Carbon availability and microbial activity manipulate the temperature sensitivity of anaerobic degradation in a paddy soil profile.

Soil contains a substantial amount of organic carbon, and its feedback to global warming has garnered widespread attention due to its potential to modulate atmospheric carbon (C) storage. Temperature sensitivity (Q10) has been widely utilized as a measure of the temperature-induced enhancement in soil organic carbon (SOC) decomposition. It is currently rare to incorporate Q10 of CO2 and CH4 into the study of waterlogged soil profiles and explore the possibility of artificially reducing Q10 in rice fields. To investigate the key drivers of Q10, we collected 0-1 m paddy soil profiles, and stratified the soil for submerged anaerobic incubation. The relationship between SOC availability, microbial activity, and the Q10 of CO2 and CH4 emissions was examined. Our findings indicate that as the soil layer deepens, soil C availability and microbial activity declined, and the Q10 of anaerobic degradation increased. Warming increased C availability and microbial activity, accompanied by weakened temperature sensitivity. The Q10 of CO2 correlated strongly with soil resistant C components, while the Q10 of CH4 was significantly influenced by labile substrates. The temperature sensitivity of CH4 (Q10 = 3.99) was higher than CO2 emissions (Q10 = 1.78), indicating the need for greater attention of CH4 in predicting warming's impact on anaerobic degradation in rice fields. Comprehensively assessing CO2 and CH4 emissions, the 20-40 cm subsurface soil is the most temperature-sensitive. Despite being a high-risk area for C loss and CH4 emissions, management of this soil layer in agriculture has the potential to reduce the threat of global warming. This study underscores the importance of subsurface soil in paddy fields, advocating greater attention in scientific simulations and predictions of climate change.

A low-methane rice with high-yield potential realized via optimized carbon partitioning.

Global rice cultivation significantly contributes to anthropogenic methane emissions. The methane emissions are caused by methane-producing microorganisms (methanogenic archaea) that are favoured by the anoxic conditions of paddy soils and small carbon molecules released from rice roots. However, different rice cultivars are associated with differences in methane emission rates suggesting that there is a considerable natural variation in this trait. Starting from the hypothesis that sugar allocation within a plant is an important factor influencing both yields and methane emissions, the aim of this study was to produce high-yielding rice lines associated with low methane emissions. In this study, the offspring (here termed progeny lines) of crosses between a newly characterized low-methane rice variety, Heijing 5, and three high-yielding elite varieties, Xiushui, Huayu and Jiahua, were selected for combined low-methane and high-yield properties. Analyses of total organic carbon and carbohydrates showed that the progeny lines stored more carbon in above-ground tissues than the maternal elite varieties. Also, metabolomic analysis of rhizospheric soil surrounding the progeny lines showed reduced levels of glucose and other carbohydrates. The carbon allocation, from roots to shoots, was further supported by a transcriptome analysis using massively parallel sequencing of mRNAs that demonstrated elevated expression of the sugar transporters SUT-C and SWEET in the progeny lines as compared to the parental varieties. Furthermore, measurement of methane emissions from plants, grown in greenhouse as well as outdoor rice paddies, showed a reduction in methane emissions by approximately 70 % in the progeny lines compared to the maternal elite varieties. Taken together, we report here on three independent low-methane-emission rice lines with high yield potential. We also provide a first molecular characterisation of the progeny lines that can serve as a foundation for further studies of candidate genes involved in sugar allocation and reduced methane emissions from rice cultivation.

Liquid fertilizers produced by microwave-assisted acid hydrolysis of livestock and poultry wastes and their effects on hot pepper cultivation.

