Identification of Novel Variants in 8 Families With Meige Syndrome Using Whole-exome Sequencing

doi:10.21203/rs.3.rs-783526/v1

Background: Meige syndrome is a type of cranial dystonia characterized by blepharospasm and infraorbital dystonia and may be related to movement disorders of the mandibular and facial muscles, mouth, jaw, tongue, pharynx and cervical muscles. However, the etiopathogenesis of this disease condition remains unknown. Our present study aimed to find clues to the pathogenic factors of Meige Syndrome using whole-exome sequencing.

Results: The study included 13 clinically diagnosed patients with Meige syndrome, a subtype of facial dystonia, from eight families (marked as Family 1 to Family 8) and two matched controls in two of the eight families. The genomic DNA was extracted from peripheral blood for whole-exome sequencing (WES). Quality control filtering, genome repeat filtering, genomAD/1000g filtering, exonic & splicing site filtering, hazard filtering, Varsome (ACMG) filtering were used to find the genes predicted to be damaging in Meige Syndrome. Among 582,715 SNP or indel variants. One variant in PALM3 (rs374267554, NC_000019.9:g.14167249G>A) passed our analysis and detection criteria. We verified the variant site using Sanger sequencing in another 48 patients. Structural analysis of the PALM3 variant predicted its potential effects on pathogenicity.

Conclusions: Our findings contribute to a better understanding of the impact of the PALM3 variant on the pathogenicity of Meige Syndrome. Sequencing PALM3 in larger Meige Syndrome cohorts and functional studies will need to be performed to further elucidate the association between PALM3 and the disease.

Internal Medicine

Meige Syndrome

Blepharospasm

Whole-exome sequencing

Variants

PALM3

The main clinical feature of Meige Syndrome, which is characterized by blepharospasm and infraorbital dystonia, may be related to movement disorders of the mandibular and facial muscles, mouth, jaw, tongue, pharynx and cervical muscles. Meanwhile, it has also been reported that the patients exhibit tremor and Parkinson's disease phenotype [1, 2].

The basal ganglia and motor cortex are usually abnormal in patients with dystonia. But Liu et al. pointed out that decreased grey matter volume was found in the precuneus and inferior parietal cortex instead of basal ganglia and motor cortex in the Meige Syndrome patients. They argued that the precuneus is far more critical than the basal ganglia and motor cortex in the pathophysiology of the Meige Syndrome. The precuneus lies deep in the parietal lobe and interacts with the adjacent posteromedial cortex. In addition, it has been proved that there is an extensive connection between the precuneus and the motor area [3]. These may explain why the precuneus plays an essential role in the pathophysiology of Meige Syndrome. Detailed examination of Meige Syndrome by Jochim et al. showed that functional connections were altered in a wide range of brain regions such as basal ganglia, cerebellar, sensorimotor, and visual areas [4].

The therapeutic interventions for Meige Syndrome include oral medications, botulinum toxin injections, and surgical procedures. A study on the clinical medication use of Meige Syndrome showed that benzodiazepine drugs, muscle relaxants, antispasmodic drugs, anticholinergic drugs and dopamine-related drugs are mainly used to treat Meige Syndrome [5]. By local injection, botulinum toxin can alleviate the symptoms of Meige Syndrome for a while. Many safety studies had shown its efficacy [6], and in the long run, there were no significant side effects [7]. However, this regime requires maintaining a long period of continuous injection. Bilateral globus pallidus internus stimulation is a beneficial treatment option for refractory Meige Syndrome, which can significantly improve dyskinesia symptoms [8–10]. Some patients had mild dizziness or transient gait instability, numbness of limbs and slurred speech after operation [11].

The pathophysiology of Meige Syndrome is not well understood, but recent researches support that environmental triggers and genetic susceptibility lead to altered plasticity and reduced cortical inhibition, which are detected by neurophysiology and neuroimaging techniques [2]. Nowadays, there are a few relevant publications on the etiology of Meige Syndrome. In families with multiple patients, the inheritance pattern is autosomal dominant, and penetrance is reduced [12]. GNAL, ANO3, CIZ1, and REEP4 were considered to be related to the onset of the adult cervical or cranial-cervical dystonia [13–16].

