Proteolytic ectodomain shedding of muscle-specific tyrosine kinase in myasthenia gravis.

Autoantibodies to muscle-specific tyrosine kinase (MuSK) proteins at the neuromuscular junction (NMJ) cause refractory generalized myasthenia gravis (MG) with dyspnea more frequently than other MG subtypes. However, the mechanisms via which MuSK, a membrane protein locally expressed on the NMJ of skeletal muscle, is supplied to the immune system as an autoantigen remains unknown. Here, we identified MuSK in both mouse and human serum, with the amount of MuSK dramatically increasing in mice with motor nerve denervation and in MG model mice. Peptide analysis by liquid chromatography-tandem-mass spectrometry (LC-MS/MS) confirmed the presence of MuSK in both human and mouse serum. Furthermore, some patients with MG have significantly higher amounts of MuSK in serum than healthy controls. Our results indicated that the secretion of MuSK proteins from muscles into the bloodstream was induced by ectodomain shedding triggered by neuromuscular junction failure. The results may explain why MuSK-MG is refractory to treatments and causes rapid muscle atrophy in some patients due to the denervation associated with Ab-induced disruption of neuromuscular transmission at the NMJ. Such discoveries pave the way for new MG treatments, and MuSK may be used as a biomarker for other neuromuscular diseases in preclinical studies, clinical diagnostics, therapeutics, and drug discovery.

Management guideline for Werner syndrome 2020 1. Dyslipidemia and fatty liver associated with Werner syndrome.

For the purpose of examining the characteristics of dyslipidemia and fatty liver in patients with Werner syndrome in Japan in recent years, we searched all case reports of Japanese Werner syndrome reported on Medical Online and PubMed since 1996, and collected and examined the data and clinical features described in these reports. In addition, as there are few descriptions of treatment methods in these reports from Medical Online and PubMed, we analyzed 12 cases for which detailed data on treatment methods are available at Chiba University. Geriatr Gerontol Int 2021; 21: 133-138.

Management guideline for Werner syndrome 2020 8. Calcification in tendons associated with Werner syndrome.

AIM: To clarify the diagnostic value of the calcification in the Achilles tendon for Werner syndrome. METHODS: Calcification of the Achilles tendon in the plain radiograph was investigated in 92 patients with Werner syndrome provided from the nationwide secondary survey in 2010. And the same investigation was performed for 2151 feet in 1853 patients without Werner syndrome, who underwent foot and ankle surgeries at the department of orthopaedic surgery in Nara Medical University from 2004 to 2015. RESULT AND CONCLUSION: Achilles tendon calcification was observed in 70 (76.1%) out of 92 patients with Werner syndrome, whereas that was observed only in 19 feet (0.88%) without Werner syndrome, accompanied by 1 to 4 calcified masses with a maximum diameter ranging from 9.7mm to 63.2mm. The frequency of Achilles tendon calcification in patients with Werner syndrome is far higher than that of patients without Werner syndrome. Achilles tendon calcification could be included in the diagnostic criteria for Werner syndrome. Geriatr Gerontol Int 2021; 21: 163-165.

Management guideline for Werner syndrome 2020. 2. Sarcopenia associated with Werner syndrome.

AIM: Sarcopenia is defined as a condition that combines decreased skeletal muscle mass with weakness or decreased physical function. It is well known that in older adults, the presence of sarcopenia is a risk of frailty, falls and physical dysfunction. Patients with Werner syndrome are characterized by visceral fat accumulation and thin limbs, but the prevalence of sarcopenia in patients with Werner syndrome has not been investigated. METHODS: A literature search was conducted using Werner syndrome and skeletal muscle as keywords. We also analyzed data from our 7 Werner syndrome patients. RESULTS: A literature search on the relationship between Werner syndrome and skeletal muscle yielded only one article reported from Japan. According to this paper, a decrease in skeletal muscle mass (appendicular skeletal muscle index) was observed in all 9 Werner syndromes investigated. On the other hand, in our 7 Werner syndrome patients, their appendicular skeletal muscle indexes were below the standard value except for one male patient who had continued resistance exercise. CONCLUSION: The decrease in skeletal muscle mass frequently occurs in patients with Werner syndrome. However, resistance exercise may prevent the appearance of sarcopenia and requires early intervention in patients with Werner syndrome. Geriatr Gerontol Int 2021; 21: 139-141.

Management guideline for Werner syndrome 2020. 3. Diabetes associated with Werner syndrome.

