EA2-causing missense and nonsense mutations in CACNA1A produced mutant channels with diminished whole cell calcium channel activity in vitro due to loss of function. Altered biophysical properties or reduced efficiency of plasma membrane targeting of mutant channels may contribute to abnormal neuromuscular transmission, manifesting as myasthenic syndrome.

Horizontal gaze palsy with progressive scoliosis (HGPS) is a rare, autosomal recessive disorder characterized by a congenital absence of conjugate horizontal eye movement, with progressive scoliosis developing in childhood or adolescence. The authors identified two unrelated consanguineous families with HGPS. Genomewide homozygosity mapping and linkage analysis mapped the disease locus to a 30-cM interval on chromosome 11q23-25 (combined maximum multipoint lod score Z = 5.46).

Synaptopodin is the first member of a novel class of proline-rich actin-associated proteins. In brain, it is present in the neck of a subset of mature telencephalic spines and is associated closely with the spine apparatus, a Ca(2+) storing organelle within the spine compartment. The characteristic region- and lamina-specific distribution of synaptopodin in rat brain suggested that the distribution pattern of synaptopodin depends on the cytoarchitectonic arrangement of spine-bearing neurons. To test this hypothesis, synaptopodin was studied in the cortex, striatum, and hippocampus of normal and reeler mice, in which developmental cell migration defects have disrupted the normal array of cells. In situ hybridization histochemistry as well as light- and electron microscopic immunocytochemistry were used. In brain of normal mice, the pattern of synaptopodin mRNA-expressing cells corresponds to that of spine-bearing neurons and synaptopodin protein is found in a region- and lamina-specific distribution pattern. It is specifically sorted to the spine neck where it is associated closely with the spine apparatus. In brain of reeler mice, the pattern of synaptopodin mRNA-expressing cells corresponds to that of the abnormally positioned spine-bearing neurons and the region- and lamina-specific distribution pattern is absent or altered. Nevertheless, synaptopodin was specifically sorted to the spine neck, as in controls. These data demonstrate that the light microscopic distribution pattern of synaptopodin protein depends on the position and orientation of the spine-bearing neurons. The intracellular sorting process, however, is independent of positional cues.

The cytoarchitecture of the brain is disrupted severely in reeler mice. This is caused by a deficiency in the protein, Reelin, which is essential for the normal migration and positioning of neurons during development. Although cell migration is clearly affected by the reeler mutation, it is believed that the total number of neurons is not. Thus, we were surprised to find an unusually large number of calretinin-immunopositive cells, presumably Cajal-Retzius cells, in the molecular layer of the adult reeler hippocampus (Deller et al. [1999]; Exp. Neurol. 156:239-253). This suggested that the reeler mutation affects the number of neurons in the hippocampus. In order to verify this hypothesis, unbiased stereological methods were employed. Calretinin immunostaining was used as a marker for Cajal-Retzius cells in control as well as reeler mice and Nissl staining was used to identify hippocampal principal neurons. Total numbers of calretinin-immunopositive cells, calretinin-immunoreactive Cajal-Retzius cells, and Nissl-stained neurons were estimated in different subfields of the reeler and the control hippocampus. Stereological estimates (P < 0.05) revealed that the total number of calretinin-immunopositive and Cajal-Retzius cells in reeler mice are 1.5 and 2.1 times that of controls, respectively. No significant difference in total neuron number was found in any hippocampal subfield. These data demonstrate that the reeler mutation affects the number of calretinin-immunoreactive Cajal-Retzius cells in the adult hippocampus, probably due to a reduced excitatory innervation by entorhinal terminals in the absence of reelin. However, the reeler mutation does not affect mechanisms that determine total hippocampal neuron number.