Abstract The cardiovascular system’s hemodynamics is pivotal for tissue oxygen and nutrient delivery. However, accurately characterizing its blood flow characteristics remains a major challenge due to the complex distribution and geometry of the cardiovascular system. This study introduces a novel multi - fractal vascular tree (MFVT) model. By integrating heterogeneous fractal dimensions and scaling laws, considering vessel branching and tortuosity, the model depicts blood flow across various vessels. Formulas for blood flow rates in single vessels, fractal vessel trees, and bundles of fractal vessel trees were derived, along with the analytical expression for cardiovascular system permeability. The model’s reliability was verified via four case studies, with a maximum relative error of less than 5% between theoretical and experimental values. Sensitivity analyses showed that parameters significantly influenced blood flow. For instance, as the maximum diameter of zero-level vessels increased from 0.2 to 4 mm, the flow rate rose notably. When the diameter ratio increased from 0.5 to 0.8, the flow rate also increased, especially at higher pressure differences. An increase in the initial length of zero-level vessels from 5 to 50 mm led to a decrease in the flow rate. These phenomena indicate that blood flow resistance is negatively correlated with vessel diameter and positively correlated with vessel length. This work advances the mechanistic understanding of blood flow distribution and provides a computational tool for studying vascular pathologies.

ObjectiveThis study aimed to uncover the genetic variations and their corresponding clinical features in a Chinese family affected by epidermolysis bullosa (EB).MethodsWe enrolled a Chinese family clinically diagnosed with EB and conducted whole-exome sequencing on the proband to identify genetic variations. I-TASSER and PyMOL software were used to examine the structural and functional implications of the identified mutant proteins.ResultsThe study identified an autosomal-dominant form of epidermolysis bullosa simplex (EBS) in the family, attributed to a novel missense variation c.A527G (D176G) in the ITGB4 gene. By bioinformatics analyses, we found that the wild-type D176 forms one hydrogen bond with a distance of 3.1 Å from F201, one hydrogen bond with a distance of 2.7 Å from K177, and two hydrogen bonds with a distance of 3.2 Å from Y304; however, the mutant G176 only forms one hydrogen bond with F201 at a distance of 3.2 Å.ConclusionsThis study confirms the dominant mode of inheritance of the missense ITGB4 mutation observed in EB. The novel missense variation c.A527G (D176G) in ITGB4 involves a transition from a polar to non-polar amino acid and a decrease in intermolecular hydrogen bonding, which was associated with EB development.

Purpose:To identify genetic variants in Chinese families with colorectal cancer. Methods:Expression of mismatch-repair proteins was assessed via immunohistochemistry in three probands. Genetic variants were identified using whole-exome sequencing. In silico analyses were performed to assess the pathogenicity of these variants and their impacts on protein three-dimensional (3D) structure. Results:Two known missense variants (PMS2:NM_000535:exon11:c.1847T>C:p.V616A and PMS2:NM_000535:exon14:c.2444C>T:p.S815L) and a novel frameshift variant (MSH2:NM_000251:exon3:c.579delG:p.Q193fs) were found in families 1, 2, and 3, respectively. Protein 3D modeling showed that the c.2444C>T variant in the PMS2 protein locally altered the protein structure. In the wild-type PMS2 protein, S815 formed hydrogen bonds with N708 (3.1 Å), A811 (2.9 Å and 3.2 Å), and C812 (3.6 Å), whereas the mutant L815 did not form hydrogen bonds with nearby residues. The c.579delG variation in the MSH2 protein led to truncation from 934 amino acids to 212 amino acids, altered the sequence of the Domain 2 region, and caused the loss of Domains 3, 4, and 5. Conclusion:The two missense variants of the PMS2 gene (PMS2:NM_000535:exon11:c.1847T>C:p.V616A and PMS2:NM_000535:exon14:c.2444C>T:p.S815L) were considered variants of uncertain significance, whereas the novel frameshift variant of the MSH2 gene (MSH2:NM_000251:exon3:c.579delG:p.Q193fs) was considered likely pathogenic.

