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Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias

  • Cheng-Tsung Hsiao,

    Roles Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Visualization, Writing – original draft

    Affiliations Division of Neurology, Department of Internal Medicine, Taipei Veterans General Hospital Taoyuan Branch, Taoyuan, Taiwan, Republic of China, Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China, Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China

  • Yo-Tsen Liu,

    Roles Investigation, Methodology, Project administration, Supervision

    Affiliations Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China, Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China

  • Yi-Chu Liao,

    Roles Formal analysis, Investigation, Methodology, Supervision, Writing – review & editing

    Affiliations Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China, Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China

  • Ting-Yi Hsu,

    Roles Investigation, Methodology

    Affiliations Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China, Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China

  • Yi-Chung Lee,

    Roles Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing – review & editing

    Affiliations Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China, Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China, Brain Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China

  • Bing-Wen Soong

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Writing – review & editing

    bwsoong@ym.edu.tw

    Affiliations Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China, Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China, Brain Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China, Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan, Republic of China

Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias

  • Cheng-Tsung Hsiao, 
  • Yo-Tsen Liu, 
  • Yi-Chu Liao, 
  • Ting-Yi Hsu, 
  • Yi-Chung Lee, 
  • Bing-Wen Soong
PLOS
x

Correction

8 Feb 2018: Hsiao CT, Liu YT, Liao YC, Hsu TY, Lee YC, et al. (2018) Correction: Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias. PLOS ONE 13(2): e0192866. https://doi.org/10.1371/journal.pone.0192866 View correction

Abstract

Background

The inositol 1,4,5-triphosphate (IP3) receptor type 1 gene (ITPR1) encodes the IP3 receptor type 1 (IP3R1), which modulates intracellular calcium homeostasis and signaling. Mutations in ITPR1 have been implicated in inherited cerebellar ataxias. The aim of this study was to investigate the role of ITPR1 mutations, including both large segmental deletion and single nucleotide mutations, in a Han Chinese cohort with inherited cerebellar ataxias in Taiwan.

Methodology and principal findings

Ninety-three unrelated individuals with molecularly unassigned spinocerebellar ataxia selected from 585 pedigrees with autosomal dominant cerebellar ataxias, were recruited into the study with elaborate clinical evaluations. The quantitative PCR technique was used to survey large segmental deletion of ITPR1 and a targeted sequencing approach was applied to sequence all of the 61 exons and the flanking regions of ITPR1. A novel ITPR1 mutation, c.7721T>C (p.V2574A), was identified in a family with dominantly inherited cerebellar ataxia. The proband has an adult-onset non-progressive pure cerebellar ataxia and her daughter is afflicted with a childhood onset cerebellar ataxia with intellectual sub-normalities.

Conclusion

ITPR1 mutation is an uncommon cause of inherited cerebellar ataxia, accounting for 0.2% (1/585) of patients with dominantly inherited cerebellar ataxias in Taiwan. This study broadens the mutational spectrum of ITPR1 and also emphasizes the importance of considering ITPR1 mutations as a potential cause of inherited cerebellar ataxias.

Introduction

The inositol 1,4,5-triphosphate (IP3) receptor type 1 gene (ITPR1) encodes the IP3 receptor type 1 (IP3R1), that functions on the endoplasmic reticulum (ER) membrane in a tetrameric form and modulates intracellular calcium homeostasis and signaling [1]. IP3R1 is abundant in the central nervous system, especially in the Purkinje cells [2, 3]. Mutations in ITPR1 have been implicated in a small group of patients with cerebellar ataxias and different ITPR1 mutations may result in similar but still distinguishable phenotypes. Heterozygous large segmental deletions of ITPR1 were first identified in an Australian and two Belgium families with adult-onset, very slowly progressive, pure cerebellar ataxia that was designated as spinocerebellar ataxia (SCA) type 15 (SCA15; MIM #606658) [4]. Soon, patients with similar ITPR1 mutations were also identified in Japanese families and Caucasian pedigrees in France and United States [510]. Missense mutations in ITPR1 were later found to cause SCA15 [6, 11, 12] or SCA29 that features a congenital non-progressive cerebellar ataxia (MIM #117360) [1320]. There is a wide phenotypic diversity linked to ITPR1 missense mutations. Two ITPR1 missense mutations (p.N587D and p.S1487D, reference sequence NM_001168272) were recognized as a cause of ataxic cerebral palsy [21], while an ITPR1 missense mutation (p.I2583N, reference sequence NM_001168272) was recently identified to result in severe pontine and cerebellar hypoplasia [22]. Homozygous, compound heterozygous and heterozygous mutations in ITPR1 could also cause Gillespie syndrome, which features a non-progressive cerebellar ataxia, aniridia, congenital hypotonia, and intellectual sub-normality (MIM #206700) [23, 24].

