An eccentric calpain, CAPN3/p94/calpain-3

AbstractCalpains are Ca2+-regulated proteolytic enzymes that are involved in a variety of biological phenomena. Calpains process substrates by limited proteolysis to modulate various protein functions in the cell, and are thus called “modulator proteases.” CAPN3, previously called p94 or calpain-3, has unique features that are not found in any of the other 14 human calpains, or even in other proteases.For instance, CAPN3 undergoes extremely rapid and exhaustive autodegradation. CAPN3 is also the first (and so far, the only) intracellular enzyme found to depend on Na+ for its activation. CAPN3 has both proteolytic and non-proteolytic functions. It has the interesting distinction of being the only protease, other than a few virus proteases, with the ability to regain protease function after its autolytic dissociation; this occurs through a process known as intermolecular complementation (iMOC). Gene mutations causing CAPN3 defects are responsible for limb-girdle muscular dystrophy type 2A (LGMD2A).Unusual characteristics of CAPN3 have fascinated researchers, but have also hampered conventional biochemical analysis. In this review, we describe significant findings about CAPN3 from its discovery to the present, and suggest promising avenues for future CAPN3 research

Identification of five genetic variants as novel determinants of type 2 diabetes mellitus in Japanese by exome-wide association studies

We performed exome-wide association studies to identify single nucleotide polymorphisms that either influence fasting plasma glucose level or blood hemoglobin A1c content or confer susceptibility to type 2 diabetes mellitus in Japanese. Exome-wide association studies were performed with the use of Illumina Human Exome-12 DNA Analysis or Infinium Exome-24 BeadChip arrays and with 11,729 or 8635 subjects for fasting plasma glucose level or blood hemoglobin A1c content, respectively, or with 14,023 subjects for type 2 diabetes mellitus (3573 cases, 10,450 controls). The relation of genotypes of 41,265 polymorphisms to fasting plasma glucose level or blood hemoglobin A1c content was examined by linear regression analysis. After Bonferroni’s correction, 41 and 17 polymorphisms were significantly (P < 1.21 × 10−6) associated with fasting plasma glucose level or blood hemoglobin A1c content, respectively, with two polymorphisms (rs139421991, rs189305583) being associated with both. Examination of the relation of allele frequencies to type 2 diabetes mellitus with Fisher’s exact test revealed that 87 polymorphisms were significantly (P < 1.21 × 10−6) associated with type 2 diabetes mellitus. Subsequent multivariable logistic regression analysis with adjustment for age and sex showed that four polymorphisms (rs138313632, rs76974938, rs139012426, rs147317864) were significantly (P < 1.44 × 10−4) associated with type 2 diabetes mellitus, with rs138313632 and rs139012426 also being associated with fasting plasma glucose and rs76974938 with blood hemoglobin A1c. Five polymorphisms—rs139421991 of CAT, rs189305583 of PDCL2, rs138313632 of RUFY1, rs139012426 of LOC100505549, and rs76974938 of C21orf59—may be novel determinants of type 2 diabetes mellitus

Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome‑wide association study

An exome‑wide association study (EWAS) was performed to identify genetic variants, particularly low‑frequency or rare coding variants with a moderate to large effect size, that confer susceptibility to atrial fibrillation in Japanese. The EWAS for atrial fibrillation was performed with 13,166 subjects (884 patients with atrial fibrillation and 12,282 controls) using an Illumina HumanExome‑12 DNA Analysis BeadChip or Infinium Exome‑24 BeadChip arrays. The association of atrial fibrillation with allele frequencies of 41,243 single nucleotide polymorphisms (SNPs) that passed quality control was examined with Fisher\u27s exact test. Based on Bonferroni\u27s correction, a P<1.21x10‑6 was considered statistically significant. The EWAS for atrial fibrillation revealed that 122 SNPs were significantly associated with this condition. The association of the identified SNPs to atrial fibrillation was further examined by multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension. Eight SNPs were related (P<0.01) to atrial fibrillation, among which three polymorphisms, rs11552708 [G/A (G67R)]of TNF superfamily member 13 (TNFSF13; dominant model; P=9.36x10‑9; odds ratio, 0.58), rs113710653 [C/T (E231 K)] of spermatogenesis and centriole associated 1 like (SPATC1L; dominant model; P=1.09x10‑5; odds ratio, 3.27), and rs11231397 [G/C (R300T)] of solute carrier family 22 member 25 (SLC22A25; additive model; P=3.71x10‑5; odds ratio, 1.77), were significantly (P<1.02x10‑4) associated with this condition. The minor T allele of rs113710653 and the minor C allele of rs11231397 were risk factors for atrial fibrillation, whereas the minor A allele of rs11552708 was protective against this condition. In addition, rs77538589 [C/T (G117R)] of SALL4 exhibited a tendency to be associated with atrial fibrillation (dominant model; P=0.0002; odds ratio, 1.88), with the minor T allele representing a risk factor for this condition. TNFSF13, SPATC1L, SLC22A25 and SALL4 may thus be novel susceptibility loci for atrial fibrillation in the Japanese population