ObjectiveThis study aimed to characterize the pathogenic variants in three colon cancer families suspected of Lynch syndrome (LS), providing experimental evidence for precision screening and genetic counseling of the disease.MethodsThree suspected LS families were first identified, and subsequently, immunohistochemical analysis was performed on colon tissue samples from probands to assess the expression of four DNA mismatch repair proteins. Whole-exome sequencing was conducted to screen for potential pathogenic variants within the families. The SWISS-MODEL online platform was used to predict the three-dimensional structures of the mutant and wild-type proteins based on bioinformatics analysis. The predicted structures were then visualized using PyMOL software.ResultsTwo known MSH2 missense variants were identified: NM_000251.3:c.2633A>T:p.E878V in Family 1 and NM_000251.3:c.998G>A:p.C333Y in Family 2. A novel variant, designated as NM_000251.3:c.507del:p.Q170Rfs*4, was identified in the MSH2 gene of Family 3. This variant is caused by the deletion of an adenine at nucleotide position 507 within the MSH2 coding sequence, resulting in a frameshift. Consequently, glutamine at amino acid position 170 is altered to arginine, and a premature termination codon is introduced three residues downstream. This frameshift is predicted to generate a truncated protein of only 172 amino acids.ConclusionThe MSH2 missense variant NM_000251.3:c.2633A>T:p.E878V was classified as a variant of uncertain significance regarding its role in LS. In contrast, the NM_000251.3:c.998G>A:p.C333Y missense variant was confirmed as pathogenic. Furthermore, the novel frameshift deletion NM_000251.3:c.507del:p.Q170Rfs*4 was also identified as a pathogenic variant.

Objective:The objectives of the present study were to identify the genetic variations in a Chinese patient with Usher syndrome and to determine the pathogenicity of the identified variations. Methods:Whole-exome sequencing was performed for the proband. Alphafold3 and PyMOL software were used to determine the impact of a variation on three-dimensional protein structure. A Minigene Splicing Assay was performed to investigate the impact of a variant on MYO7A splicing. Results:Two compound heterozygous missense and splicing variations of MYO7A (NM_000260:c.487G > A:p.G163R, rs1472566324 and c.2187 + 2_2187 + 8del, rs1416744060) were identified in the proband. After glycine (G, WT) is replaced by arginine (R, rs1472566324), arginine forms additional hydrogen bonds with the surrounding amino acids. In the Minigene Splicing Assay, abnormal splicing bodies (associated with an Exon18 jump) were observed in the mutant plasmids (rs1416744060). This abnormal splicing event caused a deletion of 31 aa inside the protein, generating a truncated protein of 2,184 aa. Conclusion:Compound heterozygous missense and splicing variants of MYO7A (rs1472566324 and rs1416744060) were the likely pathogenic variants of a patient with Usher syndrome type 1B.

Background:This study aimed to analyze the pathogenic variants in one family with colorectal cancer and another with endometrial cancer and provide appropriate personalized prevention strategies for carriers of these genetic mutations. Methods:One proband with colorectal cancer and another with endometrial cancer and their family members were enrolled in this study. Whole-exome sequencing was used to identify pathogenic gene mutations in both families. We compared the structural difference between the wild-type and mutant MSH2 proteins using SWISS-MODEL and PyMOL visualization software. Results:We identified one novel mutation (NM_000251.2:c.1486delT:p.L496*) in the MSH2 gene in Family I and a known mutation (NM_001258271.1:c.884 + 4A > G) in the MLH1 gene in Family II. The novel mutation (NM_000251.2:c.1486delT:p.L496*) caused a stop gain mutation, resulting in the absence of amino acids 496-934 in the mutant MSH2 protein. This led to the loss of Domain 5 and alterations in the sequences of Domain 3 and Domain 4 regions, resulting in premature termination of MSH2 protein coding. The known mutation (NM_001258271.1:c.884 + 4A > G) in MLH1 causes the skipping of exon 10, producing a truncated protein and undergoing nonsense-mediated decay based on literature reports. Thus, 5-fluorouracil-based adjuvant chemotherapy is not recommended for patients with lynch syndrome. Conclusion:The novel stop gain mutant (NM_000251.2:c.1486delT:p.L496*) in MSH2 is deemed pathogenic for LS, and the mutant (NM_001258271.1:c.884 + 4A > G) in MLH1 has been further confirmed to be pathogenic. These findings expand the spectrum of mismatch repair gene variations in the ethnic group Han of China and reaffirm the importance of genetic testing for LS.