The important role played by ITPR1 in the cerebellum is also demonstrated by the following facts. First, the ataxin-1, ataxin-2 and ataxin-3 are important players in the IP3 pathway and aberrations in the IP3 pathway have been shown in patients with SCA1, SCA2 or SCA3 [25]. Second, carbonic anhydrase 8 (CA8) is capable of inhibiting IP3 binding to IP3R1. CA8 mutations disrupt the formation of synapses of the Purkinje cells and are associated with an autosomal dominant spinocerebellar ataxia plus mental retardation [26]. Furthermore, autoantibody to IP3R1 may induce autoimmune cerebellar ataxia in the humans [27, 28]. All these evidences support the association between ITPR1 mutations and cerebellar ataxia.

Although ITPR1 mutations have been identified in a small number of cases with inherited cerebellar ataxia, the relevant research in Han Chinese populations remains limited. The aim of this study was to investigate the role of ITPR1 mutations, including both large deletion and single nucleotide mutations, in a Han Chinese cohort with inherited cerebellar ataxias in Taiwan.

Methods and subjects

Patients and ethics statement

Ninety-three individuals with molecularly unassigned SCA, selected from 585 unrelated patients with dominantly inherited cerebellar ataxias, after excluding SCA1, 2, 3, 6, 7, 8, 10, 12, 17, 31, 35, 36 and dentatorubral pallidoluysian atrophy (DRPLA) [2931], were enrolled. Clinical evaluations included standard neurological examination, Scale for the Assessment and Rating of Ataxia (SARA) [32, 33], as well as nerve conduction studies and electromyography. Brain magnetic resonance image (MRI) and magnetic resonance spectroscopy (MRS), focusing on the cerebellar hemispheres and vermis, were also performed to assess the cerebellar atrophy and metabolite changes. The protocol for this study was approved by the institutional review board of Taipei Veterans General Hospital and all the participants had given written informed consents.

Detection of large segmental deletions in ITPR1

Genomic DNA was extracted from the white blood cells in the peripheral blood with standard protocols. We looked for large segmental deletions in ITPR1 utilizing the TaqMan® Copy Number Assays kit on an ABI 7500 Fast Real-Time PCR system (Applied Biosystems, Foster City, CA). Eight TaqMan® detecting probes were selected with reference to those reported previously [34]. All of the detecting probes used in this study are listed in the S1 Table.

Targeted sequencing and variant calling to detect single nucleotide or oligonucleotide variants

Targeted sequencing covering the coding exons and flanking introns of ITPR1 (reference sequence: NM_001168272) was carried out by using SeqCap EZ Choice Enrichment Kits (Roche/Nimblegen) according to the manufacturer’s protocol. The enriched DNA library was subjected to massively parallel sequencing using HiSeq2000 platform (Illumina®) with 100-bp paired-end reads. The generated FASTQ files were aligned to the GRCh38 reference sequence using Novoalign V.2.07.19 and the PICARD tool MarkDuplicates. Calling was performed using SAMtools V.0.18. The resulting calls were annotated with ANNOVAR. Only variants with the following functional consequences: frameshift, stop gain, stop loss, non-synonymous missense or splice site variants and a global minor allele frequency (MAF) < 0.001 (based on the single nucleotide polymorphism database (dbSNP Build 144, http://www.ncbi.nlm.nih.gov/snp/) were kept. Sanger sequencing was used to further validate variants identified by targeted sequencing.

In silico analysis

To predict the pathogenicity of the ITPR1 sequence variants, multiple bioinformatics softwares were used, including MutationTaster (http://www.mutationtaster.org) [35], SIFT (http://sift.jcvi.org) [36], and Combined Annotation Dependent Depletion (CADD) (http://cadd.gs.washington.edu) [37]. Amino acid sequences of IP3R1 orthologs from multiple species were aligned using the UniProt Website (http://www.uniprot.org) to investigate whether the variation occurs on a phylogenetically conserved amino acid.

