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 <i>ITPR1</i>‐related spinocerebellar ataxia's

Dijk, Tessa van; Barth, Peter; Reneman, Liesbeth; Appelhof, Bart; Baas, Frank; Poll-Thé, Bwee Tien

doi:10.1002/ajmg.a.37962

Cited by 35 publications

(40 citation statements)

References 25 publications

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“…The presentation for this patient was also nonprogressive but was much more severe in both clinical and radiological features than the patients reported here [27]. …”

Section: Resultsmentioning

confidence: 61%

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia

Zambonin

Bellomo

Ben‐Pazi

et al. 2017

Orphanet J Rare Dis

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BackgroundSpinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible.ResultsClinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3–12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort.ConclusionsOur findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0672-7) contains supplementary material, which is available to authorized users.

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“…The presentation for this patient was also nonprogressive but was much more severe in both clinical and radiological features than the patients reported here [27]. …”

Section: Resultsmentioning

confidence: 61%

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia

Zambonin

Bellomo

Ben‐Pazi

et al. 2017

Orphanet J Rare Dis

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“…Mutation of residues I2550 (Zambonin et al, 2017, van Dijk et al, 2017) and V2541 (Hsiao et al, 2017) in ITPR1 also result in ataxia symptoms. Similar to residues in the LBD and selectivity filter, residue I2550 is also associated with multiple diseases as mutation I2550N is causative for pontocerebellar hypoplasia (PCH), while mutation I2550T is causative for SCA29 (Zambonin et al, 2017, van Dijk et al, 2017).…”

Section: Ip3r Mutations Associated With Human Disease By Domain: Mutamentioning

confidence: 99%

“…Similar to residues in the LBD and selectivity filter, residue I2550 is also associated with multiple diseases as mutation I2550N is causative for pontocerebellar hypoplasia (PCH), while mutation I2550T is causative for SCA29 (Zambonin et al, 2017, van Dijk et al, 2017). The I2550 residue has been previously identified as potentially structurally significant as it may serve as a constriction site in the channel pore (Baker et al, 2017, Fan et al, 2015, Bhanumathy et al, 2012).…”

Section: Ip3r Mutations Associated With Human Disease By Domain: Mutamentioning

confidence: 99%

Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

et al. 2018

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Summary Calcium release into the cytosol via the inositol 1,4,5-trisphosphate receptor (IP3R) calcium channel is important for a variety of cellular processes. As a result, impairment or inhibition of this release can result in disease. Recently, mutations in all four domains of the IP3R have been suggested to cause diseases such as ataxia, cancer, and anhidrosis; however, most of these mutations have not been functionally characterized. In this review we summarize the reported mutations, as well as the associated symptoms. Additionally, we use clues from transgenic animals, receptor stoichiometry, and domain location of mutations to speculate on the effects of individual mutations on receptor structure and function and the overall mechanism of disease.

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“…Ip3r1 is predominantly expressed in the central nervous system (CNS), especially in cerebellar Purkinje cells (PCs) (Furuichi et al, 1993). Ip3r1 gene mutations in humans are associated with different types of autosomal dominant spinocerebellar ataxia (SCA) including late-onset spinocerebellar ataxia type 15 (SCA15) (Hara et al, 2008; Marelli et al, 2011; Obayashi et al, 2012; Tipton et al, 2017; van de Leemput et al, 2007; van Dijk et al, 2017), congenital nonprogressive spinocerebellar ataxia and mild cognitive impairment (SCA29) (Huang et al, 2012; Klar et al, 2017; Wang et al, 2018; Zambonin et al, 2017), infantile-onset cerebellar ataxia with mild cognitive deficit (Sasaki et al, 2015), and childhood-onset ataxic cerebellar palsy with moderate intellectual disability (Parolin Schnekenberg et al, 2015). Recently, mutations in the Ip3r1 gene were identified in patients with Gillespie syndrome.…”

Section: Introductionmentioning

confidence: 99%

A missense mutation of Ip3r1 in Dp2 mice leads to short-term mydriasis and unfolded protein response in the iris constrictor muscles

Chen

et al. 2018

Preprint

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Ip3r1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. Mutations in the Ip3r1 gene in humans may cause Gillespie syndrome (GS) typically presents as fixed dilated pupils in affected infants, which was referred to as iris hypoplasia. However, there is no report of mice with Ip3r1 heterozygous mutations showing dilated pupils. Here, we report a new Ip3r1 allele (dilated pupil 2; Dp2) with short-term dilated pupil phenotype derived from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. This allele carries a G5927A transition mutation, which is predicted to result in a C1976Y amino acid change in the open reading frame. Histology and pharmacological tests show that the dilated pupil phenotype is a mydriasis caused by the functional defect in the iris constrictor muscles in Dp2. The dilated pupil phenotype in Dp2 was referred to as mydriasis and excluding iris hypoplasia. IHC analysis revealed increased expression of BIP protein, the master regulator of unfolded protein response (UPR) signaling, in Dp2 mice that did not recover. Apart from the dilated pupil phenotype (mydriasis), there are no other abnormal phenotypes including Ip3r1-related ataxia that may be found. This study is the first report of an Ip3r1 mutation being associated with the mydriasis phenotype. Dp2 mice represent a valuable self-healing model that may be used to study the therapeutic approach for Ip3r1-related diseases or diseases caused by similar pathomechanisms.

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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

Cited by 35 publications

References 25 publications

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia

Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

A missense mutation of Ip3r1 in Dp2 mice leads to short-term mydriasis and unfolded protein response in the iris constrictor muscles

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