Liquid fertilizers (LFs) produced by microwave-assisted acid hydrolysis of livestock and poultry wastes were applied to potted hot pepper (Capsicum annuum L.) to evaluate their potential to be used as amino acid LFs. A preliminary experiment was conducted to determine the optimum acid-hydrolysis conditions for producing LFs from a mixture of pig hair and faeces (P) and another mixture of chicken feathers and faeces (C). Two LFs were produced under the optimum acid-hydrolysis conditions (acidification by sulphuric acid (7.5 mol L-1) in a microwave (200 W) for 90 minutes), and a commercial amino acid LF (Guo Guang (GG)) was used for comparison. P, C and GG fertilizers were tested in potted hot pepper cultivation at two doses, whereas no fertilizer application served as the control (CK). P and C fertilizers significantly increased the fruit yield compared with GG fertilizer, particularly at the higher dose. Moreover, the treatments improved the fruit vitamin C and soluble sugar contents in the order of C > P > GG compared with CK. These results could be attributed to more types of amino acids in C fertilizer than in P and GG fertilizers. The results also indicated that the prepared fertilizers could significantly increase the shoot and root dry weight, soil available nitrogen and phosphorus contents and nitrogen, phosphorus, and potassium (NPK) uptake by plants compared with CK. In conclusion, microwave-assisted acid hydrolysis could effectively convert unusable wastes into valuable fertilizers comparable or even superior to commercial fertilizers.

The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis.

Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly understood. Here we report that expression levels of the E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse hearts upon I/R injury. Genetic ablation of MARCH2 aggravated myocardial infarction and cardiac dysfunction upon myocardial I/R injury. Single-cell RNA-seq analysis suggested that loss of MARCH2 prompted activation of NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found to act as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and fostering the recruitment of NLRP3. MARCH2 directly interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, resulting in reduced PGAM5-MAVS co-condensation, and consequently inhibition of NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 significantly ameliorated I/R-induced mouse heart dysfunction. Altogether, our findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury.

Twelve-year conversion of rice paddy to wetland does not alter SOC content but decreases C decomposition and N mineralization in Japan.

Land-use change worldwide has been driven by anthropogenic activities, which profoundly regulates terrestrial C and N cycles. However, it remains unclear how the dynamics and decomposition of soil organic C (SOC) and N respond to long-term conversion of rice paddy to wetland. Here, soil samples from five soil depths (0-25 cm, 5 cm/depth) were collected from a continuous rice paddy and an adjacent wetland (a rice paddy abandoned for 12 years) on Shonai Plain in northeastern Japan. A four-week anaerobic incubation experiment was conducted to investigate soil C decomposition and N mineralization. Our results showed that SOC in the wetland and rice paddy decreased with soil depth, from 31.02 to 19.66 g kg-1 and from 30.26 to 18.86 g kg-1, respectively. There was no significant difference in SOC content between wetland and rice paddy at any depth. Soil total nitrogen (TN) content in the wetland (2.61-1.49 g kg-1) and rice paddy (2.91-1.78 g kg-1) showed decreasing trend with depth; TN was significantly greater in the rice paddy than in the wetland at all depths except 20-25 cm. Paddy soil had significantly lower C/N ratios but significantly larger decomposed C (Dec-C, CO2 and CH4 production) and mineralized N (Min-N, net NH4+-N production) than wetland soil across all depths. Moreover, the Dec-C/Min-N ratio was significantly larger in wetland than in rice paddy across all depths. Rice paddy had higher exponential correlation between Dec-C and SOC, Min-N and TN than wetland. Although SOC did not change, TN decreased by 14.1% after the land-use conversion. The Dec-C and Min-N were decreased by 32.7% and 42.2%, respectively, after the12-year abandonment of rice paddy. Conclusively, long-term conversion of rice paddy to wetland did not distinctly alter SOC content but increased C/N ratio, and decreased C decomposition and N mineralization in 0-25 cm soil depth.

New vegetable field converted from rice paddy increases net economic benefits at the expense of enhanced carbon and nitrogen footprints.