Geoghegan et al. reported a novel GNAL mutation in familial dystonia patients with involuntary movement of the posterior neck muscles [17]. Patients with heterozygous GNAL mutations usually show adult-onset focal neck, laryngeal, and/or segmental dystonia. This condition is usually a familial autosomal dominant inheritance or sporadic inheritance [18, 19]. Related to abnormal ion channel function, the mutations in ANO3 cause autosomal-dominant inheritance of craniocervical dystonia [15, 20]. Xiao et al. first reported that the mutations in CIZ1 cause adult-onset primary cervical dystonia [13]. However, because of the genetic heterogeneity of primary dystonia, researchers from China and Germany did not see such results in their cohort [21, 22]. The sequencing results of REEP4 showed two non-synonymous SNVs, a potential splice site variant and an indel, all of which are predicted to be damaging in patients with blepharospasm [23].

Although significant progress has been made in understanding the pathogenesis of Meige Syndrome, no unified theory has emerged yet. Patients with Meige Syndrome have different clinical manifestations, and the underlying disease neural pathways may also be heterogeneous. The whole-exome sequencing (WES) is beneficial for the genetic diagnosis of many diseases. In the current work, we aimed to seek possible genes to help understand Meige Syndrome's pathology using WES in eight families with Meige Syndrome.

2.1. Patients

The study included 13 clinically diagnosed patients with Meige Syndrome from eight families (marked as Family 1 to Family 8) and two healthy people without Meige Syndrome in two of the eight families. All the collected patients were confirmed by neurologists or ophthalmologists, which met the disease's diagnostic criteria. All patients and their families signed the informed consent form. The research scheme was approved by the Ethics Committee of the Institute of Clinical Pharmacology, Xiangya Medical College, Central South University, and applied for the clinical trial approval number (registration number: ChiCTR-CCC-14004202) from China Clinical Trial Registration Center.

2.2. Exome sequencing and data analysis

The genomic DNA was extracted from peripheral blood according to the manufacture's instructions for WES. The SAMtools package (v0.1.18) was used to filter the duplicate reads and call the SNPs and indels. Variant Effect Predictor was employed to annotate the SNP/ indels. Variant sites whose sequencing depth and quality did not meet the requirements (Depth ≥ 8, Quality ≥ 20) were excluded. Considering that Meige Syndrome is an autosomal dominant inheritance, we ruled out variants on the sex chromosome and recessive genetic variants [24]. Then we selected the low-frequency variants (lower than 1% in gnomAD and 1000 Genomes Project database) in the exonic & splicing region for further analysis. Synonymous variants were also screened out. SIFT (http://sift.jcvi.org/), Polyphen 2 (http://genetics.bwh.harvard.edu/pph2/), MutationTaster (http://mutationtaster.org/), GERP + + scores (http://mendel.stanford.edu/SidowLab/downloads/gerp/), InterVar (http://wintervar.wglab.org/) were used to evaluate the harmfulness of variants. Finally, genome variants of at least two patients in any family and one patient outside the family were selected as candidate variant sites. Figure 2 shows the flow chart of variant calling and removal at each step.

As there was neither a solved structure (crystal structure) nor homologous templates available in the database (www.rcsb.org/), we built a 3D structure of the wild type PALM3 protein in-silicon. We used the software RaptorX for the prediction of the secondary structure of the protein. The protein tertiary structure prediction was completed by the Robetta web service. The best predicted 3D protein structure was energy minimized. The quality of protein structure was quantified by confidence (C) score, template model (TM) score, and root mean square deviation (RMSD) [25]. Pymol was used to analysis the stability of mutant PALM3 protein.

The protein-protein interaction (PPI) network was constructed according to the STRING database (www.string-db.org). The GO (Gene Ontology) enrichment analysis was performed by the R package ClusterProfiler. Comparisons among different groups were made using the Student t-test. Differences were considered to be significant with filtering (logFC > 1 or logFC < -1, p.adjust < 0.05).

3.1. Clinical characteristics

Out of 13 Meige Syndrome patients from eight families in this study, five were men and eight were women. The mean onset age was 50.15 ± 8.47 years, and the mean age at enrollment was 61.54 ± 9.19 years. Eight patients had symptoms in the eyes and jaw, while the other five patients only had symptoms in the eyes. The clinical data of patients with Meige Syndrome and healthy people are shown in Table 1. Figure 1 provides the pedigrees of Family 1–8.

