OBJECTIVE: To explore the clinical features and genetic etiology of a patient with primary distal renal tubular acidosis (dRTA). METHODS: A child who was diagnosed with primary dRTA at the Xi'an Children's Hospital in April 2021 due to poor appetite and persistent crying was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was carried out for the child. Candidate variants were validated by Sanger sequencing of his family members. RESULTS: The child, a 1-month-and-18-day male, had featured poor appetite, persistent crying, poor weight gain and dehydration. Laboratory examination has suggested metabolic acidosis, hyperchloremia, hypokalemia, abnormal alkaline urine and anemia. Ultrasonographic examination of the urinary system revealed calcium deposition in renal medulla. DNA sequencing revealed that he has harbored compound heterozygous variants of the ATP6V0A4 gene, namely c.1363dupA (p.M455NfsX14) and c.2257C>T (p.Q753X), which were respectively inherited from his father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were classified as pathogenic (PVS1+PM3+PM2_Supporting). CONCLUSION The compound heterozygous variants of c.1363dupA (p.M455NfsX14) and c.2257C>T (p.Q753X) of the ATP6V0A4 gene probably underlay the pathogenesis of primary dRTA in this patient. Discovery of the c.2257C>T (p.Q753X) variant has also expanded the mutational spectrum of the ATP6V0A4 gene.
Humans ; Male ; Acidosis, Renal Tubular/genetics* ; Family ; Genomics ; Hypokalemia ; Infant

As a representative chemotherapeutic drug, docetaxel (DTX) has been used for breast cancer treatment for decades. However, the poor solubility of DTX limits its efficacy, and the DTX based therapy increases the metastasis risk due to the upregulation of C-X-C chemokine receptor type 4 (CXCR4) expression during the treatment. Herein, we conjugated CXCR4 antagonist peptide (CTCE) with DTX (termed CTCE-DTX) as an anti-metastasis agent to treat breast cancer. CTCE-DTX could self-assemble to nanoparticles, targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy. Thus, the CTCE-DTX NPs achieved promising efficacy on inhibiting both bone-specific metastasis and lung metastasis of triple-negative breast cancer. Our work provided a rational strategy on designing peptide-drug conjugates with synergistic anti-tumor efficacy.

Objective:To explore the feasibility of extracting the key plane of the normal fetal palate on the 11-13 + 6 week from tomography ultrasonography imaging based on artificial intelligence. Methods:The fetal volume datas of 235 cases of 11-13 + 6 week normal fetal were collected from the Department of Ultrasound in the Luohu District People′s Hospital of Shenzhen and Huazhong University of Science and Technology Union Shenzhen Hospital from May 2020 to April 2021. The data acquisition was completed by sonographers A and B by using the GE Voluson E10 color Doppler ultrasound diagnostic instrument. All datas were marked offline by sonographer C. Tomographic imaging was performed on all included data by sonographer D, the tomographic images were saved and the time-consuming was recorded, and the datas of the sonographer group were obtained. The labeled data were randomly divided into the training set and test set for model transfer learning and testing.The 4-fold cross-validation was adopted to record the test set image output by the model and the time consumption to obtain the intelligent group data. A senior sonographer performed image analysis on the two groups of data images. The feasibility of the intelligent model was verified by comparing the score of the plane of retronasal triangle(RTP), the acquisition rate of RTP, the acquisition rate of the fault, and the time-consuming difference between the sonographer group and the intelligent group. Results:①There was no significant difference in the overall distribution of RTP scores between the sonographer group and intelligent group [5 (5, 6) points vs 5 (5, 6) points, Z=0.355, P=0.722]. The RTP acquisition rate of the sonographer group and intelligent group was not statistically significant (78.72% vs 76.60%, χ 2=0.55, P=0.458). The consistency and correlation of RTP obtained by the two groups were high (Kappa=0.645, φ=0.646, both P<0.001). ②The effective layers of the sonographer group were 9 (8, 9) and the intelligent group was 8 (7, 9). The fault acquisition rate of the doctor group was higher than that of the intelligent group (78.72% vs 68.51%, χ 2=12.52, P=0.001). The consistency and correlation of the two groups in obtaining faults were media (Kappa=0.503, φ=0.521, both P<0.001). ③The time-consuming of the intelligent group was significantly lower than that of the sonographer group [1.50 (1.23, 1.75)s vs 26.94 (22.28, 30.48)s, Z=11.440, P<0.001]. Conclusions:This research model can quickly and accurately realize the extraction and tomography of the key plane of the normal fetal palate on the 11-13 + 6 week.