Results

General information

For the 93 patients with molecularly unassigned autosomal dominant cerebellar ataxia recruited in this study, the average age at symptom onset was 37.2 ± 18.1 years (range from 1 to 74 years). The common symptoms shared by most patients included gait disturbance (87.1%), dysarthria (52.7%) and appendicular incoordination (50.5%). Tremor was observed in only 19.4% of the subjects, and cognitive impairment in 15.1% of the patients. The flow chart outlining selection of the study cohort and demographics of the study cohort could be found in supplementary S1 Fig and S2 Table.

Genetic analyses

We did not identify any individual carrying a large segmental deletion of ITPR1 (S2 Fig). The targeted sequencing panel, which covered the sequences of all 61 exons and exon-intron boundary regions of ITPR1, had a full coverage of the targeted regions and an average depth of 485X for each targeted base. Only one novel missense variant, c.7721T>C (p.V2574A), in exon 58 of ITPR1 was identified to be a potential causal variant. Sanger sequencing confirmed the variant in the proband (II-3) with dominantly inherited cerebellar ataxia and further revealed that the variant was present in her affected daughter (III-1) and absent in her unaffected brother (II-1) (Fig 1). The variant is not present in 1000 Genomes Project data (1000G, http://www.1000genomes.org/), the single nucleotide polymorphism database (dbSNP Build 144, http://www.ncbi.nlm.nih.gov/snp/) or the Genome Aggregation Database (gnomAD) (http://gnomad.broadinstitute.org).

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Fig 1. The pedigree and electropherogram of the patients carrying ITPR1 c.7721T>C mutation.

(A) The pedigree of the individuals carrying ITPR1 p.V2574A (c.7721T>C) mutation in this study. The proband (II-3) is denoted by an arrow. Filled symbols represent symptomatic members, open symbols indicate unaffected individuals, circles stand for females, squares stand for males, WT/WT indicates wild type, and WT/MT stands for individuals harboring the heterozygous mutation. (B) The electropherograms of the patients (II-3 and III-1) carrying the ITPR1 mutation (WT/MT) and a healthy family member (II-1) carrying two alleles of wild type ITPR1. The stars denote the location of the mutation.

https://doi.org/10.1371/journal.pone.0187503.g001

Probing the pathogenicity of the ITPR1 sequence variant c.7721T>C through bioinformatics analyses

In silico analysis with MutationTaster predicted this novel variant c.7721T>C (p.V2574A) as disease-causing with a high probability value of 0.999, indicating a high security of this prediction [35]. SIFT predicted c.7721T>C (p.V2574A) as damaging with a score of 0.01 and the threshold of SIFT score for pathogenicity was ≦ 0.05 [36]. The Combined Annotation Dependent Depletion (CADD) program estimated the Phred score of this sequence variant as 27.2, predicting that ITPR1 p.V2574A was the top 0.19% most deleterious variant in the genome [37]. All of the bioinformatics predictions unanimously supported the pathogenicity of the c.7721T>C (p.V2574A) in ITPR1 (Table 1). The V2574 residue was highly conserved from human to honeybee, which further supported the pathogenic role of ITPR1 p.V2574A (Fig 2B). The sequence change was not observed in 1,062 ethnically matched control chromosomes either.

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Fig 2. The structure of human IP3R1.

(A) The number 1 ~ 19 represent the amino acid residue substitutions reported as far associating with cerebellar ataxia. The blue rectangle represents the IP3 binding region, the red curve line denotes the coupling/regulatory region, and the yellow cylinders stand for the transmembrane segments. (B) The amino acid sequence of the sixth transmembrane segment of human IP3R1 was annotated by the UniProt. The ITPR1 p.V2574A mutation resides in an evolutionarily conserved region, as shown by aligning the amino acid sequences of IP3R1 protein orthologs from various species.