Functional tooth number and mortality

Aim: Previous studies on the association between intraoral conditions and mortality in community-dwelling older individuals reported that fewer present teeth (PT) are significant risk factors for mortality. However, how the number of PT relative to the number of functional teeth (FT), including both present and rehabilitated teeth, influences mortality has not been investigated fully. This study examined the impact of the number of FT on mortality among community-dwelling Japanese older adults. Methods: This study was a retrospective, observational and population-based follow-up study, which examined 1188 older individuals who participated in an annual geriatric health examination from 2009 to 2015. The average follow-up period was 1697.0 ± 774.5 days. The primary outcome was all-cause mortality at follow-up. The numbers of PT and FT of each participant were counted during an oral examination. In addition, demographics, clinical variables, blood nutrient markers, physical functions and perceived masticatory function were measured. Results: Kaplan–Meier analysis, followed by a log-rank test, revealed that fewer PT (P < 0.001) and FT (P = 0.002) were significantly associated with a reduced survival rate. Cox's proportional hazard analysis indicated that the number of FT, but not the number of PT, was a significant independent mortality risk factor after adjusting for demographics, clinical variables, nutrient markers and physical functioning (P = 0.036, hazard ratio: 2.089). Conclusions: Current results suggest that the number of FT more strongly predicts all-cause mortality than the number of PT among community-dwelling older adults. Further studies are necessary to consider the confounding of socioeconomic status and disability status

Functional teeth and independence

Aim: To examine the relationship between the number of present and functional teeth at baseline and future incidence of loss of independence. Methods: Participants were community-dwelling older individuals who participated in a comprehensive geriatric health examination conducted in Kusatsu town, Japan, between 2009 and 2015. The primary endpoint was the incidence of loss of independence among participants, defined as the first certification of long-term care insurance in Japan. The numbers of present and functional teeth at baseline were determined via an oral examination. Demographics, clinical variables (e.g., history of chronic diseases and psychosocial factors), blood nutritional markers, physical functions, and perceived masticatory function were assessed. Results: This study included 1121 individuals, and 205 individuals suffered from loss of independence during the follow-up period. Kaplan–Meier estimates of loss of independence for participants with smaller numbers of present and functional teeth were significantly greater than for those with larger numbers of teeth. Cox proportional hazard analyses indicated that a smaller number of present teeth was not a significant risk factor after adjusting for demographic characteristics. However, the number of functional teeth was a significant risk factor after the adjustment (hazard ratio: 1.975 [1.168–3.340]). Additionally, higher hazard ratios were observed in other adjusted models, but they were not statistically significant. Conclusions: The number of functional teeth may be more closely related to the future incidence of loss of independence than the number of present teeth. This novel finding suggests that prosthodontic rehabilitation for tooth loss possibly prevents the future incidence of this life-event

Number of functional teeth more strongly predicts all‐cause mortality than number of present teeth in Japanese older adults

Aim Previous studies on the association between intraoral conditions and mortality in community‐dwelling older individuals reported that fewer present teeth (PT) are significant risk factors for mortality. However, how the number of PT relative to the number of functional teeth (FT), including both present and rehabilitated teeth, influences mortality has not been investigated fully. This study examined the impact of the number of FT on mortality among community‐dwelling Japanese older adults. Methods This study was a retrospective, observational and population‐based follow‐up study, which examined 1188 older individuals who participated in an annual geriatric health examination from 2009 to 2015. The average follow‐up period was 1697.0 ± 774.5 days. The primary outcome was all‐cause mortality at follow‐up. The numbers of PT and FT of each participant were counted during an oral examination. In addition, demographics, clinical variables, blood nutrient markers, physical functions and perceived masticatory function were measured. Results Kaplan–Meier analysis, followed by a log‐rank test, revealed that fewer PT (P  Conclusions Current results suggest that the number of FT more strongly predicts all‐cause mortality than the number of PT among community‐dwelling older adults. Further studies are necessary to consider the confounding of socioeconomic status and disability status