Objective:To explore the clinical and molecular genetic characteristics of patients with maturity-onset diabetes of the young type 2(MODY2).Methods:Clinical data and laboratory results were collected from five MODY2 patients and their family members diagnosed in the Department of Endocrinology, Genetics, and Metabolism of Xi ′an Children′s Hospital in the recent two years. Whole exome sequencing was carried out on every proband to identify potential variants, then the suspected variants were verified with Sanger sequencing in family numbers.Results:Among the 5 probands, except for proband 4 who presented with polydipsia and polyuria, hyperglycemia in the rest of the children was accidentally identified. Urine routine, urinary protein, and blood lipid of the five probands were all normal, and HbA 1C was between 5.96% and 8.15%. Moreover, an important discovery in this study was that proband 5 had insulin resistance(IRS), which was different from previous studies. It was confirmed by genetic analysis that a glucokinase(GCK) gene variant existed in every MODY2 pedigree. There were four GCK variants in this study, including c. 146C>T(p.T49I), c. 1237T>G(p.Y413D), c. 683C>T(p.T228M) and c. 952G>T(p.G318W), among which the C. 1237T>G(P.y413d) and C. 952G>T(P.G318W) had not been reported till now. All probands received lifestyle intervention, and the blood glucose control was relatively stable. Conclusion:There is MODY2 patient complicated with IRS. MODY2 patients can be controlled well by lifestyle interventions. In addition, we discovered two novel variants of GCK, which extend the mutation spectrum of this gene.

Objective:To provide molecular evidence for clinical diagnosis and genetic counseling by analyzing the clinical characteristics and identifying the pathogenic genes in a SPONASTRIME-type spondyloepimetaphyseal dysplasia(SEMDSP)family.Methods:Clinical data of the family members was collected and analyzed. Case 2 was identified as the proband for whole-exome sequencing and variant analysis. Suspected variants were validated across family numbers using Sanger sequencing.Results:The two affected individuals in this family, a brother and a sister, both presented as short stature. The initial diagnosis for the sister(case 1)was made at the age of 4 years and 2 months(height: 88.6 cm), and for the brother(case 2)at 4 years and 4 months(height: 81.6 cm). Both individuals exhibited distinctive facial features, including frontal bossing, midface hypoplasia with depressed nasal bridge, upturned nostrils, ocular hypertelorism, and epicanthus, thick hair, short lingual frenulum, stubby fingers and palms, and absence of scoliosis. The parents displayed normal phenotypes. Laboratory tests indicated growth hormone deficiency in both affected individuals. Imaging studies revealed significant bone age delay in case 2, while case 1 showed longitudinal striations at the distal radius but with bone age matching their actual age(5 years and 11 months). Despite receiving recombinant human growth hormone treatment, both patients had inadequate responses. Genetic testing identified compound heterozygous mutations in the TONSL gene shared by the two siblings. These mutations included a paternally inherited c. 1291-14_1291-11delCCTC and a maternally inherited c. 1909_1920delACGCTGCAGCAG. Notably, SEMDSP families have not been reported in China, and the c. 1909_1920delACGCTGCAGCAG mutation is a novel variant.Conclusion:Two patients were diagnosed as spondyloepimetaphyseal dysplasia, SPONASTRIME type, and the compound heterozygous variant was the genetic cause of this family.

OBJECTIVE: To explore the genetic basis for an infant with permanent neonatal diabetes mellitus (PNDM). METHODS: Clinical data of the child was collected. Targeted capture-next generation sequencing was carried out to identify the potential variants. Candidate variant was verified by Sanger sequencing of her family members. RESULTS: The child was a 4-month-and-26-day female featuring onset of ketoacidosis accompanied with fasting blood glucose of 24.4 mmol/L, positive urine glucose, decreased serum C-peptide, HbA1c of 9.58%, and negative diabetes autoantibody. Genetic testing revealed that she has carried a heterozygous c.314T>G (p.L105R) variant of the INS gene. Sanger sequencing verified that neither of her parents has carried the same variant, which was also unreported in the literature. The variant was classified as likely pathogenic based on the ACMG guidelines. CONCLUSION The c.314T>G (P.L105R) variant of the INS gene probably underlay the genetic etiology in this child. Genetic testing should be conducted for children with suspected PNDM for early diagnosis and appropriate treatment.
Humans ; Infant ; Child ; Infant, Newborn ; Female ; Mutation ; Insulin/genetics* ; Diabetes Mellitus/genetics* ; Genetic Testing

Objective:To analyze the clinical and genetic characteristics of five patients with familial male-limited precocious puberty(FMPP).Methods:The clinical data, laboratory and imaging results of the five patients with FMPP were collected. Whole exome sequencing was carried out to identify the potential variants. Suspected variants were verified by Sanger sequencing of family numbers.Results:Of the five patients, four were children and one was an adult. All the four children presented to hospital with premature sexual development at age less than 4 years. Serum testosterone was elevated, luteinizing hormone(LH) and follicle stimulating hormone(FSH) basal values were at prepubertal levels, and gonadotropin-releasing hormone(GnRH) stimulation test suggested peripheral precocious puberty. Genetic analysis revealed the mutations of LHCGR genes in all the five patients. Patients 1, 2, 3, and 4 carried the same heterozygous mutation c. 1713G>C(p.M571I), and the patient 5 carried the c. 1741T>C(p.C581R)variation. The four children were treated with anti-androgen preparations and the third-generation aromatase inhibitors, all of which were effective.Conclusion:The c. 1713G>C mutation of LHCGR gene is a novel one which expands the mutation spectrum of LHCGR gene. Combined treatment with bicaluamide and the third generation aromatase inhibitors can improve clinical symptoms and delay epiphyseal closure in children with FMPP.