Abbreviation: ER: endoplasmic reticulum

#Remarks: All the nucleotide positions and amino acid residues represented here were converted to the reference sequence of NM_001168272 for CDS and NP_001161744 for protein sequence.

https://doi.org/10.1371/journal.pone.0187503.g002

Clinical characteristics of patients with the ITPR1 mutation

The pedigree of our SCA patients with ITPR1 p.V2574A mutation is shown in Fig 1A. The clinical characteristics of the index case and her offspring were summarized in Table 2. The proband (II-3, Fig 1A) had experienced an insidious and non-progressive gait disturbance since age 30. Upon examination at age 35 years, she was found to have fine tremors over the head and hands, especially when getting nervous, and her hand-writing was sloppy. Mild dysarthria and dysphagia were also noticed. She had normal cognitive functions. The eye movements were full in all directions but with mild saccadic pursuits. There was no focal weakness and the muscle tone was normal. Diffusely decreased deep tendon reflexes were found with flexor plantar responses. There was mild unsteadiness on tandem walking. The latest SARA score was 4.5 at the tenth year after the disease onset (S1 Video). Nerve conduction studies and electromyography were unremarkable. Brain MRI at the tenth year after disease onset demonstrated a few tiny non-specific hyperintense spots in the white matter of cerebral hemispheres on T2-weighted images and a mild atrophy of the cerebellar hemispheres and vermis on T1-weighted images (Fig 3). The MRS revealed NAA/Cr ratios of 1.16, 1.02 and 0.87 in the right cerebellar hemisphere, left cerebellar hemisphere and cerebellar vermis, respectively, indicating a very mild biochemical abnormality.

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Table 2. The clinical characteristics of the cases reported in this paper.

https://doi.org/10.1371/journal.pone.0187503.t002

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Fig 3. Brain MRI of the patients carrying ITPR1 mutation.

The neuroimages of II-3 are shown as A1-E1, and her daughter’s images (III-1) are A2-E2. The T1-weighted sagittal view images denote a mild atrophy of the anterior and posterior lobes of the cerebellar vermis (A1 and A2). The T1-weighted axial view images demonstrate a mild atrophy of the cerebellar hemispheres (B1-C1 and B2-C2). The sizes of the pons and cerebellar peduncles are within normal ranges. The fluid-attenuated inversion recovery (FLAIR) axial view image features normal cerebral cortex, basal ganglia and midbrain (D1-E1 and D2-E2).

https://doi.org/10.1371/journal.pone.0187503.g003

The proband’s daughter (III-1) had experienced a childhood-onset non-progressive cerebellar ataxia and cognitive impairment since age of 7 years. Mild slurred speech, saccadic pursuits and unsteady tandem walking on neurological examination, a SARA score of 5.5 (S2 Video) and mini-mental state examination (MMSE) score of 25 were documented at the 13th year after the symptom onset. The nerve conduction studies were normal. Brain MRI featured a mild atrophy of the cerebellar hemispheres and vermis on the T1-weighted images (Fig 3). There was no obvious biochemical abnormality in the right cerebellar hemisphere, left cerebellar hemisphere or vermis (NAA/Cr ration of 1.55, 1.25 and 1.02, respectively) on MRS at the 13th year after the onset.

Discussion

We identified a novel missense ITPR1 mutation, c.7721T>C (p.V2574A), in a patient with a slowly progressive cerebellar ataxia from 93 unrelated patients with molecularly unassigned SCA. Since these 93 patients were selected from a cohort of 585 unrelated patients with dominantly inherited cerebellar ataxias after a comprehensive genetic testing for SCA, mutation in ITPR1 accounts for 0.2% (1/585) of dominantly inherited cerebellar ataxias in Taiwan. Several lines of evidence support the pathogenicity of this ITPR1 mutation, namely, p.V2574A. First, the sequence change was absent in 1,062 ethnically matched control chromosomes. Second, the variant was absent in several genetic polymorphism databases, including dbSNP, 1000 Genomes Project and gnomAD database. Third, the variant occurs at an evolutionarily conserved amino acid residue of the IP3R1 protein (Fig 2) and a deleterious effect was unanimously predicted by several bioinformatics programs, including MutationTaster [35], SIFT [36] and CADD [37] (Table 1). Furthermore, this variant has a perfect genotype-phenotype co-segregation in the pedigree (Fig 1). These evidences substantially support the pathogenicity of this mutation and classify it as a “likely pathogenic variant” according to the guideline for the interpretation of sequence variants recommended by the American College of Medical Genetics and Genomics and the Association of Molecular Pathology [38].