Purpose:This study aimed to examine pathogenic variations in three families clinically diagnosed with suspected Lynch syndrome (LS). Methods:Three probands clinically diagnosed suspected LS were subjected to immunohistochemical analysis of DNA mismatch repair (MMR) protein. Whole-exome sequencing and Sanger sequencing were performed to screen pathogenic variations. I-TASSER and PyMOL were used to analyze changes in the functional domains of mutant proteins. Results:A known missense variation (GRCh37 chr2:g.47702367G>A, MSH2:NM_000251:c.1963G>A:p.V655I), a known stop-gain variant (GRCh37 chr2:g.47709984G>T, MSH2:NM_000251:c.2701G>T:p.E901X), and a known frameshift insertion variation (GRCh37 chr2:g.48032124 dupA, MSH6:NM_000179:c.3514dupA:p.R1172Kfs*5) in Family 1, Family 2, and Family 3, respectively, were observed. The c.1963G>A variation caused the 655th amino acid of MSH2 to change from valine to isoleucine, and there were no significant changes in both the overall and local protein models in MSH2. Further, the c.2701G>T variation caused the 901st amino acid of MSH2 to change from glutamic acid to a premature stop codon in exon 16, and the deletion of amino-acids 901-934 caused changes in the Domain 5 of MSH2 protein. Furthermore, the c.3514dupA variation caused the 1172nd amino acid of MSH6 to change from arginine to lysine, followed by frameshift, which caused changes in the Domain 5 of MSH6 protein. Conclusion:The missense variation (MSH2:NM_000251:c.1963G>A:p.V655I) and the stop-gain variation (MSH2:NM_000251:c.2701G>T:p.E901X) were considered uncertain significance for LS, and another pathogenic variation (MSH6:NM_000179:c.3514dupA:p.R1172Kfs*5) has been further confirmed.

BACKGROUND:Peutz-Jeghers syndrome (PJS), a rare dominantly inherited disease, is primarily characterized by hamartomatous polyps and melanotic macules as well as by an increased risk of cancer. The current study aimed to identify the pathogenic gene and pathogenic mechanism of a proband with PJS, thereby offering precise prevention and treatment strategies for PJS. METHODS:A detailed clinical examination was performed of the proband diagnosed with PJS and her family members. In addition, peripheral venous blood was collected from the family members to extract genomic DNA. The pathogenic genes of the proband were identified using whole-exome sequencing, and the candidate pathogenic variants were verified via Sanger sequencing. Meanwhile, co-segregation tests were performed among six family members. Finally, reverse transcription-polymerase chain reaction (RT-PCR) was performed to assess transcript variants in the peripheral blood cells of patients and non-related healthy controls. RESULTS:Genetic testing revealed a rare splicing variant c.921-1G > C in STK11 in the proband and in her sister and nephew, and the variant co-segregated among the affected family members and nonrelated healthy controls. The proband phenotypically presented with a rare gastric-type adenocarcinoma of the cervix. RT-PCR revealed that the STK11 c.921-1G > C variant could produce two transcripts. Of note, 40 base pairs were deleted in the aberrant transcript between exons 3 and 4, resulting in a frameshift variant and premature termination of the amino acid in exon 6 and ultimately leading to the loss of its functional domain in the STK11 protein. Finally, RT-PCR showed that compared with healthy controls, STK11 mRNA expression level was < 50% in patients. CONCLUSION:The present study results indicated that the rare splicing variant c.921-1G > C in intron 7 of STK11 may be a pathogenic variant in patients with PJS. However, this variant (in intron 7) may not produce abnormal transcripts (deletion of 40 base pairs between exons 3 and 4), and PJS may be attributed to the decrease in STK11 expression. Therefore, this study emphasized the importance of genetic counseling, pre-symptomatic monitoring, and early complication management in PJS.

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. This condition is characterized by germline variants in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2. In this study, we analyzed the molecular defects and clinical manifestations of two families affected with CRC and proposed appropriate individual preventive strategies for all carriers of the variant. We recruited two families diagnosed with CRC and combined their family history and immunohistochemical results to analyze the variants of probands and those of other family members by using whole exome sequencing. Subsequently, gene variants in each family were screened by comparing them with the variants available in the public database. Sanger sequencing was performed to verify the variant sites. An online platform ( https://www.uniprot.org ) was used to analyze the functional domains of mutant proteins. A novel frameshift variant (NM_001281492, c.1129_1130del, p.R377fs) in MSH6 and a known deleterious variant (NM_000249.4:c.1731G > A, p.S577S) in MLH1 were identified in the two families with CRC. Using bioinformatics tools, we noted that the frameshift variant reduced the number of amino acids in the MSH6 protein from 1230 to 383, thereby leading to no MSH6 protein expression. The silent variant caused splicing defects and was strongly associated with LS. 5-Fluorouracil-based adjuvant chemotherapy is not recommended for patients with LS. The novel frameshift variant (MSH6, c.1129_1130del, p.R377fs) is likely pathogenic to LS, and the variant (MLH1, c.1731G > A, p.S577S) has been further confirmed to be pathogenic to LS. Our findings underscore the significance of genetic testing for LS and recommend that genetic consultation and regular follow-ups be conducted to guide individualized treatment for cancer-afflicted families, especially those with a deficiency in MMR expression.

