The nematode Caenorhabditis briggsae is an emerging model organism that allows evolutionary comparisons with C. elegans and exploration of its own unique biological attributes. To produce a high-resolution C. briggsae recombination map, recombinant inbred lines were generated from reciprocal crosses between two strains and genotyped at over 1,000 loci. A second set of recombinant inbred lines involving a third strain was also genotyped at lower resolution. The resulting recombination maps exhibit discrete domains of high and low recombination, as in C. elegans, indicating these are a general feature of Caenorhabditis species. The proportion of a chromosome's physical size occupied by the central, low-recombination domain is highly correlated between species. However, the C. briggsae intra-species comparison reveals striking variation in the distribution of recombination between domains. Hybrid lines made with the more divergent pair of strains also exhibit pervasive marker transmission ratio distortion, evidence of selection acting on hybrid genotypes. The strongest effect, on chromosome III, is explained by a developmental delay phenotype exhibited by some hybrid F2 animals. In addition, on chromosomes IV and V, cross direction-specific biases towards one parental genotype suggest the existence of cytonuclear epistatic interactions. These interactions are discussed in relation to surprising mitochondrial genome polymorphism in C. briggsae, evidence that the two strains diverged in allopatry, the potential for local adaptation, and the evolution of Dobzhansky-Muller incompatibilities. The genetic and genomic resources resulting from this work will support future efforts to understand inter-strain divergence as well as facilitate studies of gene function, natural variation, and the evolution of recombination in Caenorhabditis nematodes.

Despite a growing number of ion channel genes implicated in hereditary ataxia, it remains unclear how ion channel mutations lead to loss-of-function or death of cerebellar neurons. Mutations in the geneKCNMA1, encoding the α-subunit of the BK channel have emerged as responsible for a variety of neurological phenotypes. We describe a mutation (BKG354S) inKCNMA1, in a child with congenital and progressive cerebellar ataxia with cognitive impairment. The mutation in the BK channel selectivity filter dramatically reduced single-channel conductance and ion selectivity. The BKG354Schannel trafficked normally to plasma, nuclear, and mitochondrial membranes, but caused reduced neurite outgrowth, cell viability, and mitochondrial content. Small interfering RNA (siRNA) knockdown of endogenous BK channels had similar effects. The BK activator, NS1619, rescued BKG354Scells but not siRNA-treated cells, by selectively blocking the mutant channels. When expressed in cerebellum via adenoassociated virus (AAV) viral transfection in mice, the mutant BKG354Schannel, but not the BKWTchannel, caused progressive impairment of several gait parameters consistent with cerebellar dysfunction from 40- to 80-d-old mice. Finally, treatment of the patient with chlorzoxazone, a BK/SK channel activator, partially improved motor function, but ataxia continued to progress. These studies indicate that a loss-of-function BK channel mutation causes ataxia and acts by reducing mitochondrial and subsequently cellular viability.

BackgroundThe nematode C. briggsae serves as a useful model organism for comparative analysis of developmental and behavioral processes. The amenability of C. briggsae to genetic manipulations and the availability of its genome sequence have prompted researchers to study evolutionary changes in gene function and signaling pathways. These studies rely on the availability of forward genetic tools such as mutants and mapping markers.ResultsWe have computationally identified more than 30,000 polymorphisms (SNPs and indels) in C. briggsae strains AF16 and HK104. These include 1,363 SNPs that change restriction enzyme recognition sites (snip-SNPs) and 638 indels that range between 7 bp and 2 kb. We established bulk segregant and single animal-based PCR assay conditions and used these to test 107 polymorphisms. A total of 75 polymorphisms, consisting of 14 snip-SNPs and 61 indels, were experimentally confirmed with an overall success rate of 83%. The utility of polymorphisms in genetic studies was demonstrated by successful mapping of 12 mutations, including 5 that were localized to sub-chromosomal regions. Our mapping experiments have also revealed one case of a misassembled contig on chromosome 3.ConclusionsWe report a comprehensive set of polymorphisms in C. briggsae wild-type strains and demonstrate their use in mapping mutations. We also show that molecular markers can be useful tools to improve the C. briggsae genome sequence assembly. Our polymorphism resource promises to accelerate genetic and functional studies of C. briggsae genes.

Dyskinesia in Parkinson disease (PD) usually involves the neck, trunk, limbs, and face.1-3 Isolated or predominant respiratory involvement is rarely reported, and can lead to inappropriate cardiopulmonary tests and management. We report successful diagnosis and treatment of such a case for the first time using bilateral subthalamic nucleus deep brain stimulation (STN DBS). Classification of evidence. This is a single observation without control (Class IV).Case report. A 64-year-old right-handed man with an 8-year history of PD presented with respiratory distress. His PD started with resting tremor, bradykinesia, and rigidity in his right hand, which gradually spread to the other side. His parkinsonism responded well to carbidopa/levodopa, with dosages being gradually escalated to 25/250 mg strength 1 tablet QID, until about 10 months prior to his visit, when he developed apparent respiratory distress, with involuntary rapid, strenuous, and distressful breathing (video clip 1 on the Neurology ® Web site at Neurology.org), accompanied by anxiety and mild tremor of the hands. He had these spells several times daily, lasting about 2 hours each time, leading to several emergent visits and hospitalizations for extensive workups, including EKG, stress echocardiogram, pulmonary function, and chest CT pulmonary embolism protocol, but none was revealing.After carefully checking his diary, we found that the respiratory distress started about 1 hour after 1 tablet of 25/250 mg strength carbidopa/levodopa, which lasted for 2 hours, as also confirmed by our prolonged observation in clinic. We hypothesized that his isolated respiratory distress was peak-dose respiratory dyskinesia, although we also had to rule out other possibilities, such as akathisia, given his anxiety, or nonmotor respiratory dysrhythmia.To test these hypotheses, we first added an additional tablet of 25/100 mg strength carbidopa/levodopa on each dose, which made his respiratory distress much worse, suggesting dyskinesia as the cause of his respiratory distress. We then reduced the carbidopa/ levodopa to 25/100 mg each dose, which led to complete resolution of the respiratory distress but aggravated his parkinsonism (video clip 2).We then resumed 25/250 mg carbidopa/levodopa every 6 hours QID with additional amantadine 100 mg bid, which did not improve his respiratory symptoms. We therefore reduced carbidopa/levodopa to 25/100 mg strength 2 tablets each dose with amantadine 100 mg BID, which only minimally improved his respiratory symptom, while his parkinsonism was slightly worsened.Given the fact that STN DBS could control general dyskinesia and parkinsonism and reduce the levodopa equivalent dose, 4 DBS was considered. The patient had 56% improvement on Unified Parkinson's Disease Rating Scale (UPDRS)-III score at levodopa "on" (score 20) compared to "off" state (score 45). Bilateral STN DBS was subsequently successfully placed as described elsewhere, 5 with documentation of exact lead placement using intraoperative CT fused with preoperative planning MR...

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