Development of a Multiplex Ligation-Dependent Probe Amplification Assay for Diagnosis and Estimation of the Frequency of Spinocerebellar Ataxia Type 15

Ganesamoorthy, Devika; Bruno, Damien L.; Schoumans, Jacqueline; Storey, Elsdon; Delatycki, Martin B.; Zhu, Danqing; Wei, M.; Nicholson, Garth A.; Gardner, R. J McKinlay; Slater, Howard R.

doi:10.1373/clinchem.2009.124958

Cited by 40 publications

(48 citation statements)

References 10 publications

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“…Figure 1, 13 different ITPR1 gene deletions have been previously described. 4,[6][7][8][9][10][11] As shown in the present study, we confirmed that the present probe sets could detect ITPR1 deletion, and we further identified a new family with such mutation. It should be reminded that the present TaqMan system could overlook small deletions in ITPR1, but such small deletion is thought to be extremely rare from the following two reasons.…”

Section: Resultssupporting

confidence: 87%

“…The other is that previous studies using multiplex ligation-dependent prove amplification assay, a comprehensive technique detecting small deletion in any exons, did not find such small deletions in their cohort. 9,10 From these points, we consider that the present screening system using four sets of primers and probes is a feasible and efficient technique to screen heterozygous ITPR1 deletions in a large sample set.…”

Section: Resultsmentioning

confidence: 99%

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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

et al. 2012

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Spinocerebellar ataxia type 15 (SCA15) is an autosomal dominant neurodegenerative disorder clinically characterized by late-onset, slowly progressive pure cerebellar ataxia. This disease is caused by a heterozygous deletion of the inositol 1, 4, 5-triphosphate receptor type 1 (ITPR1) gene, suggesting that haploinsufficiency of the receptor function is the plausible disease mechanism. To clarify the prevalence of SCA15 in Japan, we designed four sets of probes and primers in different regions of ITPR1 and performed TaqMan PCR assay to search for gene deletions in 226 index SCA patients excluded for repeat expansion disorders. Deletion was found in only one patient, in whom gait ataxia started at 51 years of age and progressed to show cerebellar ataxia. This study demonstrates a simple but efficient method for screening ITPR1 deletion. We also conclude that ITPR1 gene deletions are much rare in Japan than in Europe, comprising only 0.3% in all SCAs in Japan.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

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

et al. 2012

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“…SCA15 is a recently identified autosomal dominant spinocerebellar ataxia, described in only seven families worldwide, three Japanese, two Australian, and two of British origin [5,[7][8][9][10][11][12]. A partial deletion of the ITPR1 gene was invariably detected in all cases except for a Japanese family in which a missense P1059L mutation has been suggested as causative [12].…”

Section: Discussionmentioning

confidence: 99%

“…SCA15 locus has been mapped in an Australian family on chromosome 3p24.2-pter [7]. Subsequently, partial deletions of the inositol triphosphate receptor type I gene (ITPR1) have been identified in the original SCA15 family and in other five ADCA pedigrees originating from Australia (n= 1), Japan (n=2, one of whom was previously classified as SCA16), and UK (n=2) [9][10][11][12]. In addition, a possible missense mutation in the same gene was found in a Japanese family [12].…”

Section: Introductionmentioning

confidence: 99%

Two Italian Families with ITPR1 Gene Deletion Presenting a Broader Phenotype of SCA15

et al. 2010

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Spinocerebellar ataxia type15 (SCA15) is a pure ataxia characterized by very slow progression. Only seven families have been identified worldwide, in which partial deletions and a missense mutation of the inositol triphosphate receptor type I gene (ITPR1) have been reported. We examined a four-generation Italian family segregating an autosomal dominant cerebellar ataxia, in which linkage analysis was positive for the SCA15 locus. We performed a genomic real-time polymerase chain reaction to search for ITPR1 gene deletions in this family and in 60 SCA index cases negative for mutations in the SCA1-3, 6-8, 10, 12,and dentatorubral-pallidoluysian atrophy genes. The deleted segments were characterized using a custom array comparative genomic hybridization analysis. We have identified two families with an ITPR1 gene deletion: in one, the deletion involved ITPR1 only, while in the other both sulfatase-modifying factor 1 and ITPR1. Clinical data of ten patients and brain MRI (available for six) showed that the phenotype substantially overlapped known SCA15 cases,but we also noted buccolingual dyskinesias, facial myokymias,and pyramidal signs never reported in SCA15. ITPR1 expression analysis of two deleted cases showed a half dose. Our results further support ITPR1 gene as causative of SCA15. The families reported show that SCA15 is present in Italy and has a greater variability in the age at onset and clinical features than previously reported. We propose that the search for ITPR1 deletions is mandatory in the clinical hypothesis of SCA15 and that ITPR1-reduced expression in blood may be a useful marker to identify SCA15 patients harboring genomic deletions and possibly point mutations causing reduction of mRNA level.

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“…As no duplications or deletions of SLC33A1 have been reported so far, no positive control was available. However, the technique can be regarded as rather robust, and homemade probe sets developed by other groups (ie, Ganesamoorthy et al 20 ), as well as by our groups (unpublished), have been successfully used in unambiguously detecting copy number alterations. Moreover, high overall data quality (data not shown) argues for the applicability of this assay; therefore, we believe that our findings are not likely to be false negative.…”

Section: Methodsmentioning

confidence: 99%

A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42)

et al. 2010

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The most frequent causes of autosomal dominant (AD) hereditary spastic paraplegias (HSP) (ADHSP) are mutations in the SPAST gene (SPG4 locus). However, roughly 60% of patients are negative for SPAST mutations, despite their family history being compatible with AD inheritance. A mutation in the gene for an acetyl-CoA transporter (SLC33A1) has recently been reported in one Chinese family to cause ADHSP-type SPG42. In this study, we screened 220 independent SPAST mutationnegative ADHSP samples for mutations in the SLC33A1 gene by high-resolution melting curve analysis. Conspicuous samples were validated by direct sequencing. Moreover, copy number variations affecting SLC33A1 were screened by multiplex ligation-dependent probe amplification assay. We could not identify potentially disease-causing mutations in our patients either by mutation scanning or by gene dosage analysis, as for the latter specific positive controls are not available to date. As our sample represents ADHSP patients for whom SPAST mutations and almost in all cases ATL1 and REEP1 mutations had been excluded, we consider SLC33A1 gene mutations as being very rare in a European ADHSP cohort, if present at all. To date, as SPG42 has still not been identified in a second, unrelated family, systematic genetic testing for SLC33A1 mutations is not recommended.

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Development of a Multiplex Ligation-Dependent Probe Amplification Assay for Diagnosis and Estimation of the Frequency of Spinocerebellar Ataxia Type 15

Cited by 40 publications

References 10 publications

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

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

Two Italian Families with ITPR1 Gene Deletion Presenting a Broader Phenotype of SCA15

A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42)

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