AIMS: To evaluate the characteristics of diabetes associated with Werner syndrome. METHODS: A literature search was done with search term "Werner syndrome" and "Diabetes". RESULTS AND CONCLUSIONS: Prevalence of diabetes is extremely high in Werner syndrome. Diabetes associated with Werner syndrome is classified as "accompanied with other diseases and conditions and the one occurring mainly in association with other genetic syndromes." This type of diabetes is marked by accumulated visceral fat and high insulin resistance, despite low body mass index. Thiazolidine derivatives and metformin are effective for glycemic control. New antidiabetic drugs, such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, could be potentially beneficial for patients with Werner syndrome. Furthermore, the establishment of diet therapy as well as exercise therapy is warranted. Geriatr Gerontol Int 2021; 21: 142-145.

Management guideline for Werner syndrome 2020. 6. Skin ulcers associated with Werner syndrome: Prevention and non-surgical and surgical treatment.

AIM: To provide guidelines on the diagnosis, treatment, and prevention of skin ulcers in Werner syndrome. METHODS: This article was based on literature from 1996, when WRN was identified as a gene responsible for Werner syndrome, and we evaluated several authentic clinical cases of genetically diagnosed patients. There were 63 patients with Werner syndrome in the Japanese reports retrieved from Medical Online between January 1996 and December 2017. There were 56 patients with Werner syndrome in English reports written by Japanese authors and retrieved from PubMed during the same period. RESULTS: Records on skin ulcers were found in 27 (43%) out of 63 patients and 22 (40%) out of 56 patients from the Japanese and English reports, respectively. The reported ulcers were often located at the distal one-third of the lower legs. There were 8 patients with callosities in the foot in the Japanese reports and 9 patients in the English reports. A skin ulcer in Werner syndrome is generally intractable. Weight-bearing ulcers or callosity should be critically assessed in surgical procedures because they have effects on patient pain and gait. By adopting a recently advanced technique to facilitate wound healing, the cases of ulcers that were difficult to treat and those requiring major operations can be closed with minimally invasive surgery. CONCLUSIONS: Skin ulcers in Werner syndrome are refractory, and they lead to reduced quality of life of patients. A callosity in Werner syndrome is an important therapeutic target for the prevention of ulcers. Geriatr Gerontol Int 2021; 21: 153-159.

Management guideline for Werner syndrome 2020. 7. Skin ulcer associated with Werner syndrome: Dermatological treatment.

Skin ulcers in Werner's syndrome often arise from hyperkeratotic lesions and trauma to pressure points such as the plantar region, and are more difficult to treat than wound healing in healthy individuals. Multiple factors contribute to the intractable skin ulcers in Werner's syndrome, including skin thinning, sclerosis, fatty tissue loss, impaired blood flow, calcification, and excessive pressure due to osteoarticular deformity. Treatment includes topical application of a keratolytic agent for keratosis around the ulcer. Treatment of ulcers is the same as for normal ulcers, and if the ulcer is associated with infection and necrotic tissue, surgical debridement with a scalpel or scissors should be performed as much as possible after washing with saline or mildly warm water or with an antibacterial agent. Topical medications that promote softening and debridement of the necrotic tissue are used with careful control of moisture in the wound. Topical agents that promote granulation should be used in wounds where necrotic tissue has been removed without infection. Dressings to maintain a moist environment in the wound may also be useful. If the wound does not improve with conservative treatment, surgical treatment should be considered. Geriatr Gerontol Int 2021; 21: 160-162.

Serum growth differentiation factor 15 level is associated with muscle strength and lower extremity function in older patients with cardiometabolic disease.

AIMS: Sarcopenia is a serious problem because of its poor prognosis. Growth differentiation factor 15 (GDF15) is associated with mitochondrial dysfunction, inflammation, insulin resistance and oxidative stress, which may play crucial roles for the development of sarcopenia. We aimed to examine whether serum GDF15 level is associated with muscle mass, strength and lower extremity function in older patients with cardiometabolic disease. METHODS: Serum GDF15 levels were measured in 257 patients with cardiometabolic diseases (including 133 patients with diabetes) who had visited the frailty clinic, using a latex turbidimetric immunoassay. Appendicular skeletal muscle index, handgrip strength, timed-up-and-go test and gait speed were evaluated. Power, speed, balance and total scores based on the sit-to-stand test were calculated to assess lower extremity function. RESULTS: The highest tertile of serum GDF15 was independently associated with low handgrip strength, low gait speed, long timed-up-and-go time and scores of lower extremity function but not an appendicular skeletal muscle index in multiple logistic regression analyses after adjustment for covariates. Patients in the highest tertile of GDF15 were at the risk of having three to nine times lower grip strength, three times lower gait speed, five to six times lower mobility and five to 11 times reduction in lower extremity function as compared with those in the lowest GDF15 tertile dependent on the models. CONCLUSIONS: Elevated serum GDF15 level was independently associated with low muscle strength and lower extremity function in older patients with cardiometabolic disease. Serum GDF15 could be one of the biomarkers for muscle weakness and low physical performance. Geriatr Gerontol Int 2020; 20: 980-987.

