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.
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.
Citation: Hsiao C-T, Liu Y-T, Liao Y-C, Hsu T-Y, Lee Y-C, Soong B-W (2017) Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias. PLoS ONE 12(11): e0187503. https://doi.org/10.1371/journal.pone.0187503
Editor: Francesc Palau, Sant Joan de Déu Children′s Hospital, SPAIN
Received: March 27, 2017; Accepted: October 20, 2017; Published: November 29, 2017
Copyright: © 2017 Hsiao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: 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.
Competing interests: The authors have declared that no competing interests exist.
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 . 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) . Soon, patients with similar ITPR1 mutations were also identified in Japanese families and Caucasian pedigrees in France and United States [5–10]. 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) [13–20]. 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 , while an ITPR1 missense mutation (p.I2583N, reference sequence NM_001168272) was recently identified to result in severe pontine and cerebellar hypoplasia . 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 . 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 . 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) [29–31], 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 . 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) , SIFT (http://sift.jcvi.org) , and Combined Annotation Dependent Depletion (CADD) (http://cadd.gs.washington.edu) . 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.
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.
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).
(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.
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 . 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 . 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 . 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.
(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.
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.
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).
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.
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 , SIFT  and CADD  (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 .
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 ), might affect the binding affinity and transmission of the IP3 signaling which further disrupts the calcium influx, resulting in cerebellar ataxia . Similar to ITPR1 p.G2580A (annotated as p.G2547A, reference sequence NM_001099952, in the original literature ) and p.I2583N (annotated as p.I2550N, reference sequence NM_001099952, in the original literature ) 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).
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, 17–19, 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) , 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.
S1 Table. Probes used in qPCR for detecting copy number variation.
S1 Fig. Flow chart outlining selection of the study cohort.
S2 Fig. Average estimated copy number detected by each probes used in the copy number analysis with qPCR technique.
S3 Fig. The crystallographic structure of IP3R1.
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.
- 1. Foskett JK, White C, Cheung KH, Mak DO. Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev. 2007;87(2):593–658. pmid:17429043
- 2. Nakanishi S, Maeda N, Mikoshiba K. Immunohistochemical localization of an inositol 1,4,5-trisphosphate receptor, P400, in neural tissue: studies in developing and adult mouse brain. The Journal of neuroscience: the official journal of the Society for Neuroscience. 1991;11(7):2075–86. Epub 1991/07/01. pmid:1648604.
- 3. Yamada N, Makino Y, Clark RA, Pearson DW, Mattei MG, Guenet JL, et al. Human inositol 1,4,5-trisphosphate type-1 receptor, InsP3R1: structure, function, regulation of expression and chromosomal localization. Biochem J. 1994;302:781–90. Epub 1994/09/15. pmid:7945203
- 4. van de Leemput J, Chandran J, Knight MA, Holtzclaw LA, Scholz S, Cookson MR, et al. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS genetics. 2007;3(6):e108. Epub 2007/06/26. pmid:17590087
- 5. Knight MA, Kennerson ML, Anney RJ, Matsuura T, Nicholson GA, Salimi-Tari P, et al. Spinocerebellar ataxia type 15 (sca15) maps to 3p24.2-3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant. Neurobiol Dis. 2003;13(2):147–57. Epub 2003/06/28. pmid:12828938.
- 6. Hara K, Shiga A, Nozaki H, Mitsui J, Takahashi Y, Ishiguro H, et al. Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families. Neurology. 2008;71(8):547–51. Epub 2008/06/27. pmid:18579805.
- 7. Di Gregorio E, Orsi L, Godani M, Vaula G, Jensen S, Salmon E, et al. Two Italian families with ITPR1 gene deletion presenting a broader phenotype of SCA15. Cerebellum. 2010;9(1):115–23. Epub 2010/01/19. pmid:20082166.
- 8. Novak MJ, Sweeney MG, Li A, Treacy C, Chandrashekar HS, Giunti P, et al. An ITPR1 gene deletion causes spinocerebellar ataxia 15/16: a genetic, clinical and radiological description. Movement disorders: official journal of the Movement Disorder Society. 2010;25(13):2176–82. Epub 2010/07/30. pmid:20669319.