BACKGROUND:Fabry disease (FD), an X-linked lysosomal disorder, is marked by a lack of alpha-galactosidase A (α-Gal A). Agalsidase beta, a recombinant form of α-Gal A, is fundamental to enzyme replacement therapy for FD but requires close monitoring for adverse events (AEs). RESEARCH DESIGN AND METHODS:This study retrospectively analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) database for agalsidase beta-related AEs. Disproportionality analysis was used for data analysis. RESULTS:A total of 7,611 AE reports for agalsidase beta were analyzed. The most common AEs included pyrexia, pain, chills, malaise, and nausea. Several system organ classes including Cardiac Disorders, General Disorders and Administration Site Conditions, and Vascular Disorders, showed positive signals. Subgroup analysis by gender revealed differences in AE reporting, with males exhibiting a higher reporting odds ratio for certain preferred terms such as Renal Transplant and Drug Specific Antibody Present. CONCLUSION:The FAERS database analysis of agalsidase beta AEs identified a significant number of cardiovascular, renal, and cerebrovascular system-related reports. While agalsidase beta is generally well-tolerated, the study underscores the necessity for gender-specific treatment approaches due to the higher incidence of certain AEs in males.

Purpose To determine the relationship between HLA-B gene mutations and levofloxacin-induced toxic epidermal necrolysis (TEN). Methods A 71-year-old Chinese woman developed TEN after oral administration of solifenacin (5 mg) and levofloxacin (0.5 g) for cystitis. HLA-B*5801 and HLA-B*1502 alleles were detected using real-time PCR. Findings After supportive therapy (antiallergic treatments, plasma exchange, etc) and withdrawal of the culprit medication levofloxacin, the patient was discharged with re-epithelialization of the exfoliated skin. The patient was HLA-B*1502 allele positive and HLA-B*5801 allele negative. Implications This is the first report of levofloxacin-induced TEN suspected to be caused by mutations in the HLA-B*1502 allele.

Background: We assessed the response to sulfonylureas and the functional characteristics of HNF1A mutations in patients with maturity-onset diabetes of the young type 3 (MODY3). Methods: We recruited a family with suspected MODY in this study, and gene sequencing (wholeexome sequencing) was used to screen germline mutations. Luciferase reporter assays were used to evaluate the activity of the mutated genes. Results: Heterozygous HNF1A variant (NM_000545.8:c.1330_1331del, p.Gln444fs) was identified in the proband and was not found in his father, grandmother, and nonrelated healthy controls. The mutant protein had 552 amino acids, 110 fewer than the wild type protein. Furthermore, the amino acid sequence was completely different between the mutant protein and the wild type protein starting from the 444th amino acid. Luciferase reporter assays revealed that the variant had impaired HNF4A promoter-regulation activity. The patient did not achieve good hypoglycemic effects during long-term treatment with insulin and metformin. The effect of hypoglycemic treatment was highly significant after the addition of sulfonylurea drugs. Conclusions: The HNF1A p.Gln444fs variant associated with MODY3, and most likely a truncated protein, impaired HNF1A transcriptional activity. The variant carrier experienced an enhanced response to sulfonylureas.

单基因糖尿病是以单基因突变为特征的一种糖尿病,因其异质性,以及与1、2型糖尿病有重叠,临床上难以准确诊断.正确的诊断对某些类型的单基因糖尿病至关重要,然而,目前临床上仍缺乏简单的临床标准来选择患者进行基因检测,甚至难以解释基因检测的结果.本文对单基因糖尿病的分类(包括青少年成年起病型糖尿病、新生儿糖尿病、线粒体糖尿病和综合征型糖尿病)、临床诊断及相应的治疗手段进行综述,旨在为单基因糖尿病的诊断提供依据,并为其个体化治疗提供帮助.