China accounts for around 50 % of the global vegetable harvested area which is expected to increase continuously. Large cropland areas, including rice paddy, have been converted into vegetable cultivation to feed an increasingly affluent population and increase farmers' incomes. However, little information is available on the balance between economic benefits and environmental impacts upon rice paddy conversion into vegetable fields, especially during the initial conversion period. Herein, the life cycle assessment approach was applied to compare the differences in agricultural input costs, yield incomes, net economic benefits (NEB), carbon (C) and nitrogen (N) footprints and net ecosystem economic benefits (NEEB) between the double rice paddy (Rice) and newly vegetable field (Veg) converted from Rice based on a four-year field experiment. Results showed that yield incomes from Veg increased by 96-135 %, outweighing the increased agricultural input costs due to higher inputs of labor and pesticide, thus significantly increasing NEB by 80-137 %, as compared to Rice. Rice conversion into Veg largely increased C footprints by 2.3-10 folds and N footprints by 1.1-2.6 folds, consequently increasing the environmental damage costs (EDC) by 2.2 folds on average. The magnitudes of increases in C and N footprints and EDC due to conversion strongly declined over time. The NEEB, the trade-offs between NEB and EDC, decreased by 18 % in the first year, while increasing by 63 % in the second year and further to 135 % in the fourth year upon conversion. These results suggested that rice paddy conversion into vegetable cultivation could increase the NEB at the expense of enhanced EDC, particular during the initial conversion years. Overall, these findings highlight the importance of introducing interventions to mitigate C and N footprints from newly converted vegetable field, so as to maximize NEEB and realize the green and sustainable vegetable production.

The ubiquitin codes in cellular stress responses.

Ubiquitination/ubiquitylation, one of the most fundamental post-translational modifications, regulates almost every critical cellular process in eukaryotes. Emerging evidence has shown that essential components of numerous biological processes undergo ubiquitination in mammalian cells upon exposure to diverse stresses, from exogenous factors to cellular reactions, causing a dazzling variety of functional consequences. Various forms of ubiquitin signals generated by ubiquitylation events in specific milieus, known as ubiquitin codes, constitute an intrinsic part of myriad cellular stress responses. These ubiquitination events, leading to proteolytic turnover of the substrates or just switch in functionality, initiate, regulate, or supervise multiple cellular stress-associated responses, supporting adaptation, homeostasis recovery, and survival of the stressed cells. In this review, we attempted to summarize the crucial roles of ubiquitination in response to different environmental and intracellular stresses, while discussing how stresses modulate the ubiquitin system. This review also updates the most recent advances in understanding ubiquitination machinery as well as different stress responses and discusses some important questions that may warrant future investigation.

Fertilization intensities at the buffer zones of ponds regulate nitrogen and phosphorus pollution in an agricultural watershed.

The sudden increase in water nutrients caused by environmental factors have always been a focus of attention for ecologists. Fertilizer inputs with spatio-temporal characteristics are the main contributors to water pollution in agricultural watersheds. However, there are few studies on the thresholds of nitrogen (N) and phosphorus (P) fertilization rates that affect the abrupt deterioration of water quality. This study aims to investigate 28 ponds in Central China in 2019 to reveal the relationships of basal and topdressing fertilization intensities in surrounding agricultural land with pond water N and P concentrations, including total N (TN), nitrate (NO3--N), ammonium (NH4+-N), total P (TP), and dissolved P (DP). Abrupt change analysis was used to determine the thresholds of fertilization intensities causing sharp increases in the pond water N and P concentrations. Generally, the observed pond water N and P concentrations during the high-runoff period were higher than those during the low-runoff period. The TN, NO3--N, TP, DP concentrations showed stronger positive correlations with topdressing intensities, while the NH4+-N concentrations exhibited a higher positive correlation with basal intensities. On the other hand, the NO3--N concentrations had a significant positive correlation with the topdressing N, basal N, and catchment slope interactions. Significant negative correlations were observed between all water quality parameters and pond area. Spatial scale analysis indicated that fertilization practices at the 50 m and 100 m buffer zone scales exhibited greater independent effects on the variations in the N and P concentrations than those at the catchment scale. The thresholds analysis results of fertilization intensities indicated that pond water N concentrations increased sharply when topdressing and basal N intensities exceeded 163 and 115 kg/ha at the 100 and 50 m buffer zone scales, respectively. Similarly, pond water P concentrations rose significantly when topdressing and basal P intensities exceeded 117 and 78 kg/ha at the 50 m buffer zone scale, respectively. These findings suggest that fertilization management should incorporate thresholds and spatio-temporal scales to effectively mitigate pond water pollution.