So far, there have been 16 mutations in ITPR1 associated with autosomal dominant cerebellar ataxia and 5 with dominantly inherited Gillespie syndrome (Table 3 and Fig 2A). Most of the mutations locate in the IP3 binding domain and the coupling/regulatory region of IP3R1. Mutations localized in the coupling/regulatory domain of IP3R1, such as ITPR1 p.P1068L (originally annotated as p.P1059L, reference sequence NM_002222 [6]), might affect the binding affinity and transmission of the IP3 signaling which further disrupts the calcium influx, resulting in cerebellar ataxia [11]. Similar to ITPR1 p.G2580A (annotated as p.G2547A, reference sequence NM_001099952, in the original literature [17]) and p.I2583N (annotated as p.I2550N, reference sequence NM_001099952, in the original literature [22]) mutations, the p.V2574A mutation identified in this study is also situated in the sixth transmembrane domain (S6) adjacent to the S5-S6 pore-loop. As a result, these three mutations might alter the structure of the calcium-selective channel and affect the calcium influx through the channel. Moreover, since the functional IP3R1 is a tetrameric structure [39,40], mutations in the transmembrane domain might disrupt the assembly conformation of the functional channels which is essential for the intracellular calcium release (Fig 2 and S3 Fig).

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Table 3. The molecular and clinical characteristics of ITPR1-associated autosomal dominant cerebellar ataxias in the literature.

https://doi.org/10.1371/journal.pone.0187503.t003

The clinical features of the individuals with ITPR1-associated cerebellar ataxia are quite heterogeneous. Tremors and vermis atrophy are common but not pathognomonic. The onset of ataxia could be in the infantile stage, early childhood [14, 15, 1719, 21], or adulthood [6, 20], and intellectual impairment were frequently found in the individuals with an earlier age at onset of disease. Our pedigree demonstrated a certain diversity in the clinical presentations. The proband (II-3) presented with an adult-onset ataxia but her offspring (III-1) featured a childhood-onset ataxia and intellectual sub-normalities. Both cases demonstrated non-progressive cerebellar ataxia and mild atrophy of the vermis. These inter-familial and intra-familial heterogeneities suggest that there might be modifying factors underlying the pathogenesis of ITPR1-associated cerebellar ataxia.

There are several validated methods to detect copy number variation (CNV) in the genome, including multiplex ligation-dependent probe amplification (MLPA) [12, 41], array comparative genomic hybridization (CGH) [6], qPCR [9, 10, 34] and fine sequence array. We first looked for CNV utilizing the qPCR method with multiple probes covering most of the deletion hot spots but failed to find any ITPR1 large deletions in our cohort. We further surveyed ITPR1 mutations with high throughput targeted sequencing and found an ITPR1 missense mutation. Our findings emphasize the importance of using multiple diagnostic tools to detect both CNV and single nucleotide variants in ITPR1. ITPR1 missense mutations-associated cerebellar ataxia might have been under-estimated prior to the high-throughput sequencing era. Given that IP3R1 consists of 2,743 amino acids and the full-length ITPR1 gene is composed of 10,197 base pairs and 61 exons, it is technically challenging and time- and cost-consuming to perform genetic screening in such a large gene. The diagnostic proficiency has significantly improved with the next generation sequencing technology. Researches focusing on the missense mutation in ITPR1 might be much feasible from now on.

ITPR1 missense mutation is an uncommon but unneglectable cause of cerebellar ataxia in Taiwan. Cases with non-progressive cerebellar ataxia and vermis atrophy might be candidates with mutations in ITPR1. Our findings have broadened the mutational spectrum of ITPR1 and emphasized the role of ITPR1 in cerebellar function.

Supporting information

S1 Table. Probes used in qPCR for detecting copy number variation.

https://doi.org/10.1371/journal.pone.0187503.s001

(DOCX)

S2 Table. Demographics of the study cohort.

https://doi.org/10.1371/journal.pone.0187503.s002

(DOCX)

S1 Fig. Flow chart outlining selection of the study cohort.

https://doi.org/10.1371/journal.pone.0187503.s003

(TIFF)

S2 Fig. Average estimated copy number detected by each probes used in the copy number analysis with qPCR technique.

https://doi.org/10.1371/journal.pone.0187503.s004

(TIFF)

S3 Fig. The crystallographic structure of IP3R1.

https://doi.org/10.1371/journal.pone.0187503.s005

(TIFF)

Acknowledgments

The study was funded by the Ministry of Science and Technology, Taiwan (MOST 103-2314-B-010-049-MY3), Taipei Veterans General Hospital (V103C-109, V104E9-006, V105C-048, V105E9-006-MY2-1, V105D9-006-MY2-2), and the Brain Research Center, National Yang-Ming University (104AC-B19), Republic of China.

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