C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers

Nuclear import receptors (NIRs) not only transport RNA-binding proteins (RBPs) but also modify phase transitions of RBPs by recognizing nuclear localization signals (NLSs). Toxic arginine-rich poly-dipeptides from C9orf72 interact with NIRs and cause nucleocytoplasmic transport deficit. However, the molecular basis for the toxicity of arginine-rich poly-dipeptides toward NIRs function as phase modifiers of RBPs remains unidentified. Here we show that arginine-rich poly-dipeptides impede the ability of NIRs to modify phase transitions of RBPs. Isothermal titration calorimetry and size-exclusion chromatography revealed that proline:arginine (PR) poly-dipeptides tightly bind karyopherin-β2 (Kapβ2) at 1:1 ratio. The nuclear magnetic resonances of Kapβ2 perturbed by PR poly-dipeptides partially overlapped with those perturbed by the designed NLS peptide, suggesting that PR poly-dipeptides target the NLS binding site of Kapβ2. The findings offer mechanistic insights into how phase transitions of RBPs are disabled in C9orf72-related neurodegeneration

Impact of number of functional teeth on independence of Japanese older adults

Aim To examine the relationship between the number of present and functional teeth at baseline and future incidence of loss of independence. Methods Participants were community-dwelling older individuals who participated in a comprehensive geriatric health examination conducted in Kusatsu town, Japan, between 2009 and 2015. The primary endpoint was the incidence of loss of independence among participants, defined as the first certification of long-term care insurance in Japan. The numbers of present and functional teeth at baseline were determined via an oral examination. Demographics, clinical variables (e.g., history of chronic diseases and psychosocial factors), blood nutritional markers, physical functions, and perceived masticatory function were assessed. Results This study included 1121 individuals, and 205 individuals suffered from loss of independence during the follow-up period. Kaplan–Meier estimates of loss of independence for participants with smaller numbers of present and functional teeth were significantly greater than for those with larger numbers of teeth. Cox proportional hazard analyses indicated that a smaller number of present teeth was not a significant risk factor after adjusting for demographic characteristics. However, the number of functional teeth was a significant risk factor after the adjustment (hazard ratio: 1.975 [1.168–3.340]). Additionally, higher hazard ratios were observed in other adjusted models, but they were not statistically significant. Conclusions The number of functional teeth may be more closely related to the future incidence of loss of independence than the number of present teeth. This novel finding suggests that prosthodontic rehabilitation for tooth loss possibly prevents the future incidence of this life-event

Identification of rs7350481 at chromosome 11q23.3 as a novel susceptibility locus for metabolic syndrome in Japanese individuals by an exome-wide association study

We have performed exome-wide association studies to identify genetic variants that influence body mass index or confer susceptibility to obesity or metabolic syndrome in Japanese. The exome-wide association study for body mass index included 12,890 subjects, and those for obesity and metabolic syndrome included 12,968 subjects (3954 individuals with obesity, 9014 controls) and 6817 subjects (3998 individuals with MetS, 2819 controls), respectively. Exome-wide association studies were performed with Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of genotypes of single nucleotide polymorphisms to body mass index was examined by linear regression analysis, and that of allele frequencies of single nucleotide polymorphisms to obesity or metabolic syndrome was evaluated with Fisher’s exact test. The exome-wide association studies identified six, 11, and 40 single nucleotide polymorphisms as being significantly associated with body mass index, obesity (P <1.21 × 10–6), or metabolic syndrome (P <1.20 × 10–6), respectively. Subsequent multivariable logistic regression analysis with adjustment for age and sex revealed that three and five single nucleotide polymorphisms were related (P < 0.05) to obesity or metabolic syndrome, respectively, with one of these latter polymorphisms—rs7350481 (C/T) at chromosome 11q23.3—also being significantly (P < 3.13 × 10–4) associated with metabolic syndrome. The polymorphism rs7350481 may thus be a novel susceptibility locus for metabolic syndrome in Japanese. In addition, single nucleotide polymorphisms in three genes (CROT, TSC1, RIN3) and at four loci (ANKK1, ZNF804B, CSRNP3, 17p11.2) were implicated as candidate determinants of obesity and metabolic syndrome, respectively