Mitigating ammonia volatilization in rice cultivation: The impact of partial organic fertilizer substitution.

Optimizing water and nitrogen management to minimize NH3 volatilization from paddy fields has been extensively studied. However, there is limited research on the combined effect of different rates of organic fertilizer substitution (OFS) and irrigation methods in rice cultivation, exploring an effective water and nitrogen combination is beneficial to mitigate NH3 volatilization. To address this gap, we conducted a two-year field experiment to investigate NH3 volatilization under different OFS rates (0%, 25%, and 50%) combined with continuous flooding irrigation (CF) and alternate wet and dry irrigation (AWD). Our findings revealed that NH3 fluxes exhibited similar emission patterns after each fertilization event and significantly decreased with increasing rates of OFS during the basal stage. Compared to no substitution (ON0), the low (ON25) and high (ON50) rates of OFS reduced cumulative NH3 emissions by 18.9% and 16.6%, and lowed NH3 emission factors (EFs) by 26.7% and 23.3%, respectively. Although OFS resulted in a slight reduction in rice yield, yield-scaled NH3 emissions were significantly reduced by 11.9% and 6.5% under the low and high substitution rates, respectively. This reduction was mainly attributed to the slight yield reduction observed at the low substitution rate. Furthermore, when combined with ON0, AWD irrigation had the potential to increase NH3 volatilization. However, this increase was not observed when combined with ON25 and ON50. During each fertilization stage, floodwater + concentration emerged as the prominent environmental factor influencing NH3 volatilization, showing a stronger and more positive correlation compared to other factors such as floodwater pH, soil pH, and NH4+ concentration. Based on our findings, we recommend implementing effective water and nitrogen management strategies to minimize NH3 volatilization in rice cultivation. This involves applying a lower rate of organic fertilizer substitution during the basal stage, maintaining high water levels during fertilization, and implementing mild AWD irrigation during non-fertilization periods.

Ascription of nosZ gene, pH and copper for mitigating N2O emissions in acidic soils.

Soil nitrous oxide (N2O) emissions are alarming for global warming and climate change. N2O reduction is carried out only by nosZ gene encoded N2O-reductase, which is highly sensitive to acidic pH and copper (Cu) contents. Therefore, a microcosm study was conducted to examine the attribution of soil pH management, Cu supply and nosZ gene abundance for N2O emission mitigation. Cu was applied at the dose of 0, 10, 25 and 50 mg kg-1 to three acidic soils (Soil 1, 2 and 3) without and with dolomite (0 and 5 g kg-1). Cu application and soil pH increment substantially enlarged the abundance of nosZ gene, and consequently mitigated soil N2O emissions; highest reduction with 25 Cu mg kg-1. Decline in NH4+ and subsequently accumulation of NO3-, and large contents of MBC and DOC in dolomite treated soils led to a substantial N2O reduction. The cumulative N2O emissions were lowest in the treatment of 25 Cu mg kg-1 with dolomite application for each soil. Results suggest that soil pH increment, an adequate Cu supply, and nosZ gene abundance can potentially lower soil N2O emissions in acidic soils.

Rethinking terrestrial dissolved organic matter in dam reservoirs before mixing: Linking photodegradation and biodegradation and the phenanthrene binding behavior.

