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OBJECTIVE: To investigate the correlation between morphological typing and monoclonality of bone marrow plasma cells, and explore the diagnostic value of plasma cell morphological typing for high-risk smoldering multiple myeloma(HR-SMM). METHODS: The correlation between the morphological characteristics and the monoclonality of bone marrow plasma cells was analyzed in 84 patients with HR-SMM who treated in our hospital. The consistency of morphologically abnormal bone marrow plasma cells with serum free light chain (sFLC) ratio, next-generation sequencing (NGS) detection results, and its correlation with monoclonal plasma cells detected by flow cytometry (FCM) were further verified. The immunoglobulin types and levels of non-involved immunoglobulins in serum of the patients were detected, and the distribution of plasma cell clusters in patients with different disease was observed. RESULTS: The mean percentage of mature plasma cells were decreased successively in the order of reactive plasmacytosis (RP) group, monoclonal gammopathy of undetermined significance (MGUS) group, smoldering multiple myeloma (SMM) group, HR-SMM group and multiple myeloma (MM) group; while the mean percentage of immature, primitive, reticular and flaming plasma cells were increased successively in the order of RP group, MGUS group, SMM group, and HR-SMM group, and the difference between any two groups was statistically significant (P < 0.05).The average proportion of abnormal plasma cells in the bone marrow of HR-SMM patients was 96.2% of the total plasma cells. The proportion of abnormal plasma cells were in good agreement with the sFLC ratio and the results of NGS detection in HR-SMM patients (kappa=0.879 and kappa=0.891, both >0.75)ï¼and showed good correlation with the monoclonal plasma cells with immunophenotype of CD45-/CD38+/CD138+/CD56+/CD19-( γ=0.825). The levels of non-involved immunoglobulin in IgG, IgA and IgM type HR-SMM patients were all decreased by more than 25% compared with the normal reference range, and the differences were statistically significant (P < 0.05). There was no significant difference in the distribution ratio of plasma cell clusters among different disease groups (P >0.05). CONCLUSION: In HR-SMM patients, the immature, primitive, reticular and flaming plasma cells in bone marrow are considered as abnormal plasma cells, and they are correlated with monoclonal plasma cells. The proportion of abnormal plasma cells in total plasma cells of bone marrow and the reduction extent of non-involved immunoglobulin level in patients have certain reference value for the diagnosis of HR-SMM.
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Mieloma Múltiple , Células Plasmáticas , Humanos , Mieloma Múltiple/patología , Mieloma Múltiple Quiescente/diagnóstico , Médula Ósea/patología , Células de la Médula Ósea , Citometría de Flujo , FumarRESUMEN
Introduction: Soil has the highest carbon sink storage in terrestrial ecosystems but human farming activities affect soil carbon deposition. In this study, land cultivated for 70 years was selected. The premise of the experiment was that the soil could be finely categorized by subtype classification. We consider that farming activities affect the soil bacterial community and soil organic carbon (SOC) deposition differently in the three subtypes of albic black soils. Methods: Ninety soil samples were collected and the soil bacterial community structure was analysed by high-throughput sequencing. Relative changes in SOC were explored and SOC content was analysed in association with bacterial concentrations. Results: The results showed that the effects of farming activities on SOC deposition and soil bacterial communities differed among the soil subtypes. Carbohydrate organic carbon (COC) concentrations were significantly higher in the gleying subtype than in the typical and meadow subtypes. RB41, Candidatus-Omnitrophus and Ahniella were positively correlated with total organic carbon (TOC) in gleying shallow albic black soil. Corn soybean rotation have a positive effect on the deposition of soil carbon sinks in terrestrial ecosystems. Discussion: The results of the present study provide a reference for rational land use to maintain sustainable development and also for the carbon cycle of the earth.
