We propose that KCNJ5 is a second gene causing Andersen-Tawil syndrome. The inhibitory effects of mutant Kir3.4 on inwardly rectifying potassium channels may account for the clinical presentation in both skeletal and heart muscles.

MUNIX could serve as a sensitive technique to detect denervation of clinically intact muscles of ALS patients.

Familial hypokalemic periodic paralysis (HypoPP) is a rare skeletal muscle disease caused by the dysregulation of sarcolemmal excitability. HypoPP is characterized by repeated episodes of paralytic attacks with hypokalemia, and several variants in CACNA1S coding for CaV1.1 and SCN4A coding for NaV1.4 have been established as causative mutations. Most of the mutations are substitutions to a non-charged residue, from the positively charged arginine (R) in transmembrane segment 4 (S4) of a voltage sensor in either CaV1.1 or NaV1.4. Mutant channels have aberrant leak currents called “gating pore currents,” and the widely accepted consensus is that this current is the essential pathological mechanism that produces susceptibility to anomalous depolarization and failure of muscle excitability during a paralytic attack. Here, we have identified five HypoPP cases from two different ethnic backgrounds, Japanese and French, with charge-preserving substitutions in S4 from arginine, R, to lysine, K. An R to K substitution has not previously been reported for any other HypoPP families. One case is R219K in NaV1.4, which is located at the first charge in S4 of Domain I. The other four cases all have R897K in CaV1.1, which is located at the first charge in S4 of Domain III. Gating pore currents were not detected in expression studies of CaV1.1-R897K. NaV1.4-R219K mutant channels revealed a distinct, but small, gating pore current. Simulation studies indicated that the small-amplitude gating pore current conducted by NaV1.4-R219K is not likely to be sufficient to be a risk factor for depolarization-induced paralytic attacks. Our rare cases with typical HypoPP phenotypes do not fit the canonical view that the essential defect in HypoPP mutant channels is the gating pore current and raise the possibility that HypoPP pathogenesis might be heterogeneous and diverse.

Myotonic dystrophy type 1 (DM1) is a multi-system disorder caused by CTG repeats in the myotonic dystrophy protein kinase (DMPK) gene. This leads to the sequestration of splicing factors such as muscleblind-like 1/2 (MBNL1/2) and aberrant splicing in the central nervous system. We investigated the splicing patterns of MBNL1/2 and genes controlled by MBNL2 in several regions of the brain and between the grey matter (GM) and white matter (WM) in DM1 patients using RT-PCR. Compared with amyotrophic lateral sclerosis (ALS, as disease controls), the percentage of spliced-in parameter (PSI) for most of the examined exons were significantly altered in most of the brain regions of DM1 patients, except for the cerebellum. The splicing of many genes was differently regulated between the GM and WM in both DM1 and ALS. In 7 out of the 15 examined splicing events, the level of PSI change between DM1 and ALS was significantly higher in the GM than in the WM. The differences in alternative splicing between the GM and WM may be related to the effect of DM1 on the WM of the brain.

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Myotonic dystrophy type I (DM1) is a multiorgan disease caused by CTG-repeat expansion in the DMPK gene. Sequestration of the splicing factor MBNL1 results in aberrant splicing in many genes in DM1 skeletal muscle, whereas MBNL2 plays a leading role in missplicing in the central nervous system (CNS) of patients with DM1. Splicing misregulation of most MBNL2-regulated genes occurs in the temporal cortex but not in the cerebellum of autopsied patients with DM1. To understand the diversity at macroscopic and microscopic levels in CNS of patients with DM1. Using autopsied brain tissues, we examined alternative splicing ratios of MBNL2-regulated genes and expression levels of potential splicing factors. We found differences in splicing abnormalities among tested regions of the CNS from patients with DM1. In the frontal and temporal cortices and the hippocampus, many genes were aberrantly spliced, but severity differed among the brain regions. By contrast, there were no significant differences in the ratio of splicing variants for most of the genes in the cerebellar cortex and spinal cord between DM1 and control samples. We failed to find any change in the amount of potential factors (MBNL and CUGBP proteins and DMPK mRNA) which explain the modest missplicing in the cerebellum. LASER capture microdissection demonstrated splicing misregulation in the molecular layer of the cerebellum but not in the granular layer. This is the first study to reveal missplicing in a functional cell layer of DM1 and to compare splicing misregulation in a wide region of the CNS using statistical analysis.