (frameshift, nonsense, and splice site), or de novo missense variants predicted to be deleterious by several bioinformatics pre- dictors, and (2) absent from control databases (EVS and gnomAD).

After removing cases ascertained or reported multiple times, we identified 60 additional individuals from 55 families with SHANK3 mutations classified as pathogenic or likely pathogenic according to ACMG [25]. All the mutations with parental samples available were de novo.

Three families had multiple affected sib- lings, consistent with germline mosaicism [9, 22, 43]. Four de novo missense variants reported in children with ASD, ID, or infantile spasms (p.Thr337Ser, p.Ser1197Gly, p.Ala1214Pro, and p.Arg1255Gly) [15, 44–46] were classified as variants of uncertain significance because, although not present in controls, in silico predictions did not provide consistent evidence for pathogenicity (Additional file 1: Tables S1, S3).

Given that SHANK3 is highly constrained against missense variation (Exome Aggregation Consortium Z score 4.92) [47], further studies are needed to determine the pathogenicity of these and other missense variants.
Three of the mutations in our cohort are recurrent, having been previously observed in unrelated individuals (Fig. 1a, Additional file 1: Table S1).

The mutation in S6, p.Leu1142Valfs153, was reported in a boy with ASD [13]. The mutation c.3679dupG (p.Ala1227Glyfs69), shared by three of our patients (S7, S8, B1), is within a stretch of eight guanines and has been identified in three independent cases [9, 15, 20]. p.Arg1255Leufs25, present in S9, has been reported in three unrelated pa- tients [13, 21]. The donor splice site at position c.2265 +1 is another hotspot: there are three individuals with a G>A substitution [16, 24, 48], and one with a deletion of the same G (c.2265+1delG), shown to result in a frameshift (p.Ser755Serfs1) [11]. Overall, there were four recurrent and 56 private pathogenic/likely pathogenic mutations in SHANK3 (Fig. 1a, Additional file 1: Table S1).

We also searched for potentially deleterious variants inherited from unaffected parents or present in popula- tion controls (Additional file 1: Table S4). An inherited frameshift variant reported as pathogenic in two unrelated children with ASD [12, 49], and classified as damaging in the Human Gene Mutation Database, is in fact intronic when annotated in the correct reference sequence, NM_033517.1 [49], and is present 173 times in gnomAD (chr22:g.51135705dupG, hg19).

An inherited substitution in a splice region (c.1772-4G>A) reported in ASD [12] is present seven times in gnomAD and is thus unlikely to be deleterious. gnomAD contains 21 variants predicted to be loss-of-function when annotated in the Ensembl canonical transcript ENST00000262795 (which is missing the beginning of exon 11 and contains three extra, unvalidated exons).

When annotated in NM_033517.1, many of these variants are in fact intronic. The remaining 10 loss-of-function variants are all singletons; seven are flagged because they were found in sites covered in a limited number of individuals, which may indicate low-quality sites, one is located at the extreme 3′ end, and one has an abnormal allele bal- ance. These findings confirm that truncating variants in SHANK3 are highly penetrant and unlikely to be present in unaffected individuals.

Four in-frame deletions [10, 13, 19, 50] and one in- frame insertion [50] in SHANK3 have been reported in ASD/ID (Additional file 1: Table S4). Three of these vari- ants were inherited [10, 13, 50], and one was found in two controls [50], suggesting that some short in-frame dele- tions or insertions may be tolerated.

An in-frame deletion of five amino acids (p.Gly1453_Ala1457del) reported in an ASD proband and his unaffected mother [10] was detected in six individuals in the gnomAD database. gnomAD lists 15 in-frame deletions or insertions (after anno- tation in NM_033517.1); six are on multiallelic sites, and four others are flagged because of low coverage. Among the remaining in-frame variants, p.Glu1230del was observed in five individuals and p.Gly1518del in four (Additional file 1: Table S4). These findings indicate that at least some in-frame variants in SHANK3 can be present in seemingly unaffected individuals.

in gnomAD (chr22:g.51135705dupG, hg19). An inherited substitution in a splice region (c.1772-4G>A) reported in ASD [12] is present seven times in gnomAD and is thus unlikely to be deleterious. gnomAD contains 21 variants predicted to be loss-of-function when annotated in the Ensembl canonical transcript ENST00000262795 (which is missing the beginning of exon 11 and contains three extra, unvalidated exons).

When annotated in NM_033517.1, many of these variants are in fact intronic. The remaining 10 loss-of-function variants are all singletons; seven are flagged because they were found in sites covered in a limited number of individuals, which may indicate low-quality sites, one is located at the extreme 3′ end, and one has an abnormal allele bal- ance. These findings confirm that truncating variants in SHANK3 are highly penetrant and unlikely to be present in unaffected individuals.

Four in-frame deletions [10, 13, 19, 50] and one in- frame insertion [50] in SHANK3 have been reported in ASD/ID (Additional file 1: Table S4). Three of these variants were inherited [10, 13, 50], and one was found in two controls [50], suggesting that some short in-frame dele- tions or insertions may be tolerated.

An in-frame deletion of five amino acids (p.Gly1453_Ala1457del) reported in an ASD proband and his unaffected mother [10] was detected in six individuals in the gnomAD database. gnomAD lists 15 in-frame deletions or insertions (after annotation in NM_033517.1); six are on multiallelic sites, and four others are flagged because of low coverage.

Among the remaining in-frame variants, p.Glu1230del was observed in five individuals and p.Gly1518del in four (Additional file 1: Table S4). These findings indicate that at least some in-frame variants in SHANK3 can be present in seemingly unaffected individuals.

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Brandeis University

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