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is improbable that heterozygosity for the deletion of SUMF1, encoding sulfatase modifying factor 1, of itself causes or contributes to SCA15. Homozygous mutation of SUMF1 results in autosomal recessive multiple sulfatase deficiency, a metabolic disorder characterized by hepatosplenomegaly, deafness, and developmental delay [6,7]. No co-occurrence of ataxia has been described in (heterozygous) parents of patients with multiple sulfatase deficiency. Conversely, mutation of ITPR1 is biologically plausible as a cause of ataxia: the protein is highly expressed in Purkinje cells; as we have shown here, mice with mutation at this locus present with ataxia; and perturbed Ca2+ signaling has previously been implicated in the etiology of ataxia, notably in episodic ataxia type 2 and SCA6 [8]. In further support of this conclusion, analysis of protein levels of ITPR1 in Epstein-Barr virus (EBV) immortalized lymphocytes from affected and unaffected AUS1 family members revealed that all affected members showed a dramatic decrease in ITPR1 levels when compared with the family member without the deletion (Figure 4)."}

{"project":"2_test","denotations":[{"id":"17590087-12757706-85657852","span":{"begin":329,"end":330},"obj":"12757706"},{"id":"17590087-15146462-85657853","span":{"begin":331,"end":332},"obj":"15146462"},{"id":"17590087-8988170-85657854","span":{"begin":792,"end":793},"obj":"8988170"},{"id":"T64473","span":{"begin":329,"end":330},"obj":"12757706"},{"id":"T55562","span":{"begin":331,"end":332},"obj":"15146462"},{"id":"T45916","span":{"begin":792,"end":793},"obj":"8988170"}],"text":"It is improbable that heterozygosity for the deletion of SUMF1, encoding sulfatase modifying factor 1, of itself causes or contributes to SCA15. Homozygous mutation of SUMF1 results in autosomal recessive multiple sulfatase deficiency, a metabolic disorder characterized by hepatosplenomegaly, deafness, and developmental delay [6,7]. No co-occurrence of ataxia has been described in (heterozygous) parents of patients with multiple sulfatase deficiency. Conversely, mutation of ITPR1 is biologically plausible as a cause of ataxia: the protein is highly expressed in Purkinje cells; as we have shown here, mice with mutation at this locus present with ataxia; and perturbed Ca2+ signaling has previously been implicated in the etiology of ataxia, notably in episodic ataxia type 2 and SCA6 [8]. In further support of this conclusion, analysis of protein levels of ITPR1 in Epstein-Barr virus (EBV) immortalized lymphocytes from affected and unaffected AUS1 family members revealed that all affected members showed a dramatic decrease in ITPR1 levels when compared with the family member without the deletion (Figure 4)."}