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General Information
Name
spinocerebellar ataxia 15
FlyBase ID
FBhh0000070
Overview

This report includes information relevant to a preliminary model of spinocerebellar ataxia 15 (SCA15), which is a subtype of spinocerebellar ataxia; SCA15 exhibits autosomal dominant inheritance. The human gene implicated in this disease is ITPR1, an inositol 1,4,5-triphosphate (IP3) receptor, an intracellular IP3-gated calcium channel that modulates intracellular calcium signaling. This gene is also associated with the disease spinocerebellar ataxia 29 (OMIM:117360, FBhh0000072, a later-onset form) and Gillespie syndrome (OMIM:206700). There is one high-scoring fly ortholog, Itpr, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. There are two additional genes that encode inositol triphosphate receptors in human, ITPR2 and ITPR3.

The human ITPR1 gene has not been introduced into flies, however, a UAS construct of the rat gene, Rnor\Itpr1 has been. Pan-neuronal expression of Rnor\Itpr1 rescues neuronal phenotypes of Itpr mutants, including wing posture, flight, electrophysiological correlates of flight maintenance, and intracellular calcium dynamics.

Animals homozygous for severe loss-of-function mutations of Dmel\Itpr typically die during the larval stage. Several conditional alleles (cold-sensitive) have been isolated; adults raised at the permissive temperature exhibit phenotypes such as flight defective, locomotor behavior defective, and feeding behavior defective. RNAi-effected knockdown in neural tissues results in neurophysiology and neuroanatomy defects. Genetic and physical interactions of Dmel\Itpr have been described; see below and in the Itpr gene report.

[updated Feb. 2020 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: spinocerebellar ataxia, autosomal dominant
Symptoms and phenotype

The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (Margolis, 2003, pubmed:14628900). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From OMIM:164400, 2015.10.27]

The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias' (SCAs). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord; the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From OMIM:164400, 2015.10.27]

Specific Disease Summary: spinocerebellar ataxia 15
OMIM report

[SPINOCEREBELLAR ATAXIA 15; SCA15](https://omim.org/entry/606658)

Human gene(s) implicated

[INOSITOL 1,4,5-TRIPHOSPHATE RECEPTOR, TYPE 1; ITPR1](https://omim.org/entry/147265)

Symptoms and phenotype

Spinocerebellar ataxia type 15 (SCA15) is characterized by slowly progressive gait and limb ataxia, often in combination with ataxic dysarthria, titubation, upper limb postural tremor, mild hyperreflexia, gaze-evoked nystagmus, and impaired vestibulo-ocular reflex gain. Onset is between ages seven and 72 years, usually with gait ataxia but sometimes with tremor. Affected individuals remain ambulatory for ten to 54 years after symptom onset. Mild dysphagia usually after two or more decades of symptoms has been observed in members of multiple affected families and movement-induced oscillopsia has been described in one member of an affected family. [From GeneReviews, Spinocerebellar Ataxia Type 15, pubmed:20301536, 2015.12.14]

SCA15 is an autosomal dominant, adult-onset, very slowly progressive form of cerebellar ataxia. Most patients also have disabling action and postural tremor, and some have pyramidal tract affection, dorsal column involvement, and gaze palsy. Brain imaging shows cerebellar atrophy mainly affecting the vermis (summary by Synofzik et al., 2011, pubmed:21367767). Heterozygous mutation in the ITPR1 gene can also cause SCA29 (OMIM:117360), which is distinguished by onset in infancy of delayed motor development followed by nonprogressive ataxia and mild cognitive impairment. [From OMIM:606658, 2015.12.15]

Genetics

This form of autosomal dominant spinocerebellar ataxia, SCA15, is caused by heterozygous mutation in the ITPR1 gene as well as by deletions involving the ITPR1 gene. [From OMIM:606658, 2015.10.30]

Cellular phenotype and pathology
Molecular information

The ITPR1 gene encodes the inositol 1,4,5-triphosphate (IP3) receptor, an intracellular IP3-gated calcium channel that modulates intracellular calcium signaling (Berridge, 1993, pubmed:8381210; Hirota et al., 2003, pubmed:12611586). ITPR1 encodes multiple splice isoforms. The long form appears to create an additional consensus protein kinase C phosphorylation site. The long form predominates in most brain regions except for the cerebellum, while the short form predominates in peripheral tissues (Nucifora et al., 1995. pubmed:7500840). [From OMIM:147265, 2015.12.15]

External links
Disease synonyms
SCA15
SCA16
spinocerebellar ataxia 16
spinocerebellar ataxia 15, SCA15
SCA15/16
spinocerebellar ataxia type 15
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)

    Many to one (3 human to 1 Drosophila) (See DIOPT, link below)

    Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Inositol 1,4,5,-trisphosphate receptor (Itpr) encodes an intracellular ligand gated calcium channel. It functions downstream of G-protein coupled receptors that activate Gq/PLCbeta signaling and generate inositol tris-phosphate. Itpr depletion affects ecdysone release, response to nutritional stress, lipid metabolism and flight. [Date last reviewed: 2019-09-26]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human ITPR1, ITPR2, and ITPR3 (1 Drosophila to 3 human).

    Dmel\Itp-r83A shares 57% identity and 70% similarity with human ITPR1, 54% identity and 68% similarity with human ITPR2, and 52% identity and 67% similarity to human ITPR3.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (2 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, western blot
      Alleles Reported to Model Human Disease (Disease Ontology) (9 alleles)
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - molecular evidence
      CRISPR/Cas9
      ethyl methanesulfonate
      ethyl methanesulfonate
      ethyl methanesulfonate
      ethyl methanesulfonate
      loss of function allele
      P-element activity
      References (6)