With the increased construction of dam reservoirs and the demand for water security, terrestrial dissolved organic matter (DOM) has received attention because of its role in regulating water quality, ecological functions, and the fate and transport of pollutants in dam reservoirs. This study investigated the transformations of soil DOM and vegetation DOM of dam reservoirs following photodegradation and biodegradation before conservative mixing, as well as the resultant effects on phenanthrene binding. Based on the results, terrestrial DOM could undergo transformation via photodegradation and biodegradation before conservative mixing in dam reservoirs. Although both processes resulted in substantial decreases in DOM concentrations, the changes in chromophoric DOM and fluorescent DOM depended on the original DOM sources. Furthermore, the photodegradation of terrestrial DOM resulted in more pronounced photobleaching than photomineralization. In addition, photodegradation of terrestrial DOM resulted in the generation of DOM-derived by-products with low molecular weight and low aromaticity, whereas the biodegradation of terrestrial DOM resulted in DOM-derived by-products with low molecular weight and high aromaticity. Subsequently, the photodegradation and biodegradation of terrestrial DOM substantially enhanced the binding affinity of phenanthrene. Soil DOM is prior to vegetation DOM when predicting the ecological risk of HOCs. These results indicate that the terrestrial DOM in dam reservoirs should be reconsidered before conservative mixing. Further studies on the coupling effects of both biogeochemical processes, as well as on the relative contributions of soil DOM and vegetation DOM after transformation to the aquatic DOM in dam reservoirs, are required. This study provides information on the environmental effects of dam construction from the perspective of biogeochemical processes.

The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation.

The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FINmajor (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.

Feedback regulation of ubiquitination and phase separation of HECT E3 ligases.

Lipid homeostasis is essential for normal cellular functions and dysregulation of lipid metabolism is highly correlated with human diseases including neurodegenerative diseases. In the ubiquitin-dependent autophagic degradation pathway, Troyer syndrome-related protein Spartin activates and recruits HECT-type E3 Itch to lipid droplets (LDs) to regulate their turnover. In this study, we find that Spartin promotes the formation of Itch condensates independent of LDs. Spartin activates Itch through its multiple PPAY-motif platform generated by self-oligomerization, which targets the WW12 domains of Itch and releases the autoinhibition of the ligase. Spartin-induced activation and subsequent autoubiquitination of Itch lead to liquid-liquid phase separation (LLPS) of the poly-, but not oligo-, ubiquitinated Itch together with Spartin and E2 both in vitro and in living cells. LLPS-mediated condensation of the reaction components further accelerates the generation of polyubiquitin chains, thus forming a positive feedback loop. Such Itch-Spartin condensates actively promote the autophagy-dependent turnover of LDs. Moreover, we show that the catalytic HECT domain of Itch is sufficient to interact and phase separate with poly-, but not oligo-ubiquitin chains. HECT domains from other HECT E3 ligases also exhibit LLPS-mediated the promotion of ligase activity. Therefore, LLPS and ubiquitination are mutually interdependent and LLPS promotes the ligase activity of the HECT family E3 ligases.

Patterns of Carbon-Bound Exogenous Compounds Impact Disease Pathophysiology in Lung Cancer Subtypes in Different Ways.

Carbon-bound exogenous compounds, such as polycyclic aromatic hydrocarbons (PAHs), tobacco-specific nitrosamines, aromatic amines, and organohalogens, are known to affect both tumor characteristics and patient outcomes in lung squamous cell carcinoma (LUSC); however, the roles of these compounds in lung adenocarcinoma (LUAD) remain unclear. We analyzed 11 carbon-bound exogenous compounds in LUAD and LUSC samples using in situ high mass-resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry imaging and performed a cluster analysis to compare the patterns of carbon-bound exogenous compounds between these two lung cancer subtypes. Correlation analyses were conducted to investigate associations among exogenous compounds, endogenous metabolites, and clinical data, including patient survival outcomes and smoking behaviors. Additionally, we examined differences in exogenous compound patterns between normal and tumor tissues. Our analyses revealed that PAHs, aromatic amines, and organohalogens were more abundant in LUAD than in LUSC, whereas the tobacco-specific nitrosamine nicotine-derived nitrosamine ketone was more abundant in LUSC. Patients with LUAD and LUSC could be separated according to carbon-bound exogenous compound patterns detected in the tumor compartment. The same compounds had differential impacts on patient outcomes, depending on the cancer subtype. Correlation and network analyses indicated substantial differences between LUAD and LUSC metabolomes, associated with substantial differences in the patterns of the carbon-bound exogenous compounds. These data suggest that the contributions of these carcinogenic compounds to cancer biology may differ according to the cancer subtypes.

