MEK1-dependent MondoA phosphorylation regulates glucose uptake in response to ketone bodies in colorectal cancer cells.

The Mondo family transcription factor MondoA plays a pivotal role in sensing metabolites, such as glucose, glutamine, and lactic acid, to regulate glucose metabolism and cell proliferation. Ketone bodies are important signals for reducing glucose uptake. However, it is unclear whether MondoA functions in ketone body-regulated glucose transport. Here we reported that ketone bodies promoted MondoA nuclear translocation and binding to the promoter of its target gene TXNIP. Ketone bodies reduced glucose uptake, increased apoptosis and decreased proliferation of colorectal cancer cells, which was impeded by MondoA knockdown. Moreover, we identified MEK1 as a novel component of the MondoA protein complex using a proteomic approach. Mechanistically, MEK1 interacted with MondoA and enhanced tyrosine 222, but not serine or threonine, phosphorylation of MondoA, inhibiting MondoA nuclear translocation and transcriptional activity. Ketone bodies decreased MEK1-dependent MondoA phosphorylation by blocking MondoA and MEK1 interaction, leading to MondoA nuclear translocation, TXNIP transcription, and inhibition of glucose uptake. Therefore, our study not only demonstrated that ketone bodies reduce glucose uptake, promote apoptosis, and inhibit cell proliferation in colorectal cancer cells by regulating MondoA phosphorylation but also identified MEK1-dependent phosphorylation as a new mechanism to manipulate MondoA activity.

Long-read sequencing identified intronic (GGCCTG)n expansion in NOP56 in one SCA36 family and literature review.

BACKGROUND: Spinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats. Recent methodological advances have made repeat expansion detection with long-read sequencing (LRS) feasible. Our study investigated one family with SCA 36 and further summarized the genetic and clinical characteristics of the total of 161 patients across different ethnic groups reported worldwide. METHODS: We enrolled a pedigree of 4 patients. The proband was a 55-year-old male. And he was screened for dynamic mutations of SCA subtypes by Tri-prime PCR (TP-PCR) and capillary electrophoresis, showing NOP56 as the candidate gene. The cosegregation was conducted by screening the NOP56 gene in his daughter and further confirmed by low-coverage (∼15 ×) LRS on the Oxford Nanopore platform. RESULTS: The SCA36 pedigree included a total of 4 patients. The proband showed the initial manifestation at the age of 45 years old, which was characterized by truncal ataxia. Genetic test results showed the (GGCCTG)n expansion in NOP56 gene (3/>15 and 6/>15 times respectively). To clarify the diagnosis genetically, LRS was performed in his daughter showing a large intronic insertion (chr20: 2633004 INS 7603 bp) containing (GGCCTG)n expansion of 782 units in NOP56 as the causative mutation. CONCLUSIONS: We identified one SCA36 pedigree by combining TP-PCR with LRS. Our study suggested LRS as an effective tool for molecular diagnosis. LRS also worked as a supplementary but necessary diagnostic tool for dynamic mutation-related SCA on the basis of repeat-primed PCR as well as capillary electrophoresis.

Clinical and genetic analyses of 150 patients with paroxysmal kinesigenic dyskinesia.

BACKGROUND: Mutations in PRRT2 and 16p11.2 microdeletion including PRRT2 have been identified as the pathogenic cause of paroxysmal kinesigenic dyskinesia (PKD). OBJECTIVE: The objective was to investigate the clinical and genetic features of PKD and to analyze the genotype-phenotype correlation. METHODS: We recruited PKD patients, recorded clinical manifestations, and performed PRRT2 screening in 150 PKD patients by unified PKD registration forms. Genotype-phenotype correlation analyses were conducted in probands. High-knee-exercise (HKE) tests were applied in one hundred and six patients. RESULTS: Eight PRRT2 mutations were detected, accounting for 22.76% of the probands. Three mutations (c.649dupC, c.649delC, and c.510_513delTCTG) were already reported, while four mutations (c.252_264delCACAGACCTCAGC, c.503_504delCT, c.679C > T, and c.804C > A) were first reported. One heterozygous microdeletion of 606 kb in 16p11.2 was detected in one patient. Compared with non-PRRT2 mutation carriers, the PRRT2 mutation carriers were younger at onset, experienced longer attacks, and tended to present with complicated PKD, combined phenotypes of dystonia and chorea. 57.01% of patients could effectively induce movement disorders through the HKE test. A good response was shown in 81.93% of the patients prescribed with antiepileptic drugs. 13.54% (13/96) had abnormal EEG results. CONCLUSIONS: PRRT2 mutations are common in patients with PKD and are significantly associated with an earlier age at onset, longer duration of attacks, a complicated form of PKD, combined phenotypes of dystonia and chorea. Patients with microdeletion of 16p11.2 may have more severe manifestations. The HKE test could contribute to the diagnosis of PKD. Carbamazepine is still the first choice for PKD patients, but individualized treatment should be formulated.

TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

Health services utilization of Chinese patients with Huntington's disease: a cross-sectional study.

BACKGROUND: Huntington's disease (HD) is a hereditary disease which could have a large impact on patients' quality of life. As the neurodegenerative disorders progress, HD patients are expected to regularly take follow-up medical visits for proper treatment. This study aimed to analyze the general situation of health services utilization of Chinese HD patients and factors associated with their adherence to follow-up medical visits. METHODS: We collected data from a questionnaire-based investigation conducted by the Chinese Huntington's Disease Association. Data from 232 respondents were included to investigate whether they adhered to regular follow-up medical visits and the influencing factors. Based on Andersen's behavioral model, the independent variables were categorized into predisposing, enabling and need factors. The variables were analyzed by chi-square test and stepwise logistic regression analysis. RESULTS: Thirty-one point nine percent of the respondents had regular follow-up medical visits over the past year. Univariate analysis showed that there were significant differences with 6 factors (P < 0.05), among which, according to logistic regression, 2 enabling factors (reimbursement of health insurance, need for accompanying family members to follow-up visits) and 3 need factors (perceived stage of disease, perceived effectiveness of drugs, self-care ability) were independent influencing factors of follow-up medical behaviors of Chinese HD patients. The predisposing factors investigated here did not play a part in determining patients' adherence to follow-up visits. CONCLUSIONS: Poor adherence to medical visits among Chinese HD patients is derived from multiple factors, including reimbursement of health insurance, perceived stage of disease and effectiveness of drugs, need for accompanying family members and self-care ability. To promote HD patients' health services utilization, the improvement of the health insurance system, the enhancement of social support and the development of therapeutic approaches still have a long way to go.

The Role of Mondo Family Transcription Factors in Nutrient-Sensing and Obesity.

In the past several decades obesity has become one of the greatest health burdens worldwide. Diet high in fats and fructose is one of the main causes for the prevalence of metabolic disorders including obesity. Promoting brown or beige adipocyte development and activity is regarded as a potential treatment of obesity. Mondo family transcription factors including MondoA and carbohydrate response element binding protein (ChREBP) are critical for nutrient-sensing in multiple metabolic organs including the skeletal muscle, liver, adipose tissue and pancreas. Under normal nutrient conditions, MondoA and ChREBP contribute to maintaining metabolic homeostasis. When nutrient is overloaded, Mondo family transcription factors directly regulate glucose and lipid metabolism in brown and beige adipocytes or modulate the crosstalk between metabolic organs. In this review, we aim to provide an overview of recent advances in the understanding of MondoA and ChREBP in sensing nutrients and regulating obesity or related pathological conditions.