Objective:To investigate the clinial phenotype and genetic characteristics of a child with cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma (CEDNIK) syndrome and to improve the clinicians′ understanding of this disease.Methods:Clinical data of the child with CEDNIK syndrome diagnosed in Department of Endocrinology, Genetics and Metabolism, Xi′an Children′s Hospital in June 2020 were collected. Whole exome sequencing was carried out to identify the potential variants of SNAP29 gene. Suspected variants were verified by Sanger sequencing of family numbers. The literature about the cases of CEDNIK syndrome were reviewed.Results:The proband is a boy, who was aged 1 year and 4 months, had the manifestations of psychomotor retardation, microcephaly, feeding difficulties, severe malnutrition, recurrent respiratory tract infection, binocular esotropia, sensorineural deafness, cutaneous ichthyosis and keratosis, left cryptorchidism. Brain magnetic resonance imaging indicated congenital dysplasia. Whole exome sequencing identified a homozygous variant of c.383dupT (p.E129Rfs *5) in the SNAP29 gene of the proband, and the heterozygous variation was observed at the same locus in his parents, which conformed to the autosomal recessive inheritance. This mutataion was determined as a pathogenic mutation according to the guidelines of American College of Medical Genetics and Genomics. Literature retrieval showed currently a total of 29 cases of CEDNIK syndrome were reported, containing 8 types of SNAP29 gene mutation. However, there was no Chinese case reported. And the c.383dupT (p.E129Rfs *5) mutation found in this study was a novel one which had not been reported yet. Conclusion:The phenotype of the proband is generally consistent with the CEDNIK syndrome and the novel c.383dupT (p.E129Rfs *5) mutation of SNAP29 gene is the genetic cause.

OBJECTIVE: To explore the clinical characteristics and genetic basis of a child with 5α-reductase type 2 deficiency. METHODS: Clinical data of the child was retrospectively analyzed. Targeted capture-next generation sequencing and Sanger sequencing were carried out to detect potential variants. RESULTS: The patient's main features included micropenis and hypospadia. He was found to harbor compound heterozygous c.680G>A (p.R227Q) and c.3G>T (p.M1I) variants of the SRD5A2 gene. Among these, c.680G>A (p.R227Q) was inherited from his father and was a known pathogenic mutation, while c.3G>T (p.M1I) was inherited from his mother and was unreported previously. CONCLUSION The compound heterozygous variants of the SRD5A2 gene probably underlay the disease in this child, who was eventually diagnosed with 5α-reductase 2 deficiency.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Child ; Disorder of Sex Development, 46,XY ; Female ; Humans ; Hypospadias ; Male ; Membrane Proteins/genetics* ; Mutation ; Retrospective Studies ; Steroid Metabolism, Inborn Errors ; Steroids

OBJECTIVE: To explore the role of mitochondrial permeability transition pore (mPTP) in mediating the protective effect of gastrodin against oxidative stress damage in H9c2 cardiac myocytes. METHODS: H9c2 cardiac myocytes were treated with HO, gastrodin, gastrodin+HO, cyclosporin A (CsA), or CsA+gas+HO group. MTT assay was used to detect the survival ratio of H9c2 cells, and flow cytometry with Annexin V-FITC/PI double staining was used to analyze the early apoptosis rate after the treatments. The concentration of ATP and level of reactive oxygen species (ROS) in the cells were detected using commercial kits. The mitochondrial membrane potential of the cells was detected with laser confocal microscopy. The expression of cytochrome C was detected with Western blotting, and the activity of caspase-3 was also assessed in the cells. RESULTS: Gastrodin pretreatment could prevent oxidative stress-induced reduction of mitochondrial membrane potential, and this effect was inhibited by the application of CsA. Gastrodin significantly lowered the levels of ROS and apoptosis-related factors in HO-exposed cells, and such effects were reversed by CsA. CsA significantly antagonized the protective effect of gastrodin against apoptosis in HO-exposed cells. CONCLUSIONS Gastrodin prevents oxidative stress-induced injury in H9c2 cells by inhibiting mPTP opening to reduce the cell apoptosis.
Adenosine Triphosphate ; analysis ; Apoptosis ; drug effects ; Benzyl Alcohols ; antagonists & inhibitors ; pharmacology ; Caspase 3 ; analysis ; Cell Line ; Cell Survival ; drug effects ; Cyclosporine ; pharmacology ; Cytochromes c ; analysis ; Glucosides ; antagonists & inhibitors ; pharmacology ; Humans ; Hydrogen Peroxide ; antagonists & inhibitors ; pharmacology ; Membrane Potential, Mitochondrial ; drug effects ; Mitochondrial Membrane Transport Proteins ; physiology ; Myocytes, Cardiac ; drug effects ; metabolism ; Oxidative Stress ; Reactive Oxygen Species ; analysis