Mitigating runoff nitrate loss from soil organic nitrogen mineralization in citrus orchard catchments using green manure.

Nitrate-nitrogen (NO3--N) loss is a significant contributor to water quality degradation in agricultural catchments. The amount of nitrogen (N) fertilizer input in citrus orchard is relatively large and results in significant NO3--N loss, compared to cropland. To promote sustainable N fertilizer management, it is crucial to identify the sources of runoff NO3--N loss in citrus orchards catchments. Particularly, we poorly know the sources of NO3--N and the mitigation mechanisms in these areas, which are highly polluted with NO3--N in water bodies. In this study conducted in central China, we conducted a field experiment with four treatments (CK: no N fertilizer; CF: conventional N fertilizer, 371.3kg N ha-1 yr-1 urea; OM: CF with organic manure; GM: CF with legume green manure) and a catchment-scale experiment in two citrus orchards (34.3%; 51.6%) catchments. To determine the source of runoff NO3--N loss, we used the dual isotope tracer method (δ15N and δ18O of NO3-) to identify the sources of NO3--N, and a 15-day incubation experiment to determine the potential and rate of soil N mineralization. Our findings revealed that soil organic nitrogen (SON) mineralization was the primary contributor to runoff NO3--N loss, and soil N mineralization potential (0.65⁎⁎⁎) and rate (0.54⁎⁎⁎) were the key factors impacting NO3--N loss. Interestingly, organic manure significantly increased 29.0% of NO3--N loss derived from SON in the runoff by enhancing soil N mineralization potential (+36.6%) and rate (+77.1%). But green manure mulching significantly reduced the soil N mineralization rate (-18.6%) compared to organic manure application, making it the most effective measure to reduce NO3--N loss (-12.4%). Our study highlights the critical role of regulating SON mineralization in controlling NO3--N pollution in surface waters in citrus orchard catchments.

Clinical and molecular characterization of 10 Chinese children with congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency.

BACKGROUND: The clinical manifestations of nonclassical 11beta-hydroxylase deficiency are very similar to those of non-classical 21-hydroxylase deficiency. For this study, we investigated the relationship between the clinical and molecular features of congenital adrenal hyperplasia caused by 11beta-hydroxylase deficiency and reviewed the related literature, which are expected to provide assistance for the clinical diagnosis and analysis of congenital adrenal hyperplasia. METHODS: Clinical data for 10 Chinese patients diagnosed with congenital adrenal hyperplasia in our hospital from 2018 to 2022 were retrospectively analyzed. We examined the effects of gene mutations on protease activity and constructed three-dimensional structure prediction models of proteins. RESULTS: We describe 10 patients with 11beta-hydroxylase gene mutations (n = 5, 46,XY; n = 5, 46,XX), with 10 novel mutations were reported. Female patients received treatment at an early stage, with an average age of 2.08 ± 1.66 years, whereas male patients received treatment significantly later, at an average age of 9.77 ± 3.62 years. The most common CYP11B1 pathogenic variant in the Chinese population was found to be c.1360C > T. All mutations lead to spatial conformational changes that affect protein stability. CONCLUSIONS: Our study found that there was no significant correlation between each specific mutation and the severity of clinical manifestations. Different patients with the same gene pathogenic variant may have mild or severe clinical manifestations. The correlation between genotype and phenotype needs further study. Three-dimensional protein simulations may provide additional support for the physiopathological mechanism of genetic mutations.