Hiroyuki Morino

We report a 58‐year‐old woman with a novel splice‐site variant in the TANK‐binding kinase 1 ( TBK1 :c.993–2A>C p.Ala332TyrfsTer39) who sequentially developed primary lateral sclerosis (PLS) followed by right temporal variant frontotemporal dementia (rtvFTD). Neuroimaging demonstrated right anterior temporal atrophy before cognitive symptoms, and prosopagnosia represented the earliest manifestation of rtvFTD. Molecular analysis revealed reduced levels of correctly spliced TBK1 transcripts, consistent with haploinsufficiency. Given the shared involvement of TDP‐43 pathology in both PLS and rtvFTD, this case indicates TBK1 dysfunction as a fundamental genetic factor underlying the coexistence of these phenotypes, underscoring the clinical value of early neuroimaging and genetic evaluation.

Spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative disorders caused by pathogenic variants in more than 40 genes with diverse cellular functions. In this study, we identified the c.247C > T p.(Arg83Trp) variant in RAB3A, encoding a small GTPase involved in membrane-associated regulated exocytosis, in two families with cerebellar ataxia. Affected individuals presented with adult-onset, gradually progressive cerebellar symptoms, often accompanied by mild gait spasticity and tremors. Variable features of neurodevelopmental disorders were also observed. Brain MRI consistently revealed cerebellar atrophy, often accentuated in the vermis, and neuropathological examinations demonstrated diffuse cerebellar cortical degeneration. Functionally, the R83W mutation lies within the conserved switch II region of Rab3A, a domain critical for effector interaction. Although the mutant Rab3A R83W retained GTP-binding affinity, it failed to bind the key effector proteins RIM1 and Rabphilin-3A, highlighting the functional importance of R83 in effector complex formation, as supported by structural analysis. In PC12 cells, the R83W mutant exhibited diffuse cytoplasmic localization, in contrast to the vesicle- and neurite-tip localization of the wild-type and GTP-bound Rab3A mutant. The concordant localization pattern of R83W and GDP-bound Rab3A mutants suggests that R83W-induced mislocalization results from a failure to engage downstream effector proteins. In the cerebellum, Rab3A was predominantly localized to parallel fiber terminals and was absent from postsynaptic Purkinje cells. These findings suggest that disruption of the interaction between Rab3A and its effector proteins may underlie disease pathogenesis, possibly involving presynaptic dysfunction at parallel fiber–Purkinje cell synapses mediated by the Rab3A–RIM1 complex.

Here we report a heterozygous missense variant in the ACTB gene, NM_001101.5:c.209C>T (p.Pro70Leu), detected in a case of a mildly affected infant with Baraitser–Winter cerebrofrontofacial syndrome, characterized by unique craniofacial features, coloboma and mild developmental delay, but without lissencephaly. Baraitser–Winter cerebrofrontofacial syndrome cases with a similar mild phenotype have been reported to have the same variant in different populations, suggesting a genotype–phenotype correlation in this syndrome.

Spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative disorders caused by pathogenic variants in more than 40 genes with diverse cellular functions. In this study, we identified the c.247C>T p.(Arg83Trp) variant in RAB3A , encoding a small GTPase involved in membrane-associated regulated exocytosis, in two families with cerebellar ataxia. Affected individuals presented with adult-onset, gradually progressive cerebellar symptoms, often accompanied by mild gait spasticity and tremors. Variable features of neurodevelopmental disorders were also observed. Brain MRI consistently revealed cerebellar atrophy, often accentuated in the vermis, and neuropathological examinations demonstrated diffuse cerebellar cortical degeneration. Functionally, the R83W mutation lies within the conserved switch II region of Rab3A, a domain critical for effector interaction. Although the mutant Rab3A R83W retained GTP-binding affinity, it failed to bind the key effector proteins RIM1 and Rabphilin-3A, highlighting the functional importance of R83 in effector complex formation, as supported by structural analysis. In PC12 cells, the R83W mutant exhibited diffuse cytoplasmic localization, in contrast to the vesicle- and neurite-tip localization of the wild-type and GTP-bound Rab3A mutant. The concordant localization pattern of R83W and GDP-bound Rab3A mutants suggests that R83W-induced mislocalization results from a failure to engage downstream effector proteins. In frozen sections of the mouse cerebellum, Rab3A was predominantly localized to parallel fiber terminals and was absent from postsynaptic Purkinje cells. These findings suggest that disruption of the interaction between Rab3A and its effector proteins may underlie disease pathogenesis, possibly involving presynaptic dysfunction at parallel fiber–Purkinje cell synapses mediated by the Rab3A–RIM1 complex.