Table 1

Clinical data of patients with or without Meige Syndrome
Gene	Family	Meige	Sex	Age	Age at onset	Location at Diagnosis
M1	Family1	Yes	M	43	40	Eyes, jaw
M2	Family1	Yes	M	68	52	Eyes, jaw
M3	Family2	Yes	F	63	51	Eyes
M4	Family2	Yes	F	60	50	Eyes, jaw
M5	Family3	Yes	M	78	30	Eyes, jaw
M6	Family3	Yes	F	52	40	Eyes, jaw
C1	Family3	No	M	--	--	--
M7	Family4	Yes	F	60	55	Eyes
M8	Family4	Yes	F	66	55	Eyes
M9	Family4	Yes	F	58	55	Eyes
C2	Family4	No	M	--	--	--
M10	Family5	Yes	F	66	56	Eyes, jaw
M11	Family6	Yes	F	73	58	Eyes, jaw
M12	Family7	Yes	F	53	51	Eyes, jaw
M13	Family8	Yes	F	60	59	Eyes

Two patients (M1 and M2) in Family 1 are in a father-son relationship. The clinical symptoms of the father (M2) were spasmodic twitching of eyelids, lips and maxillofacial muscles. There was no medication for M2. The son (M1)'s clinical symptoms were blepharospasm, occasionally lower mouth twitch, and it was difficult to open eyes in severe cases.

Two sisters (M3 and M4) in Family 2 suffered from Meige Syndrome. M3 would open her mouth, pout, raise eyebrows, frown with dry eyes, soreness, tears and blurred vision when the disease occurred. M4 had the same clinical symptoms as her sister, accompanied by jaw convulsions. Both sisters' illness affected their work and life, and they had difficulty in walking due to visual impairment.

In Family3, M5 suffered from blepharospasm in both eyes, accompanied by dry eyes, soreness, tears, blurred vision, dystonia of oral and mandibular muscles, which affected work and life, such as difficulty in walking due to visual impairment. The clinical symptoms of Meige Syndrome were the same in patients M5 and M6. It was worth noting that C1 was the healthy brother of M6 and had not suffered from Meige Syndrome or other diseases so far. In addition, M6's son also suffered from the disease, but we hadn't collected his DNA sample.

The clinical phenotypes of the M7, M8, and M9 patients in Family 4 were all blepharospasm. The patients were accompanied by dry eyes, obvious spasms, and mild visual impairment. C2 among family members was a healthy control.

Patient M10 in Family 5, M11 in Family 6 and M12 in Family 7 belonged to blepharospasm with oromandibular dystonia. The patients opened their mouth, pursed their mouth, raised their eyebrows, and frowned at the onset, accompanied by dry eyes, soreness, tearing and blurred vision, blepharospasm, which affected work and life such as difficulty walking due to visual impairment. The other family members also suffered from the disease, and we had not collected blood from other patients.

Patient M13 belonged to family F8 and was clinically diagnosed with blepharospasm Meige Syndrome. The patient was accompanied by dry eyes, obvious spasms, and mild dysfunction. Her mother also suffered from this disease and died.

3.2. Gene landscape by WES

Out of 582,715 SNP or indel variants, one variant in PALM3 (rs374267554, NC_000019.9:g.14167249G > A) passed our analysis and detection criteria, as presented in Fig. 2. This variant of PALM3 was found in three patients from two families. The SITF score of this variant is 0.01(D). The Polyphen score of this variant is 0.986(D). The MutationTaster score of this variant is 0.994(D). The GERP++_NR score of this variant is 4.77. We confirmed the variant site of the PALM3 gene using sanger sequencing and verified the variant in another 48 patients (Fig. 3). There was one patient in another 48 patients who had the same variant of PALM3. In gnomAD, the allele frequency of this variant in PALM3 in East Asia is 0.003130. Polyphen predicted this variant in PALM3 (ENST00000340790.4 and ENST00000589048.1) as probably_damaging. Notably, SIFT predicted this variant in PALM3 (ENST00000340790.4 and ENST00000589048.1) as deleterious.

3.3. Structural analysis of PALM3 variant

The PALM3 protein structure predicted by Robetta (http://robetta.bakerlab.org) had a C-score of 1.27. TM-score was 0.63 ± 0.14. These scores indicated the high quality of the predicted model and accurate folding of PALM3 protein (RMSD score is 1.716 Å). Superimposition of PALM3 structures revealed the changes of the variant (rs374267554, NC_000019.9:g.14167249G > A, NP_001138500.2:p.Arg131Cys) in protein structures (Fig. 4A). The stability analysis predicted that Arg131Cys destabilizes PALM3 protein (△△G is -0.257 Kcal/mol). The mutation of Arg131Cys seems to destabilize the PALM3 protein by altering the binding mode of amino acid residues from R131 to H135, G134, P128, S102, P124 and H122 (Fig. 4B).