Objective:This study aimed to identify the molecular defects and clinical manifestations in a Chinese family with brachydactyly (BD) type A1 (BDA1) and multiple-synostoses syndrome 2 (SYNS2). Methods:A Chinese family with BDA1 and SYNS2 was enrolled in this study. Whole-exome sequencing was used to analyze the gene variants in the proband. The sequences of the candidate pathogenic variant in GDF5 was validated via Sanger sequencing. I-TASSER and PyMOL were used to analyze the functional domains of the corresponding mutant proteins. Results:The family was found to have an autosomal-dominantly inherited combination of BDA1 and SYNS2 caused by the S475N variant in the GDF5 gene. The variant was located within the functional region, and the mutated residue was found to be highly conserved among species. Via bioinformatic analyses, we predicted this variant to be deleterious, which perturb the protein function. The substitution of the negatively charged amino acid S475 with the neutral N475 was predicted to disrupt the formation of salt bridges with Y487 and impair the structure, stability, and function of the protein, consequently, the abnormalities in cartilage and bone development ensue. Conclusions:A single genetic variant (S475N) which disrupt the formation of salt bridges with Y487, in the interface of the antagonist- and receptor-binding sites of GDF5 concurrently causes two pathological mechanisms. This is the first report of this variant, identified in a Chinese family with BDA1 and SYNS2.

Introduction: Familial adenomatous polyposis (FAP) is the second most commonly inherited colorectal cancer (CRC) predisposition caused by germline mutations within the adenomatous polyposis coli (APC) gene. The molecular defects and clinical manifestations of two FAP families were analyzed, and individual prevention strategies suitable for mutation carriers in different families were proposed.Methods and results: The pathogenic gene mutations were identified among the two families using whole-exome sequencing and verified with Sanger sequencing or quantitative polymerase chain reaction (qPCR). One novel (GRCh37:Chr5: 112145676-112174368, del, 28,692 bp) and a known (c.C847T:p.R283X) mutation in the APC gene were pathogenic mutations for FAP, according to the sequencing data and tumorigenesis pattern among the family members. The two mutations led to a premature translational stop signal, synthesizing an absent or disrupted protein product.Conclusion: Our findings expand the known germline mutation spectrum of the APC gene among the Chinese population. This reaffirms the importance of genetic testing in FAP. Genetic consultation and regular follow-ups are necessary for the individualized treatment of cancer-afflicted families with APC expression deficiency. Additional work is required to develop safe and effective chemotherapy and immunotherapy for FAP based on the mutation type.

BACKGROUND Familial hypercholesterolemia(FH)is a common autosomal dominant hereditary disease.Its early diagnosis and intervention significantly improve the patient's quality of life.However,there are few types of research on the FH pathogen-ic genes in China.METHODS In this study,we recruited a family diagnosed with FH and used whole exome sequencing(WES)to analyze the proband variants.Intracellular cholesterol level,reactive oxygen species(ROS)level,and the expression of pyroptosis-related genes were detected after overexpression of wild-type or variant LDLR in L02 cells.RESULTS A heterozygous missense variant predicted to be deleterious to LDLR(c.1879G>A,p.Ala627Thr)was identified in the proband.Mechanistically,intracellular cholesterol level,ROS level,and the expression of pyroptosis-related genes,nucleotide-binding oligomerization domain-like receptor family protein 3(NLRP3)inflammasome and components(caspase 1,apoptosis-as-sociated speck-like protein containing a caspase recruitment domain(ASC)and NLRP3),gasdermin D(GSDMD),interleukin(IL)-18,IL-1β was elevated in the variant LDLR group,which was attenuated by inhibition of ROS.CONCLUSIONS FH is associated with a variant(c.1879G>A,p.Ala627Thr)in the LDLR gene.Regarding the mechanism,the ROS/NLRP3-mediated pyroptosis in hepatic cells may contribute to the pathogenesis of the LDLR variant.