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Sperm mobility (SM) is an objective index for measuring sperm motility; however, the mechanisms underlying its regulation in geese remain unclear. The present study sought to elucidate the genetic mechanism underlying SM traits in Zi geese (Anser cygnoides L.). To this end, three successive experiments were performed. In Experiment I, SM was determined in 40 ganders; the 3 ganders with the highest mobility and three with the lowest mobility were assigned to the high and low sperm mobility rank (SMR) groups, respectively. In Experiment II, the differences in fertility between the two SMR groups were assessed within two breeding flocks comprising the selected six ganders from Experiment I and 30 females (each flock had 3 ganders and 15 females). In Experiment III, the testes of the 6 ganders were harvested for histological observation and whole-transcriptome sequencing. Results revealed better fertility, well-developed seminiferous tubules, and abundant mature sperm in the high-SMR-flock compared to those of the low-SMR-flock (89 vs. 81%) (P < 0.05). Differential expression (DE) analysis identified 76 mRNAs, 344 lncRNAs, and 17 miRNAs between the SMR groups, with LOC106049708, XPNPEP3, GNB3, ADCY8, PRKAG3, oha-miR-182-5p, and ocu-miR-10b-5p identified as key mRNAs and miRNAs contributing to SM. Enrichment analysis implicated these DE RNAs in pathways related to ATP binding, cell metabolism, apelin signaling, Wnt signaling, and Adherens junctions. Additionally, competing endogenous RNA (ceRNA) networks comprising 9 DE mRNAs, 17 DE miRNAs, and 169 DE lncRNAs were constructed. Two ceRNA network pathways (LOC106049708-oha-miR-182-5p-MSTRG.2479.6 and PRKAG3-ocu-miR-10b-5p-MSTRG.9047.14) were identified as key regulators of SM in geese. These findings offer crucial insights into the identification of key genes and ceRNA pathways influencing sperm mobility in geese.
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Gansos , MicroARNs , ARN Largo no Codificante , ARN Mensajero , Motilidad Espermática , Testículo , Animales , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Gansos/genética , Gansos/fisiología , Testículo/metabolismo , Testículo/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Fertilidad/genética , Espermatozoides/fisiologíaRESUMEN
Noise-induced hearing lossï¼NIHLï¼ is an acquired sensorineural hearing loss induced by long-term noise exposure. The susceptibility of exposed people may vary even in the same noise environment. With the development of sequencing techniques, genes related to oxidative stress, immunoinflammatory, ion homeostasis, energy metabolism, DNA damage repair and other mechanisms in NIHL have been reported continuously. And some genes may interact with noise exposure indexes. In this article, population studies on NIHL-related gene polymorphisms and gene-environment interactions in the past 20 years are reviewed, aimed to providing evidence for the construction of NIHL-related risk prediction models and the formulation of individualized interventions.
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Pérdida Auditiva Provocada por Ruido , Ruido en el Ambiente de Trabajo , Humanos , Estudios de Casos y Controles , China/epidemiología , Predisposición Genética a la Enfermedad , Genotipo , Pérdida Auditiva Provocada por Ruido/genética , Polimorfismo de Nucleótido SimpleRESUMEN
As the contribution of de novo mutations (DNMs) to human genetic diseases has been gradually uncovered, analyzing the global research landscape over the past 20 years is essential. Because of the large and rapidly increasing number of publications in this field, understanding the current landscape of the contribution of DNMs in the human genome to genetic diseases remains a challenge. Bibliometric analysis provides an approach for visualizing these studies using information in published records in a specific field. This study aimed to illustrate the current global research status and explore trends in the field of DNMs underlying genetic diseases. Bibliometric analyses were performed using the Bibliometrix Package based on the R language version 4.1.3 and CiteSpace version 6.1.R2 software for publications from 2000 to 2021 indexed under the Web of Science Core Collection (WoSCC) about DNMs underlying genetic diseases on 17 September 2022. We identified 3435 records, which were published in 731 journals by 26,538 authors from 6052 institutes in 66 countries. There was an upward trend in the number of publications since 2013. The USA, China, and Germany contributed the majority of the records included. The University of Washington, Columbia University, and Baylor College of Medicine were the top-producing institutions. Evan E Eichler of the University of Washington, Stephan J Sanders of the Yale University School of Medicine, and Ingrid E Scheffer of the University of Melbourne were the most high-ranked authors. Keyword co-occurrence analysis suggested that DNMs in neurodevelopmental disorders and intellectual disabilities were research hotspots and trends. In conclusion, our data show that DNMs have a significant effect on human genetic diseases, with a noticeable increase in annual publications over the last 5 years. Furthermore, potential hotspots are shifting toward understanding the causative role and clinical interpretation of newly identified or low-frequency DNMs observed in patients.