Aggressive periodontitis causes rapid destruction of periodontal tissue. It occurs at a young age with familial clustering. We report on the first time on molecular and cellular basis of a Mendelian form of autosomal dominant aggressive periodontitis. Monoallelic mutations in the monocyte to macrophage differentiation-associated 2 (MMD2) gene, encoding MMD2, in two Japanese families with autosomal dominant aggressive periodontitis are identified. Mutations, c.347 C>T (p.A116V) and c.377 G>C (p.R126P) in MMD2, disturbed fMLP-induced activation of Ras/ERK signaling. Additionally, abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients’ neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 mutation. Our studies revealed that monoallelic mutations in MMD2 underlie the impairment of neutrophil chemotaxis, which leads to the development of autosomal dominant aggressive periodontitis.

Kcnq channels are low-threshold voltage-dependent K⁺ channels that generate M-currents, which regulate the peri-threshold membrane potential. Kcnq channels reportedly participate in band-pass frequency responses (i.e., resonance), but it remains largely unclear how they contribute to generating resonance. We examined resonance in HEK293 cells expressing mouse Kcnq2 and Kcnq3 (Kcnq2/3) using whole-cell recording. Kcnq2/3-expressing cells generated resonance-like frequency-dependent responses. Kcnh7 channels displayed a rapid opposing conductance change followed by slow activation in response to a depolarizing voltage step, properties thought to be necessary for inductor-like activity. However, Kcnq2/3 channels exhibited only slow activation. The lack of an opposing conductance change was caused by the absence of rapid Kcnq2/3 channel inactivation. These data suggest that core ion channel characteristics that cause resonance-like frequency responses are not uniform among ion channels. The opposing conductance change is not necessary for resonance-like frequency responses but is crucial for fine frequency tuning and oscillation.

Repeat expansion diseases, particularly those involving GC-rich motifs, have been increasingly recognized as contributors to neurological and neuromuscular disorders. Amyotrophic lateral sclerosis (ALS) has been linked to several such expansions, including intermediate-length repeats in genes implicated in oculopharyngodistal myopathy (OPDM). To investigate the possible involvement of CGG repeat expansions in ALS, 424 ALS patients and 312 controls of Japanese descent were screened for expansions in five genes associated with repeat expansion disorders, namely GIPC1 , RILPL1 , FMR1 , AFF2 , and NUTM2BAS1 . Repeat-primed PCR and fragment analysis revealed that four ALS patients exhibited abnormal CGG expansions in GIPC1 (33–55 repeats), whereas two control individuals harbored expanded alleles (67 and 83 repeats). No expansions in the other genes were detected. Long-read sequencing confirmed repeat sizes and showed sequence instability. Histopathological analysis of ALS patients with GIPC1 expansion demonstrated classical ALS pathology, including phosphorylated TDP-43-positive inclusions. RNA fluorescence in situ hybridization revealed nuclear foci containing GIPC1 repeat RNA exclusively in ALS patients with GIPC1 expansions, suggesting RNA-mediated toxicity. These findings indicate that a subset of ALS patients present with intermediate CGG expansions in GIPC1 , which may represent a novel pathogenic mechanism analogous to other noncoding repeat disorders. Given that GIPC1 full expansions are associated with OPDM, these results support the hypothesis of a pathological continuum between neurodegeneration and myopathy driven by repeat length and sequence context. Nonetheless, further investigations into the potential of GIPC1 CGG expansions as genetic risk factors or modifiers in ALS are warranted.

ApoA-I amyloidosis is an extremely rare form of systemic amyloidosis that commonly involves the heart, kidneys, and liver. ApoA-I amyloidosis is caused by amyloidogenic variants of APOA1 that are inherited in an autosomal dominant manner. Here, we report a 69-year-old man with sporadic cardiac amyloidosis who was born to consanguineous parents and carried a homozygous variant of p.Leu202Arg in APOA1.