- 9. Castrioto A, Prontera P, Di Gregorio E, Rossi V, Parnetti L, Rossi A, et al. A novel spinocerebellar ataxia type 15 family with involuntary movements and cognitive decline. European journal of neurology. 2011;18(10):1263–5. Epub 2011/03/09. pmid:21382133.
- 10. Marelli C, van de Leemput J, Johnson JO, Tison F, Thauvin-Robinet C, Picard F, et al. SCA15 due to large ITPR1 deletions in a cohort of 333 white families with dominant ataxia. Arch Neurol. 2011;68(5):637–43. Epub 2011/05/11. pmid:21555639
- 11. Yamazaki H, Nozaki H, Onodera O, Michikawa T, Nishizawa M, Mikoshiba K. Functional characterization of the P1059L mutation in the inositol 1,4,5-trisphosphate receptor type 1 identified in a Japanese SCA15 family. Biochemical and biophysical research communications. 2011;410(4):754–8. Epub 2011/06/22. pmid:21689634.
- 12. Ganesamoorthy D, Bruno DL, Schoumans J, Storey E, Delatycki MB, Zhu D, et al. Development of a multiplex ligation-dependent probe amplification assay for diagnosis and estimation of the frequency of spinocerebellar ataxia type 15. Clinical chemistry. 2009;55(7):1415–8. Epub 2009/05/09. pmid:19423733.
- 13. Dudding TE, Friend K, Schofield PW, Lee S, Wilkinson IA, Richards RI. Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus. Neurology. 2004;63(12):2288–92. Epub 2004/12/30. pmid:15623688.
- 14. Huang L, Chardon JW, Carter MT, Friend KL, Dudding TE, Schwartzentruber J, et al. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet journal of rare diseases. 2012;7:67. Epub 2012/09/19. pmid:22986007
- 15. Ohba C, Osaka H, Iai M, Yamashita S, Suzuki Y, Aida N, et al. Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood. Neurogenetics. 2013;14(3–4):225–32. Epub 2013/10/05. pmid:24091540.
- 16. Fogel BL, Lee H, Deignan JL, Strom SP, Kantarci S, Wang X, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA neurology. 2014;71(10):1237–46. Epub 2014/08/19. pmid:25133958
- 17. Gonzaga-Jauregui C, Harel T, Gambin T, Kousi M, Griffin LB, Francescatto L, et al. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell reports. 2015;12(7):1169–83. Epub 2015/08/11. pmid:26257172
- 18. Sasaki M, Ohba C, Iai M, Hirabayashi S, Osaka H, Hiraide T, et al. Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene. Journal of neurology. 2015;262(5):1278–84. Epub 2015/03/22. pmid:25794864.
- 19. Barresi S, Niceta M, Alfieri P, Brankovich V, Piccini G, Bruselles A, et al. Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia. Clin Genet. 2016. Epub 2016/04/12. pmid:27062503.
- 20. Shadrina MI, Shulskaya MV, Klyushnikov SA, Nikopensius T, Nelis M, Kivistik PA, et al. ITPR1 gene p.Val1553Met mutation in Russian family with mild Spinocerebellar ataxia. Cerebellum Ataxias. 2016;3:2. Epub 2016/01/16. pmid:26770814
- 21. Parolin Schnekenberg R, Perkins EM, Miller JW, Davies WI, D′Adamo MC, Pessia M, et al. De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain. 2015;138(Pt 7):1817–32. pmid:25981959
- 22. van Dijk T, Barth P, Reneman L, Appelhof B, Baas F, Poll-The BT. A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: Expanding the phenotype of ITPR1-related spinocerebellar ataxia′s. American journal of medical genetics Part A. 2017;173(1):207–12. Epub 2016/11/20. pmid:27862915.