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Bibliometría , Enfermedades Genéticas Congénitas , Mutación , Humanos , Enfermedades Genéticas Congénitas/genética , Investigación Biomédica/métodosRESUMEN
Mutations in AIFM1, encoding for apoptosis-inducing factor (AIF), cause AUNX1, an X-linked neurologic disorder with late-onset auditory neuropathy (AN) and peripheral neuropathy. Despite significant research on AIF, there are limited animal models with the disrupted AIFM1 representing the corresponding phenotype of human AUNX1, characterized by late-onset hearing loss and impaired auditory pathways. Here, we generated an Aifm1 p.R450Q knock-in mouse model (KI) based on the human AIFM1 p.R451Q mutation. Hemizygote KI male mice exhibited progressive hearing loss from P30 onward, with greater severity at P60 and stabilization until P210. Additionally, muscle atrophy was observed at P210. These phenotypic changes were accompanied by a gradual reduction in the number of spiral ganglion neuron cells (SGNs) at P30 and ribbons at P60, which coincided with the translocation of AIF into the nucleus starting from P21 and P30, respectively. The SGNs of KI mice at P210 displayed loss of cytomembrane integrity, abnormal nuclear morphology, and dendritic and axonal demyelination. Furthermore, the inner hair cells and myelin sheath displayed abnormal mitochondrial morphology, while fibroblasts from KI mice showed impaired mitochondrial function. In conclusion, we successfully generated a mouse model recapitulating AUNX1. Our findings indicate that disruption of Aifm1 induced the nuclear translocation of AIF, resulting in the impairment in the auditory pathway.
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Factor Inductor de la Apoptosis , Modelos Animales de Enfermedad , Pérdida Auditiva , Animales , Humanos , Masculino , Ratones , Factor Inductor de la Apoptosis/genética , Factor Inductor de la Apoptosis/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/genética , Técnicas de Sustitución del Gen , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/patología , Pérdida Auditiva/genética , Pérdida Auditiva/patología , Pérdida Auditiva/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Mutación , Transporte de Proteínas , Ganglio Espiral de la Cóclea/metabolismo , Ganglio Espiral de la Cóclea/patologíaRESUMEN
Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort. In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients), and 14 genes were mutated in two or more patients. Among subgroups of patients with AN, the prevalence of pathogenic and likely pathogenic variants was 54.4% and 56.2% in trios and families, while 22.9% in the cases with proband-only; 45.7% and 25.6% in the infant and non-infant group; and 33.7% and 0% in the bilateral and unilateral AN cases. Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group; other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups. In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss. The subgroups with different onset ages showed different genetic spectrums, so did bilateral and unilateral groups and sporadic and familial or trio groups.
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Pérdida Auditiva Central , Mutación , Humanos , Femenino , Masculino , Pérdida Auditiva Central/genética , Lactante , Niño , Preescolar , Estudios Retrospectivos , Adolescente , Proteínas de la Membrana/genética , Estudios de CohortesRESUMEN
This experiment aimed to study the effect of 1% Artemisia annua added to the diet on growth performance, antioxidant capacity, immunity and intestinal morphology, and gut microbiota of geese. Seventy-two 35-day-old male geese (Zi goose) with similar body weight were selected and randomly divided into 2 groups. Each treatment group of 36 geese was divided into 6 subgroups, each having 6 male geese. The experiment lasted for 21 d. Control group (CON) was fed a basal diet and the experimental group (AAL) was fed a basal diet + 1% Artemisia annua. BW, ADG, and ADFI of the AAL group increased (p < 0.05) and the FCR decreased (p < 0.05) compared with the CON group. The addition of Artemisia annua to the diet increased catalase (CAT), glutathione peroxidase (GSH-px), and superoxide dismutase (SOD) enzyme activities, increased total antioxidant capacity (T-AOC), and decreased malondialdehyde (MDA) content in serum and jejunum of geese (p < 0.05). Meanwhile, serum IgA, IgG, IgM, and lysozyme (LZM), increased at different time points in the AAL group compared to the CON group (p < 0.05), and decrease in the content of interferon-γ (IFN-γ) , IL-6 (p < 0.05), but no effect on complement C3 and C4. Morphological observation of the small intestine showed that the jejunal crypt depth was decreased in the AAL group (p < 0.05) while elevating the jejunal villus height/crypt depth (p < 0.05). 16S rRNA sequencing results showed the Artemisia annua increased the diversity of cecum microbiota, increasing the relative abundance of Bacteroides, Fecalibacterium, and Paraprevotella. In conclusion, the addition of 1% Artemisia annua to the diet could improve the growth performance, antioxidant and immune ability of geese, as well as improve the development of the jejunum intestinal tract of geese, and change the structure of the cecum microbiota, which had a positive effect on the growth and development of geese. Artemisia annua can be further developed as a feed additive.