Clinicopathological characteristics of gastric cancer with carbohydrate antigen 19-9 expression occurring in elderly individuals: An autopsy study.

The clinicopathological significance of carbohydrate antigen 19-9 (CA19-9) in gastric cancer (GC) remains obscure. Therefore, the current study aimed to clarify the clinicopathological value of CA19-9 in GC utilizing autopsy cases. We examined the expression of CA19-9 and mucin core proteins in GC immunohistochemically, and analyzed serum CA19-9 levels and clinicopathological variables or complications. We also investigated whether fucosyltransferases 2 and 3 (FUT2/3) allelic variants influence CA19-9 expression in GC. Compared to GC cases with negative CA19-9 expression (tCA19-9-N), those with positive CA19-9 expression (tCA19-9-P) demonstrated significant differences in characteristic features such as lymph node and distant organ metastases, lymphatic and venous permeation, and higher Tumor, Node, Metastasis (TNM) stages. Moreover, compared to GC cases with low serum CA19-9 levels (sCA19-9-L), those with high serum CA19-9 levels (sCA19-9-H) were related to venous permeation, higher proportion of lymph node and distant organ metastases, and higher TNM stages. Both tCA19-9-P GC and sCA19-9-H GC cases were significantly associated with coagulation abnormalities. sCA19-9-H GC cases correlated significantly with MUC1 and MUC5AC expression. FUT2/3 genotypes were not associated with CA19-9 expression in GC. These results suggest that CA19-9 can predict the risk of lymph node and distant metastases as well as of coagulation abnormalities.

The stem cell-specific intermediate filament nestin missense variation p.A1199P is associated with pancreatic cancer.

The intermediate filament nestin is upregulated in stem/progenitor cells and cancers, and regulates cell proliferation, migration, invasion and stemness. The present study comparatively analyzed serial autopsies of Japanese patients (n=2,206; males, 1,225; females, 981; median, 80.7 years old; range, 33-104 years old) with malignant tumors of whole organs, with respect to the clinical information, and 5 single nucleotide polymorphisms of the nestin gene. p.A1199P associated with pancreatic cancer (odds ratio, 4.4; 95% confidence interval, 1.9-10.0, P=0.001) while it did not associate with malignant neoplasms in other organs. p.A1199P did not associate with precancerous lesions of the pancreas. Single nucleotide polymorphisms of nestin were not associated with sex, drinking, smoking, or body weight. In conclusion, the amino acid 1,199 of nestin is localized in the tail structure of the filament and polymerizes with other intermediate filament proteins. The present results suggest that missense variations of nestin affect pancreatic carcinogenesis in Japanese patients.

[Clinical characteristics of bullous pemphigoid in elderly patients with type 2 diabetes mellitus: The association with the use of dipeptidyl peptidase-4 inhibitors].

AIM: Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by the production of autoantibodies. Several recent reports have described the occurrence of BP in diabetic patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors. However, the clinical features of BP in diabetic patients, particularly in those treated with DPP-4 inhibitors, have not yet been examined. The aim of this study was to clarify clinical characteristics of BP in elderly type 2 diabetic patients. METHODS: We found cases of BP in 15 elderly type 2 diabetic patients (11 men, 4 women) and 20 non-diabetic patients (8 men, 12 women) from September, 2012 to September, 2016. These patients had all been treated with corticosteroid therapy. We investigated the participants' basic clinical characteristics and the course of BP treatment. The differences in variables between the two groups were analyzed using Wilcoxon's test and the chi-square test. RESULTS: The mean age of type 2 diabetes patients with BP was 81.1±5.5 years. The mean HbA1c was 7.3±1.6%. A total of 87% of diabetic patients had been treated with DPP-4 inhibitors for 11.7 months prior to the BP onset. The diabetic patients had a lower prevalence of neurogenerative disease, severe ADL disabilities, and dementia than the non-diabetic patients. Furthermore, the diabetic patients with BP tended to be younger and more frequently male than those without diabetes. After stopping the DPP-4 inhibitors, the skin lesions were successfully treated with systemic corticosteroid therapy, and glycemic control was achieved using intensive insulin therapy. DPP-4 inhibitors were used in all cases where the aniti-BP180NC16a antibody showed negative conversion. CONCLUSION: BP in patients with type 2 diabetes had different clinical features from that in non-diabetic patients, suggesting an association between BP and the use of DPP-4 inhibitors.

