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contains three domains, an N-terminal inositol triphosphate binding domain, a coupling domain, and a C-terminal transmembrane domain; it also contains two protein kinase A phosphorylation sites and an ATP-binding site. Itpr1 is coupled to Ca2+ channels and facilitates Ca2+ release from the endoplasmic reticulum after binding by the intracellular second messenger inositol 1,4,5-triphosphate [9]. Itpr1 is enriched in the Purkinje cells of the cerebellum [4]. ITPR1 mutations have more than one potential pathogenic mechanism. First, the disease may be a result of haploinsufficiency at ITPR1; this concept is consistent with the observation that heterozygous deletion leads to a later onset disorder in humans, whereas homozygous deletion in mice leads to an early onset disorder, able to be expressed within the much shorter life span of the mouse. Second, we cannot rule out the existence of an alternate start site for ITPR1 that may result in a product that confers a pathogenic gain of function to the protein; however, Western blot analysis of cells derived from affected AUS1 family members, which was performed using an antibody raised against the C-terminal portion of ITPR1, failed to identify any disease-specific truncated protein products. Clearly, the identification of distinct ITPR1 mutations underlying SCA15 will help elucidate the pathogenic mechanism of this disorder."}

{"project":"2_test","denotations":[{"id":"17590087-10426189-85657855","span":{"begin":400,"end":401},"obj":"10426189"},{"id":"17590087-8538767-85657856","span":{"begin":463,"end":464},"obj":"8538767"},{"id":"T70545","span":{"begin":400,"end":401},"obj":"10426189"},{"id":"T38629","span":{"begin":463,"end":464},"obj":"8538767"}],"text":"Itpr1 contains three domains, an N-terminal inositol triphosphate binding domain, a coupling domain, and a C-terminal transmembrane domain; it also contains two protein kinase A phosphorylation sites and an ATP-binding site. Itpr1 is coupled to Ca2+ channels and facilitates Ca2+ release from the endoplasmic reticulum after binding by the intracellular second messenger inositol 1,4,5-triphosphate [9]. Itpr1 is enriched in the Purkinje cells of the cerebellum [4]. ITPR1 mutations have more than one potential pathogenic mechanism. First, the disease may be a result of haploinsufficiency at ITPR1; this concept is consistent with the observation that heterozygous deletion leads to a later onset disorder in humans, whereas homozygous deletion in mice leads to an early onset disorder, able to be expressed within the much shorter life span of the mouse. Second, we cannot rule out the existence of an alternate start site for ITPR1 that may result in a product that confers a pathogenic gain of function to the protein; however, Western blot analysis of cells derived from affected AUS1 family members, which was performed using an antibody raised against the C-terminal portion of ITPR1, failed to identify any disease-specific truncated protein products. Clearly, the identification of distinct ITPR1 mutations underlying SCA15 will help elucidate the pathogenic mechanism of this disorder."}