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Alimentación Animal , Antioxidantes , Artemisia annua , Dieta , Suplementos Dietéticos , Microbioma Gastrointestinal , Gansos , Distribución Aleatoria , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Artemisia annua/química , Gansos/crecimiento & desarrollo , Gansos/fisiología , Alimentación Animal/análisis , Masculino , Dieta/veterinaria , Antioxidantes/metabolismo , Suplementos Dietéticos/análisis , Fenómenos Fisiológicos Nutricionales de los Animales/efectos de los fármacosRESUMEN
Genetic counseling for hearing loss today originated from decoding the genetic code of hereditary hearing loss, which serves as an effective strategy for preventing hearing loss and constitutes a crucial component of the diagnostic and therapeutic framework. This paper described the main principles and contents of genetic counseling for hearing loss, the key points of counseling across various genetic models and its application in tertiary prevention strategies targeting hearing impairment. The prospects of an AI-assisted genetic counseling decision system and the envisions of genetic counseling in preventing hereditary hearing loss were introduced. Genetic counseling for hearing loss today embodies the hallmark of a new era, which is inseparable from the advancements in science and technology, and will undoubtedly contribute to precise gene intervention!
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Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Asesoramiento Genético , Sordera/genética , Pérdida Auditiva/genética , Pérdida Auditiva/terapia , Pérdida Auditiva/diagnóstico , Pérdida Auditiva Sensorineural/genéticaRESUMEN
Hyperlipidemia is characterized by elevated levels of blood lipids. The clinical manifestations are mainly atherosclerosis caused by the deposition of lipids in the vascular endothelium. The link between abnormal lipid metabolism and sudden hearing loss remains unclear. This article presents a case study of sudden hearing loss accompanied by familial hyperlipidemia. Pure tone audiometry indicated intermediate frequency hearing loss in one ear. Laboratory tests showed abnormal lipid metabolism, and genetic examination identified a heterozygous mutation in theAPOA5 gene. Diagnosis: Sudden hearing loss; hypercholesterolemia. The patient responded well to pharmacological treatment. This paper aims to analyze and discuss thepotential connection between abnormal lipid metabolism and sudden hearing loss.
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Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva Súbita , Hiperlipidemias , Humanos , Audiometría de Tonos Puros , Sordera/complicaciones , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Súbita/diagnóstico , Hiperlipidemias/complicaciones , LípidosRESUMEN
Objective:To elucidate the correlation between the GJB2 gene and auditory neuropathy, aiming to provide valuable insights for genetic counseling of affected individuals and their families. Methods:The general information, audiological dataï¼including pure tone audiometry, distorted otoacoustic emission, auditory brainstem response, electrocochlographyï¼, imaging data and genetic test data of 117 auditory neuropathy patients, and the patients with GJB2 gene mutation were screened out for the correlation analysis of auditory neuropathy. Results:Total of 16 patients were found to have GJB2 gene mutations, all of which were pathogenic or likely pathogenic.was Among them, one patient had compound heterozygous variants GJB2[c. 427C>T][c. 358_360del], exhibiting total deafness. One was GJB2[c. 299_300delAT][c. 35_36insG]compound heterozygous variants, the audiological findings were severe hearing loss.The remaining 14 patients with GJB2 gene variants exhibited typical auditory neuropathy. Conclusion:In this study, the relationship between GJB2 gene and auditory neuropathy was preliminarily analyzed,and explained the possible pathogenic mechanism of GJB2 gene variants that may be related to auditory neuropathy.
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Sordera , Pérdida Auditiva Central , Humanos , Conexinas/genética , Conexina 26/genética , Pérdida Auditiva Central/genética , Sordera/genética , MutaciónRESUMEN
Nicotinamide adenine dinucleotideï¼NADHï¼ in its reduced form of is a key coenzyme in redox reactions, essential for maintaining energy homeostasis.NADH and its oxidized counterpart, NAD+, form a redox couple that regulates various biological processes, including calcium homeostasis, synaptic plasticity, anti-apoptosis, and gene expression. The reduction of NAD+/NADH levels is closely linked to mitochondrial dysfunction, which plays a pivotal role in the cascade of various neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease.Auditory neuropathyï¼ANï¼ is recognized as a clinical biomarker in neurodegenerative disorders. Furthermore, mitochondrial dysfunction has been identified in patients with mutations in genes like OPA1and AIFM1. However, effective treatments for these conditions are still lacking. Increasing evidence suggests that administratering NAD+ or its precursors endogenously may potentially prevent and slow disease progression by enhancing DNA repair and improving mitochondrial function. Therefore, this review concentrates on the metabolic pathways of NAD+/NADH production and their biological functions, and delves into the therapeutic potential and mechanisms of NADH in treating AN.