Introduction: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominant systemic vascular disease that primarily involves small arteries. Patients with CADASIL experience migraines, recurrent ischemic strokes, cognitive decline, and dementia. The NOTCH3 gene, which is located on chromosome 19p13.12, is one of the disease-causing genes in CADASIL. Herein, we investigate the genetic and phenotypic features in a Chinese CADASIL family with heterozygous NOTCH3 mutation.Methods and Results: In the family, the proband suffered from dizziness, stroke, and cognitive deficits. Brain magnetic resonance imaging (MRI) demonstrated symmetrical white matter lesions in the temporal lobe, outer capsule, lateral ventricle, and deep brain. Whole-exome sequencing identified a known missense mutation in the proband, c.397C > T (p.Arg133Cys), which was identified in his son and granddaughter using Sanger sequencing. The proband's younger brother and younger sister also have a history of cognitive impairment or cerebral infarction, but do not have this genetic mutation, which may highlight the impact of lifestyle on this neurological disease.Conclusion: We identified a known CADASIL-causing mutation NOTCH3 (c.397C > T, p.Arg133Cys) in a Chinese family. The clinical manifestations of mutation carriers in this family are highly heterogeneous, which is likely a common feature for the etiology of different mutations in CADASIL. Molecular genetic analyses are critical for accurate diagnosis, as well as the provision of genetic counselling for CADASIL.

Background: Scrophularia ningpoensis Hemsl. is a commonly used medicinal plant in China for the treatment of diabetes mellitus (DM), but its mechanism of action remains poorly described. Type 2 diabetes mellitus (T2DM) accounts for > 90% of all DM cases and is characterized by insulin resistance. Purpose: The aim of this study was to investigate whether the insulin sensitivity can be improved by treatment with aqueous extract of S. ningpoensis (AESN) and further explore its mechanism(s) of activity. Methods: Primary mouse hepatocytes and human HepG2 hepatocytes were used to investigate the effects of AESN on cell viability, AMP-activated protein kinase (AMPK) activation and glucose output under normal culture conditions. To mimic hyperglycemia and insulin resistance in vitro, hepatocytes were exposed to high glucose (HG), and the influences of AESN on AMPK phosphorylation, NLRP3 inflammation activation, insulin signaling, lipid accumulation and glucose output were investigated. Increasing doses of AESN (50, 100 and 200 mg/kg/ day) were administered by gavage to db/db mice for 8 weeks, and then biochemical analysis and histopathological examinations were performed. Results: AESN significantly activated AMPK and inhibited glucose output in hepatocytes, but did not impact cell viability under normal culture conditions. Moreover, in HG-treated hepatocytes, AESN protected against aberrant AMPK activity, NLRP3 inflammasome activation, insulin signaling, and lipid accumulation. AMPK inhibition abolished the regulatory effects of AESN on the NLRP3 inflammasome, insulin signaling, lipid accumulation, and glucose output of hepatocytes following HG exposure. Furthermore, AESN administration reduced blood glucose and serum insulin levels, improved lipid profiles and insulin resistance, and corrected the aberrant AMPK activity and NLRP3 inflammasome activation in liver tissues. Conclusion: AESN improves insulin sensitivity via AMPK-mediated NLRP3 inflammasome inhibition.

Maturity-onset diabetes of the young (MODY) is rare monogenic diabetes. However, MODY is often undiagnosed or misdiagnosed. In this study, we aimed to investigate the pathogenic gene for diabetes and provide precise treatment for diabetes patients in three families. Three families with suspected MODY were enrolled and screened for germline mutations using Whole exome sequencing (WES). Candidate pathogenic variants were validated in other family members and non-related healthy controls. Three heterozygous missense mutations in the ABCC8 gene (NM_001287174), c.1555 C>T (p.R519C), c.3706 A>G (p.I1236V), and c.2885 C>T (p.S962L) were found in families A, B, and C, respectively. All mutation sites cosegregated with diabetes, were predicted to be harmful by bioinformatics and were not found in non-related healthy controls. Two probands (onset ages, 8 and 12 years) were sensitive to glimepiride. However, an insufficient dose (2 mg/day) led to ketoacidosis. When the dosage of glimepiride was increased to 4 mg/day, blood sugar remained under control. A dose of 4 mg glimepiride daily also effectively controlled blood sugar in an adult patient 25-year-old. In addition, all patients were sensitive to liraglutide, which could control blood sugar better. These data suggest that ABCC8 was the pathogenic gene in three families with diabetes. Glimepiride (2 mg/day) was not effective in controlling blood sugar in children with ABCC8 mutations, however, 4 mg/daily glimepiride was effective in both adults and children. Moreover, liraglutide was effective in controlling blood sugar in both adults and children with ABCC8 mutations.