- 23. Gerber S, Alzayady KJ, Burglen L, Bremond-Gignac D, Marchesin V, Roche O, et al. Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome. Am J Hum Genet. 2016;98(5):971–80. Epub 2016/04/26. pmid:27108797
- 24. McEntagart M, Williamson KA, Rainger JK, Wheeler A, Seawright A, De Baere E, et al. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect. Am J Hum Genet. 2016;98(5):981–92. Epub 2016/04/26. pmid:27108798
- 25. Bezprozvanny I. Role of inositol 1,4,5-trisphosphate receptors in pathogenesis of Huntington′s disease and spinocerebellar ataxias. Neurochemical research. 2011;36(7):1186–97. Epub 2011/01/07. pmid:21210219
- 26. Turkmen S, Guo G, Garshasbi M, Hoffmann K, Alshalah AJ, Mischung C, et al. CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS genetics. 2009;5(5):e1000487. Epub 2009/05/23. pmid:19461874
- 27. Jarius S, Scharf M, Begemann N, Stocker W, Probst C, Serysheva II, et al. Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia. Journal of neuroinflammation. 2014;11:206. Epub 2014/12/17. pmid:25498830
- 28. Jarius S, Wildemann B. ‘Medusa-head ataxia’: the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: Anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII. Journal of neuroinflammation. 2015;12:166. Epub 2015/09/18. pmid:26377085
- 29. Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, et al. Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012;72(6):859–69. pmid:23280837
- 30. Hsiao CT, Tsai PC, Liao YC, Lee YC, Soong BW. C9ORF72 repeat expansion is not a significant cause of late onset cerebellar ataxia syndrome. J Neurol Sci. 2014;347(1–2):322–4. pmid:25467142.
- 31. Lee YC, Tsai PC, Guo YC, Hsiao CT, Liu GT, Liao YC, et al. Spinocerebellar ataxia type 36 in the Han Chinese. Neurol Genet. 2016;2(3):e68. pmid:27123487
- 32. Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66(11):1717–20. Epub 2006/06/14. pmid:16769946.
- 33. Lee YC, Liao YC, Wang PS, Lee IH, Lin KP, Soong BW. Comparison of cerebellar ataxias: A three-year prospective longitudinal assessment. Movement disorders: official journal of the Movement Disorder Society. 2011;26(11):2081–7. Epub 2011/06/01. pmid:21626567.
- 34. Obayashi M, Ishikawa K, Izumi Y, Takahashi M, Niimi Y, Sato N, et al. Prevalence of inositol 1, 4, 5-triphosphate receptor type 1 gene deletion, the mutation for spinocerebellar ataxia type 15, in Japan screened by gene dosage. Journal of human genetics. 2012;57(3):202–6. Epub 2012/02/10. pmid:22318346.
- 35. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nature methods. 2010;7(8):575–6. Epub 2010/08/03. pmid:20676075.
- 36. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature protocols. 2009;4(7):1073–81. Epub 2009/06/30. pmid:19561590.
- 37. Kircher M, Witten DM, Jain P, O′Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nature genetics. 2014;46(3):310–5. Epub 2014/02/04. pmid:24487276
- 38. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine: official journal of the American College of Medical Genetics. 2015;17(5):405–24. Epub 2015/03/06. pmid:25741868
- 39. Fan G, Baker ML, Wang Z, Baker MR, Sinyagovskiy PA, Chiu W, et al. Gating machinery of InsP3R channels revealed by electron cryomicroscopy. Nature. 2015;527(7578):336–41. Epub 2015/10/13. pmid:26458101
- 40. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera—a visualization system for exploratory research and analysis. Journal of computational chemistry. 2004;25(13):1605–12. Epub 2004/07/21. pmid:15264254.
- 41. Synofzik M, Beetz C, Bauer C, Bonin M, Sanchez-Ferrero E, Schmitz-Hubsch T, et al. Spinocerebellar ataxia type 15: diagnostic assessment, frequency, and phenotypic features. Journal of medical genetics. 2011;48(6):407–12. Epub 2011/03/04. pmid:21367767.