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Enfermedades Mitocondriales , Enfermedades Neurodegenerativas , Humanos , NAD/metabolismo , Enfermedades Neurodegenerativas/terapia , Enfermedades Neurodegenerativas/metabolismo , Mitocondrias , Oxidación-ReducciónRESUMEN
Objective:To dentify the genetic and audiological characteristics of families affected by late-onset hearing loss due to GSDMEgene mutations, aiming to explore clinical characteristics and pathogenic mechanisms for providing genetic counseling and intervention guidance. Methods:Six families with late-onset hearing loss from the Chinese Deafness Genome Project were included. Audiological tests, including pure-tone audiometry, acoustic immittance, speech recognition scores, auditory brainstem response, and distortion product otoacoustic emission, were applied to evaluate the hearing levels of patients. Combining with medical history and physical examination to analyze the phenotypic differences between the probands and their family members. Next-generation sequencing was used to identify pathogenic genes in probands, and validations were performed on their relatives by Sanger sequencing. Pathogenicity analysis was performed according to the American College of Medical Genetics and Genomics Guidelines. Meanwhile, the pathogenic mechanisms of GSDME-related hearing loss were explored combining with domestic and international research progress. Results:Among the six families with late-onset hearing loss, a total of 30 individuals performed hearing loss. The onset of hearing loss in these families ranged from 10 to 50 yearsï¼mean age: 27.88±9.74 yearsï¼. In the study, four splicing mutations of the GSDME were identified, including two novel variants: c. 991ï¼7C>G and c. 1183+1G>T. Significantly, the c. 991ï¼7C>G was a de novo variant. The others were previously reported variants: c. 991-1G>C and c. 991-15_991-13del, the latter was identified in three families. Genotype-phenotype correlation analysis revealed that probands with the c. 991ï¼7C>G and c. 1183+1G>T performed a predominantly high-frequency hearing loss. The three families carrying the same mutation exhibited varying degrees of hearing loss, with an annual rate of hearing deterioration exceeding 0.94 dB HL/year. Furthermore, follow-up of interventions showed that four of six probands received interventionï¼66.67%ï¼, but the results of intervention varied. Conclusion:The study analyzed six families with late-onset non-syndromic hearing loss linked to GSDME mutations, identifying four splicing variants. Notably, c. 991ï¼7C>G is the first reported de novo variant of GSDME globally. Audiological analysis revealed that the age of onset generally exceeded 10 years,with variable effectiveness of interventions.
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Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Adolescente , Adulto Joven , Adulto , Niño , Pérdida Auditiva Sensorineural/diagnóstico , Sordera/genética , Mutación , Pérdida Auditiva/genética , LinajeRESUMEN
Objective:To analyze genetic factors and phenotype characteristics in pediatric population with slight-to-moderate sensorineural hearing loss. Methods:Children with slight-to-moderate sensorineural hearing loss of and their parents, enrolled from the Chinese Deafness Genome Project, were studied. Hearing levels were assessed using pure tone audiometry, behavioral audiometry, auditory steady state responseï¼ASSRï¼, auditory brainstem responseï¼ABRï¼ thresholds, and deformed partial otoacoustic emissionï¼DPOAEï¼. Classification of hearing loss is according to the 2022 American College of Medical Genetics and Genomicsï¼ACMGï¼ Clinical Practice Guidelines for Hearing Loss. Whole exome sequencingï¼WESï¼ and deafness gene Panel testing were performed on peripheral venous blood from probands and validations were performed on their parents by Sanger sequencing. Results:All 134 patients had childhood onset, exhibiting bilateral symmetrical slight-to-moderate sensorineural hearing loss, as indicated by audiological examinations. Of the 134 patients, 29ï¼21.6%ï¼ had a family history of hearing loss, and the rest were sporadic patients. Genetic causative genes were identified in 66ï¼49.3%ï¼ patients. A total of 11 causative genes were detected, of which GJB2 was causative in 34 casesï¼51.5%ï¼, STRC in 10 casesï¼15.1%ï¼, MPZL2 gene in six casesï¼9.1%ï¼, and USH2A in five casesï¼7.6%ï¼.The most common gene detected in slight-to-moderate hearing loss was GJB2, with c. 109G>A homozygous mutation found in 16 casesï¼47.1%ï¼ and c. 109G>A compound heterozygous mutation in 9 casesï¼26.5%ï¼. Conclusion:This study provides a crucial genetic theory reference for early screening and detection of mild to moderate hearing loss in children, highlighting the predominance of recessive inheritance and the significance of gene like GJB2, STRC, MPZL2, USH2A.