3.4. The functional annotation analysis of PALM3 protein-protein interaction (PPI) network

As shown in Fig. 5A, by constructing a protein-protein interaction (PPI) network, we had discovered 19 PALM3 interacting proteins. The GO (Gene Ontology) enrichment analysis was performed (Fig. 5B), and the neuron/ muscle/ synapse related GO terms were summarized in Table 2. Among the 19 PALM3 interacting proteins, ROBO2/PM20D1/ZHX2 were annotated by the neuron function related GO terms, ROBO2/ZDHHC17 were annotated by the synapse function related GO terms.

Table 2

The enrichment of neuron/ muscle/ synapse related GO terms with genes related to *PALM3* in protein-protein interaction (PPI) network
No.	Ontology	ID	Description	pvalue	p.adjust	geneID
1	BP	GO:0021889	olfactory bulb interneuron differentiation	0.008	0.108	ROBO2
2	BP	GO:0021884	forebrain neuron development	0.020	0.108	ROBO2
3	BP	GO:0008038	neuron recognition	0.033	0.116	ROBO2
4	BP	GO:0021879	forebrain neuron differentiation	0.036	0.116	ROBO2
5	BP	GO:0021872	forebrain generation of neurons	0.045	0.128	ROBO2
6	BP	GO:0021954	central nervous system neuron development	0.053	0.132	ROBO2
7	BP	GO:0021953	central nervous system neuron differentiation	0.120	0.199	ROBO2
8	BP	GO:1901215	negative regulation of neuron death	0.136	0.214	PM20D1
9	BP	GO:0045665	negative regulation of neuron differentiation	0.146	0.216	ZHX2
10	BP	GO:0097485	neuron projection guidance	0.177	0.233	ROBO2
11	BP	GO:0010976	positive regulation of neuron projection development	0.179	0.233	ROBO2
12	BP	GO:1901214	regulation of neuron death	0.197	0.247	PM20D1
13	BP	GO:0070997	neuron death	0.217	0.259	PM20D1
14	BP	GO:0045666	positive regulation of neuron differentiation	0.230	0.259	ROBO2
15	BP	GO:0010975	regulation of neuron projection development	0.297	0.297	ROBO2
16	CC	GO:0032589	neuron projection membrane	0.037	0.110	ROBO2
17	BP	GO:1905809	negative regulation of synapse organization	0.017	0.108	ROBO2
18	BP	GO:0051963	regulation of synapse assembly	0.071	0.146	ROBO2
19	BP	GO:0007416	synapse assembly	0.117	0.198	ROBO2
20	BP	GO:0050807	regulation of synapse organization	0.142	0.214	ROBO2
21	BP	GO:0050803	regulation of synapse structure or activity	0.147	0.216	ROBO2
22	BP	GO:0050808	synapse organization	0.250	0.272	ROBO2
23	CC	GO:0098793	presynapse	0.280	0.280	ZDHHC17

Previous research reported that GNAL, ANO3, CIZ1, and REEP4 were related to the onset of adult dystonia. These variants were not found in our cohort. This may be partly due to the small sample size. On the other side, Meige Syndrome, characterized by blepharospasm and infraorbital dystonia, is just a subtype of primary dystonia. Maybe, given the genetic heterogeneity of primary dystonia, we did not see such results in our cohort.

In order to explore the biological function of PALM3, we constructed a protein-protein interaction (PPI) network (Fig. 5A). Among the 19 PALM3 interacting proteins, ROBO2/PM20D1/ZHX2 were annotated by the neuron function related GO terms, ROBO2/ZDHHC17 were annotated by the synapse function related GO terms. PALM3 is an ATP-binding protein that may act as an adapter in the Toll-like receptor (TLR) signalling. Unfortunately, there are few PALM3 function study especially on the association between PALM3 and dystonia, reported in the literature. PALM3 belongs to the paralemmins protein family, which includes PALM1, PALM2, PALM3 and palmdelphin. PALM3 is involved in LPS-induced inflammation and LPS-TLR4 signal transduction in alveolar macrophages [26].

The protein encoded by ROBO2 belongs to the ROBO family that is highly conserved from fly to human. ROBO2 contributed to the establishment of retinotectal connections [27]. Anbalagan et al. reported the regulatory effect of this protein on actin kinetics [28].