Relationship between pancreatic intraepithelial neoplasias, pancreatic ductal adenocarcinomas, and single nucleotide polymorphisms in autopsied elderly patients.

We comparatively analyzed serially autopsied, elderly Japanese patients (n = 2205) with pancreatic intraepithelial neoplasias (PanINs) and pancreatic ductal adenocarcinomas (PDACs) on the basis of their pancreatic lesions, clinical information, and single nucleotide polymorphisms (SNPs). The incidence of PanIN-1, -2, -3, and PDACs in these patients was 55%, 12%, 1.4%, and 2.4%, respectively. The occurrence of PanINs was associated with female sex, increasing age, and lower body mass index. We did not identify any common SNPs between PanINs and PDACs. There were no common SNPs associated with PanINs and PDACs between men and women. In previously reported pancreatic cancer-associated SNPs, rs3790844 (NR5A2) showed a significant correlation with PDAC in our cohort. Six SNPs (rs7016880, rs10096633, rs10503669, rs12678919, rs17482753, rs328) that were correlated with blood lipid levels were associated with the risk for PDACs. Our data suggest that different clinicopathological characteristics and predispositions may affect pancreatic carcinogenesis in elderly Japanese patients.

Inverse Association Between Height-Increasing Alleles and Extreme Longevity in Japanese Women.

Growth hormone (GH)/insulin-like growth factor-1 (IGF-1)/insulin signaling is one of the most plausible biological pathways regulating aging and longevity. Previous studies have demonstrated that several single nucleotide polymorphisms (SNPs) in the GH/IGF-1/insulin signaling-associated genes influence both longevity and adult height, suggesting the possibility of a shared genetic architecture between longevity and height. We therefore examined the relationship between 30 height-associated SNPs and extreme longevity in a Japanese population consisting of 428 centenarians and 4,026 younger controls. We confirmed that height-increasing genetic scores (HGSs) constructed based on 30 SNPs were significantly associated with height in the controls (p = 6.95 × 10-23). HGS was significantly and inversely associated with extreme longevity in women (p = .011), but not in men, although no SNPs were significantly associated with extreme longevity after Bonferroni correction. The odds ratio for extreme longevity in the lowest HGS group (≤27) and the second lowest HGS group (28-30) relative to the highest HGS group (≥37) was 1.71 (p = .056) and 1.69 (p = .034), respectively, for women. In conclusion, the present study demonstrated an inverse association between height-increasing alleles with extreme longevity in Japanese women, providing novel insight into the genetic architecture of longevity and aging.

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.

Background characteristics and clinical features of elderly patients with hyperglycemic hyperosmolar syndrome.

AIM: Few reports have described the characteristics of hyperglycemic hyperosmolar syndrome (HHS) in the elderly. We investigated the background characteristics and clinical features of 14 elderly patients with HHS. METHODS: HHS was diagnosed based on a blood glucose level of >600 mg/dL and an effective plasma osmolality [2 (Na) + glu/18] of >320 mOsm/kg. For 14 cases of HHS, we investigated the medical and social backgrounds of the patients, their clinical findings, and the outcomes. RESULTS: The mean patient age was 83 years, and the mean body mass index was 17.8 kg/m2. Half had a history of either cerebral infarction or hip fracture. The mean duration of diabetes was 14 years, but 4 diabetes cases were newly diagnosed. There was a high prevalence of acute infection (79%) in HHS patients, especially urinary tract infection and pneumonia, with a seasonal peak in winter. Patients who had been treated with steroids, tube feeding, or both numbered 1, 2, and 1, respectively. Most HHS patients had a history of dementia. More than half of such patients were living alone or only with their spouse, and their activities of daily living showed marked deterioration. The mean blood glucose level, HbA1c, effective serum osmolality, and pH were 881 mg/dL, 10.3%, 353 mOsm/kg, and 7.39, respectively. One patient died during hospitalization, and 9 were discharged to nursing homes or other hospitals. The mean length of hospitalization was 55 days. In most cases, the insulin secretion capacity was preserved, and 9 patients were treatable with oral hypoglycemic agents alone. CONCLUSIONS: Many cases of HHS in the elderly are associated with infection, a shortage of social support, cognitive impairment, or ADL decline. Although the survival rate in our series was high, the functional prognosis was impaired.

Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome­wide association study.

An exome­wide association study (EWAS) was performed to identify genetic variants, particularly low­frequency 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 HumanExome­12 DNA Analysis BeadChip or Infinium Exome­24 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's exact test. Based on Bonferroni's correction, a P<1.21x10­6 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=9.36x10­9; odds ratio, 0.58), rs113710653 [C/T (E231 K)] of spermatogenesis and centriole associated 1 like (SPATC1L; dominant model; P=1.09x10­5; odds ratio, 3.27), and rs11231397 [G/C (R300T)] of solute carrier family 22 member 25 (SLC22A25; additive model; P=3.71x10­5; odds ratio, 1.77), were significantly (P<1.02x10­4) 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.

White Matter Hyperintensity in Elderly Patients with Diabetes Mellitus Is Associated with Cognitive Impairment, Functional Disability, and a High Glycoalbumin/Glycohemoglobin Ratio.

Aims: Although evidence has accumulated that white matter hyperintensity (WMH) is associated with the deterioration of cognitive function and impairment of activities of daily living (ADL), the clinical relevance of WMH in elderly patients with diabetes mellitus (DM) is not still clear. The aim of this study was to examine whether WMH volume is associated with ADL and cognitive function and whether glucose control and glucose variability can affect WMH volume in these patients. Methods: This cross-sectional study investigated the associations of WMH with cognitive function and instrumental ADL (IADL), as well as metabolic and vascular risk factors in a total of 178 elderly patients with diabetes. The study assessed WMH volumes and the functional status of cognition and IADL. WMH volumes were evaluated by obtaining axial T2-weighted and fluid-attenuated inversion recovery sequence images on brain magnetic resonance imaging and assessing the images using Software for Neuro-Image Processing in Experimental Research. Results: We found a significant association between WMH volumes and Mini-Mental State Examination (MMSE) scores (p = 0.039) and between WMH and IADL status (p = 0.006). Furthermore, we found significant relations of large WMH volumes with a high glycoalbumin/glycohemoglobin ratio (GA/HbA1c) (p < 0.001). Large WMH volumes were also found to be associated with a low body mass index (p = 0.014) and a low diastolic blood pressure (p = 0.024), but not with HbA1c. Multiple regression analysis showed that high GA/HbA1c, which reflects high glucose variability, was a significant determining factor for large WMH volumes. We also found that GA/HbA1c was negatively associated with both MMSE (p = 0.036) and IADL (p < 0.001). Conclusion: GA/HbA1c, which is a marker of glucose variability, was independently associated with WMH volumes, which could lead to the decline of cognition and IADL in elderly patients with DM.

An Alpha-kinase 2 Gene Variant Disrupts Filamentous Actin Localization in the Surface Cells of Colorectal Cancer Spheroids.

BACKGROUND/AIM: Alpha-kinase 2 (ALPK2), suggested to be a novel tumour-suppressor gene down-regulated by oncogenic KRAS, plays a pivotal role in luminal apoptosis in normal colonic crypts. The aim of this study was to determine the association between ALPK2 germline variants and colorectal cancer. MATERIALS AND METHODS: Missense single nucleotide variants in the exons of the ALPK2 gene in 2,343 consecutive autopsy cases (1,446 cases with cancer and 897 cases without cancer) were screened using HumanExome BeadChip arrays. To address the functional effect of a missense ALPK2 variant, a 3D floating cell culture was performed using HCT116-derived human colorectal cancer cells stably expressing wild-type (wt) ALPK2 (HCT116-wtALPK2) or amino acid-substituted (sub) ALPK2 (HCT116-subALPK2). RESULTS: We identified that one of the ALPK2 germline variants, rs55674018 (p.Q1853E), was significantly associated with the presence of cancer (adjusted odds ratio(OR)=4.39; 95% confidence interval(CI)=1.31-14.78, p=0.001). The p.Q1853E variant was present in the East Asian population and located in the immunoglobulin-like domain. Notably, the basolateral polarity of actin in the surface of HCT116-wtALPK2 spheroids was more attenuated compared to that of HCT116-subALPK2 spheroids. Furthermore, luminal apoptosis and cell aggregation were promoted by wtALPK2, but not by subALPK2 in 3D culture. CONCLUSION: The p.Q1853E variant of ALPK2, which had been accumulating in the Japanese population, induced a metastatic phenotype by disrupting ALPK2 function.