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Pérdida Auditiva Sensorineural , Síndromes de Usher , Humanos , Niño , Conexinas/genética , Conexina 26/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/diagnóstico , Mutación , Pérdida Auditiva Bilateral , Audiometría de Tonos Puros , Péptidos y Proteínas de Señalización IntercelularRESUMEN
CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>Aï¼Glu818Lysï¼ heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.
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Ataxia Cerebelosa , Deformidades Congénitas del Pie , Pérdida Auditiva Sensorineural , Atrofia Óptica , Reflejo Anormal , Pie Cavo , Humanos , Niño , Femenino , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/diagnóstico , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/diagnóstico , Atrofia Óptica/genética , Atrofia Óptica/diagnóstico , Mutación , Fenotipo , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
Hereditary endocrine and metabolic diseases , caused by genetic factors, exhibit complex and diverse symptoms, including the possibility of concurrent sensorineural deafness. Currently, there is a limited clinical understanding of hereditary endocrine and metabolic diseases that manifest with deafness, the pathogenesis remains unclear,and there is a lack of effective diagnostic and treatment methods. This article summarizes the research progress of hereditary endocrine and metabolic diseases complicated with deafness from the pathogenesis, clinical phenotype, diagnosis and treatment. Understanding the current research progress and integrating genetic analysis into clinical practice are crucial for accurate diagnosis and treatment, evaluating clinical efficacy, and providing effective genetic counseling for these diseases.
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Sordera , Pérdida Auditiva Sensorineural , Enfermedades Metabólicas , Humanos , Sordera/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/diagnóstico , Fenotipo , Enfermedades Metabólicas/complicaciones , Enfermedades Metabólicas/genética , Asesoramiento GenéticoRESUMEN
BACKGROUND: TMC1 is one of the most common deafness genes causing DFNA36. Patient-derived human induced pluripotent stem cells (iPSCs) provide an opportunity to modelling diseases. TMC1 p.M418K mutation in human is orthologous to Beethoven mice. Here, we investigated the differentiation, morphology and electrophysiological properties of hair cell-like cells (HC-like cells) derived from DFNA36 patient. METHODS: Inner ear HC-like cells were induced from iPSCs derived from DFNA36 (TMC1 p.M418K) patient (M+/-), normal control (M+/+) and genetic corrected iPSCs (M+/C). Immunofluorescence, scanning electron microscopy and whole-cell patch-clamp were used to study the mechanism and influence of TMC1 p.M418K mutation. RESULTS: In this study we successfully generated HC-like cells from iPSCs with three different genotypes. HC-like cells from M+/- showed defected morphology of microvilli and physiological properties compared to M+/+. HC-like cells from M+/C showed recovery in morphology of microvilli and physiological properties. CONCLUSIONS: Our results indicate that TMC1 p.M418K mutation didn't influence inner ear hair cell differentiation but the morphology of microvilli and electrophysiological properties and gene correction induced recovery. CRISPR/Cas9 gene therapy is feasible in human patient with TMC1 p.M418K mutation.
