inositol-1-4-5-trisphosphate and Cerebellar-Ataxia

We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.

Topics: Ataxia; Base Sequence; Biomarkers, Tumor; Cerebellar Ataxia; Consanguinity; DNA Primers; Enzyme Stability; Female; Gait Ataxia; Gait Disorders, Neurologic; Haplotypes; Homozygote; Humans; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Intellectual Disability; Iraq; Male; Mutation, Missense; Pedigree; Signal Transduction; Syndrome

Analysis of the neuropathological mutant animals offers us great information on the development and differentiation of the nervous system. I have here introduced two examples of the analyses of the various kinds of neuropathological mutant mice. First one is the mutant mice where Purkinje neurons in the cerebellum are absent. High molecular weight protein, P400, enriched in the Purikinje cells in the cerebellum was greatly decreased in the Purkinje cell deficient mutant mice, nervous, pcd, Lurcher. We demonstrated that P400 is equivalent to IP3 receptor type 1. We found that IP3 receptor type 1 plays an important role in Ca2+ wave in fertilization and long term depression in the cerebellum which is one of the typical example of neuronal plasticity in the cerebellum. Second mutant is reeler mice where neuronal positioning in the brain is abnormal. We found CR50 antigen, reelin is the key molecule as a secreted molecule from Cajal-Retzius neuron for the neuronal positioning. We produced IP3 receptor deficient mice by gene targeting. The birth rate was one fifth of the control and the animals die before 25 postnatal days. They showed cerebellar ataxia and epileptic seizure.

Topics: Animals; Brain; Brain Chemistry; Calcium Channels; Cerebellar Ataxia; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Mice; Mice, Mutant Strains; Receptors, Cytoplasmic and Nuclear; Reelin Protein