PM20D1 is a bidirectional N-fatty-acyl amino acid synthase/hydrolase, which regulates the production of N-fatty-acyl amino acids. Wang et al. indicated that PM20D1 is an mQTL in Alzheimer's disease (AD). Both the hypomethylation of PM20D1 in mild AD and the hypermethylation in hippocampal and frontal cortex brain tissues in advanced-stage AD were confirmed [29]. Since the increase of PM20D1 gene expression can alleviate the pathological changes associated with AD, Zhang San pointed out that PM20D1 may have a neuroprotective effect against AD [30].

ZHX2 is a member of the zinc fingers and acts as a transcriptional repressor. No research reported on the neurological function of this gene was found.

ZDHHC17 is a palmitoyltransferase specific for a subset of neuronal proteins, including SNAP25, DLG4/PSD95, GAD2, SYT1 and HTT. Shi et al. identified ZDHHC17 as a vital regulator of neuronal development. Knockdown of ZDHHC17 in zebrafish led to motor dysfunction [31]. ZDHHC17-dependent palmitoylation ensures the distal axon integrity in healthy optic nerves [32].

In general, it is challenging to identify rare causative variants in multifactorial disorders using (very) small sample sizes. In the future, functional research and verification should be carried out in larger Meige Syndrome populations. In addition, we also proposed other candidate genes that may be involved in the pathophysiology of Meige Syndrome, such as GNAL, ANO3, CIZ1, and REEP4.

In this study, Meige Syndrome patients showed typical symptoms associated with blepharospasm, including raised eyebrows and frowned at the onset, accompanied by dry eyes, soreness, tearing and blurred vision. The disease impacts life in all aspects and may affect the performance of daily tasks such as breathing, swallowing, writing and driving. Future studies through WES may provide better insights into the causes of Meige Syndrome and provide guidance for better treatment.

Because of the small size of our pool of patients and the genetic heterogeneity of Meige Syndrome, the role of PALM3 in Meige Syndrome still requires validation in much larger studies. Since most cases of Meige Syndrome are still idiopathic, future studies through WES methods may provide insights into the etiology of Meige Syndrome and give guidance for better therapeutic interventions.

Ethics approval and consent to participate

The research scheme was approved by the Ethics Committee of the Institute of Clinical Pharmacology, Xiangya Medical College, Central South University, and applied for the clinical trial approval number (registration number: ChiCTR-CCC-14004202) from China Clinical Trial Registration Center. The authors adhere to the Declaration of Helsinki Principles.

Consent for publication

Informed written consent for publication was obtained for all participants.

Availability of data and materials

The whole-exome sequencing data were submitted to Sequence Read Archive (SRA) submission: SUB8714944. Further data of this study are available from the corresponding author upon request.

Funding

This work was supported by the National Key Research and Development Program of China (2016YFC1306900), National Natural Science Foundation of China (81874327), Key Research and Development Program of Hunan Province (2019SK2251), Natural Science Foundation of Hunan Province, China (2018JJ4020), and Fundamental Research Funds for the Central Universities of Central South University (2017zzts224).

Competing interests

The authors declare that they have no potential conflict of interest.

Authors' contributions

ZBW conducted the experiments and wrote the manuscript. ZBW, JQ, YZ and YS participated in the approval of the local ethical committees and sample collection. XYM revised the manuscript. HHZ, XYM and ZQL approved the final manuscript. ZQL and XYM contributed equally to this article. All authors contributed to the article and approved the submitted version.

Acknowledgments

We thank all the patients and families for their contribution to this work.

We thank Dr. Guangchuang Yu, FigureYa (Xiao Ya Hua Tu) and Dr. Shipeng Guo (Chongqing Medical University) for the figure technology support. We also thank Dr. Jianming Zeng (University of Macau), and all the members of his bioinformatics team, biotrainee, for generously sharing their experience and codes.

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Identification of Novel Variants in 8 Families With Meige Syndrome Using Whole-exome Sequencing

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials And Methods

2.1. Patients

2.2. Exome sequencing and data analysis

3. Results

3.1. Clinical characteristics

3.2. Gene landscape by WES

3.3. Structural analysis of PALM3 variant

3.4. The functional annotation analysis of PALM3 protein-protein interaction (PPI) network

4. Discussion

Declarations

References

Status:

Version 1