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Pérdida Auditiva Sensorineural , Células Madre Pluripotentes Inducidas , Humanos , Animales , Ratones , Células Ciliadas Auditivas/fisiología , Pérdida Auditiva Sensorineural/genética , Mutación/genética , Cabello , Proteínas de la Membrana/genéticaRESUMEN
The widely available crop oil is an effective alternative to the increasingly scarce marine fish oil. However, simple alternative strategies have led to declining growth and the edible value of farmed fish. It is worthwhile to explore the effects of micro supplements in diets to improve the tolerance of fish to different dietary lipid sources, which finally optimizes the feeding strategies. This study aimed to investigate the regulation of L-carnitine and dietary oil conditions on nutrient composition, lipid metabolism, and glucose regulation of Rhynchocypris lagowskii. Four diets were prepared according to fish oil, fish oil supplemented with L-carnitine, corn oil, and corn oil supplemented with L-carnitine, and FO, LCFO, CO, and LCCO were labeled, respectively. R. lagowskii was fed experimental diets for 8 weeks, and the glucose tolerance test was performed. The CO diet significantly resulted in higher crude lipid content in muscle but a lower level of serum lipid parameters of R. lagowskii than the FO diet. However, dietary L-carnitine supplementation significantly reduced the crude lipid content in the hepatopancreas and muscle of the fish fed with the CO diet yet increased the serum lipid parameters. Additionally, the crude lipid content of muscle was reduced in the fish fed with an FO diet supplemented with L-carnitine. Compared with the FO diet, the CO diet significantly reduced the ratio of n3/n6 polyunsaturated fatty acid in the hepatopancreas and muscle of R.lagowskii. Dietary L-carnitine supplementation significantly reduced the contents of total saturated fatty acids and total monounsaturated fatty acids in hepatopancreas under both dietary lipid sources. The CO diet significantly up-regulated the expression of genes related to lipid uptake and adipogenesis in hepatopancreas, including lipoprotein lipase (lpl), acetyl-coenzyme A carboxylase alpha (accα), and sterol regulatory element binding protein-1 (srebp1), compared with the FO diet. While dietary L-carnitine supplementation significantly down-regulated the expressions of lpl, accα, srebp1, and fatty acid synthase in hepatopancreas and muscle of fish under both dietary lipid sources, along with up-regulated expression of carnitine palmitoyltransferase 1 in hepatopancreas. Moreover, the fish fed with a CO diet significantly increased the expression of glucose uptake and clearance and significantly down-regulated the expressions of glucose regulation-related genes, including glucose transporter 1, glycogen synthase 1, and phosphofructokinase in hepatopancreas and muscle, resulting in slower glucose uptake and clearance than fish fed with FO diet. Nevertheless, dietary L-carnitine supplementation up-regulated the expression of gluconeogenesis-related genes, including glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the hepatopancreas of R. lagowskii under both dietary lipid sources. In conclusion, a higher dietary n6 PUFA resulted in lipid deposition, decreased serum lipid parameters, and limited serum glucose utilization of R. lagowskii. While the regulatory effect of L-carnitine on lipid metabolism and glucose utilization of R. lagowskii varies with dietary lipid sources and tissues.
Asunto(s)
Ácidos Grasos Omega-3 , Metabolismo de los Lípidos , Animales , Aceite de Maíz , Carnitina/farmacología , Glucosa , Grasas de la Dieta , Dieta/veterinaria , Aceites de Pescado , Suplementos DietéticosRESUMEN
Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment involving disruptions to inner hair cells (IHCs), ribbon synapses, spiral ganglion neurons (SGNs), and/or the auditory nerve itself. The outcomes of cochlear implants (CI) for ANSD are variable and dependent on the location of lesion sites. Discovering a potential therapeutic agent for ANSD remains an urgent requirement. Here, 293T stable transfection cell lines and patient induced pluripotent stem cells (iPSCs)-derived auditory neurons carrying the apoptosis inducing factor (AIF) p.R422Q variant were used to pursue a therapeutic regent for ANSD. Nicotinamide adenine dinucleotide (NADH) is a main electron donor in the electron transport chain (ETC). In 293T stable transfection cells with the p.R422Q variant, NADH treatment improved AIF dimerization, rescued mitochondrial dysfunctions, and decreased cell apoptosis. The effects of NADH were further confirmed in patient iPSCs-derived neurons. The relative level of AIF dimers was increased to 150.7 % (P = 0.026) from 59.2 % in patient-neurons upon NADH treatment. Such increased AIF dimerization promoted the mitochondrial import of coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4), which further restored mitochondrial functions. Similarly, the content of mitochondrial calcium (mCa2+) was downregulated from 136.7 % to 102.3 % (P = 0.0024) in patient-neurons upon NADH treatment. Such decreased mCa2+ levels inhibited calpain activity, ultimately reducing the percentage of apoptotic cells from 30.5 % to 21.1 % (P = 0.021). We also compared the therapeutic effects of gene correction and NADH treatment on hereditary ANSD. NADH treatment had comparable restorative effects on functions of ANSD patient-specific cells to that of gene correction. Our findings offer evidence of the molecular mechanisms of ANSD and introduce NADH as a potential therapeutic agent for ANSD therapy.