The paired box gene 6 (PAX6) is an essential transcription factor for eye formation. Genetic alterations in PAX6 can lead to various ocular malformations including aniridia. The purpose of this study was to identify genetic defects as the underlying cause of familial ocular coloboma in a large Chinese family.

Malignant glioma is rarely curable, and factors that influence the prognosis of glioma patients are not fully understood. Lysyl hydroxylases such as PLOD1 promote the cross-linking in extracellular matrix (ECM) molecules, which contribute to ECM structural stability and maturation. However, the expression and prognostic role of PLOD1 in malignant glioma remained to be determined.

Recently, the diverse functions of microRNAs (miRNAs) in brain diseases have been demonstrated. We intended to uncover the functional role of microRNA-130b (miR-130b) in cerebral vasospasm (CVS) following subarachnoid hemorrhage (SAH). SAH was induced by injecting the autologous blood into the cisterna magna of Sprague Dawley rats. The cerebral vascular smooth muscle cells (cVSMCs) were extracted for in vitro experimentation. In vitro and in vivo assays were implemented with transfection of miR-130b mimic/inhibitor, sh-Kruppel-like factor 4 (KLF4), oe-KLF4 plasmids or p38/MAPK signaling pathway agonist (anisomycin), respectively, to elaborate the role of miR-130b in CVS following SAH. Elevated miR-130b and reduced KLF4 were found in SAH patients and rat models of SAH. KLF4 was the target gene of miR-130b. miR-130b promoted the proliferation and migration of cVSMCs through the Inhibition of KLF4. Besides, KLF4 inhibited the proliferation and migration of cVSMCs through blockage of the p38/MAPK pathway. Furthermore, in vivo assay confirmed the inhibitory effect of decreased miR-130b in CVS following SAH. In conclusion, miR-130b may activate the p38/MAPK signaling pathway through targeted inhibition of KLF4, thereby contributing to some extent to the development of cerebral vasospasm after SAH.

Syndactyly type 1 (SD1) is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and/or the second and third toes. Its four subtypes (a, b, c, and d) are defined based on variable phenotypes, but the responsible gene is yet to be identified. SD1-a has been mapped to chromosome 3p21.31 and SD1-b to 2q34-q36. SD1-c and SD1-d are very rare and, to our knowledge, no gene loci have been identified.

Thrombocytopenia 2 (THC2) is a major type of inherited thrombocytopenia caused by the persistent ANKRD26 expression during the late stage of megakaryocytopoiesis. For the first time, we generated a human induced pluripotent stem cell (hiPSC) line SHAMUi001-A from the bone marrow hematopoietic progenitor cells of a THC2 patient, who has a heterozygous mutation (c.-128G>T) in the 5'-UTR of ANKRD26 gene. SHAMUi001-A cells retain the mutation, display pluripotent stem cell characteristics, and have a normal female karyotype. This disease-specific hiPSC line will be a useful model for THC2 research.

SOX2 overlapping transcript (SOX2OT) has been reported to be an important lncRNA in various cancers. SOX2 is embedded in an intron of the SOX2OT gene. But the role of SOX2OT in esophageal squamous cell carcinoma (ESCC) and the association between SOX2OT and SOX2 remain unclear.

To characterize the etiology underlying a novel case of global developmental delay syndrome (GDDS) identified in a female child, aged 3 years old. This syndrome is a common pediatric presentation estimated to affect 3.65% of children aged 3 to 17 years.The proband's detailed family history was used to infer a likely mode of inheritance for the GDDS. Genomic DNA samples collected from the proband and her parents were evaluated using conventional karyotyping, multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization microarray (aCGH), and fluorescent in situ hybridization (FISH) analysis techniques.An analysis of the proband's family history suggested that she inherited the GDDS from her father. The conducted conventional karyotyping and MLPA methods failed to identify a causative defect for the GDDS; however, the aCGH analysis revealed both a 6.6-Mb deletion at p14-p15.3 of chromosome 10 (arr[hg19]; 100,026-6,710,183), and a 6.3-Mb duplication at p11.31-p11.32 of chromosome 18 (arr[hg19]; 136,226-6,406,733) in the proband. The conducted FISH analysis subsequently determined that these mutations resulted from a balanced translocation t(10;18)(p15.3; p11.32) carried by the proband's father. Finally, a bioinformatic analysis of the proband's mutations revealed ZMYND11 as a promising candidate causative gene for this case of GDDS.The present study demonstrates that the aCGH method can be used to effectively identify the location and approximate size of microdeletions and/or microduplications, but not balanced reciprocal translocations. The nonconventional analysis methods used in the present study may be applicable to other GDDS cases with elusive etiology, and likewise, ZMYND11 should be considered as a potential causative gene during the investigation of future GDDS cases.

Left cardiac pumping function determines the compensatory capacity of the cardiovascular system following acute high-altitude exposure. Variations in cardiac output (CO) at high altitude are inconsistent between individuals, and genetic susceptibility may play a crucial role. We sought to identify genetic causes of cardiac pumping function variations and describe the genotype-phenotype correlations.

Cisplatin is an essential chemotherapy drug in esophageal squamous cell carcinoma (ESCC). Some studies suggested that the expression of E2F1 is increased in ESCC cells after cisplatin treatment, but its mechanism remains obscure. Here, we found that miR-26b is upregulated in ESCC cell lines with cisplatin treatment, and it relies on the expression of E2F1 because E2F1 directly binds to the promoter of the miR-26b gene, thus activating the transcriptional activity of miR-26b. Cell cycle analysis suggested that miR-26b inhibits the G1/S phase transition, thus inhibiting the cell growth of ESCC cells. The cisplatin-induced cycle arrest also closely depends on the expression of miR-26b. In vivo assays revealed that the sensitivity of ESCC cells to cisplatin is decreased when the E2F1/miR-26b pathway is disturbed. A nude mouse xenograft model of cisplatin treatment showed that the tumor volume was increased in the Si-E2F1 group compared with that in the group with cisplatin treatment alone. The effect may be due to the cellular DNA damage response, because that miR-26b could target the mRNA of ATM and Rb genes via binding to their 3'UTRs, thus leading to decreased protein expression of ATM and Rb. In conclusion, our results indicate that E2F1 promotes the chemosensitization to cisplatin in ESCC. The effect may be due to the upregulation of miR-26b because cisplatin-induced cycle arrest depends on miR-26b, which may also disturb the DNA damage response by reducing the expression of ATM and Rb.

Cell senescence is associated with age-related pathological changes. Increasing evidence has revealed that mitophagy can selectively remove dysfunctional mitochondria. Overexpression of ubiquitin-specific protease 30 (USP30) has been documented to influence mitophagy and deubiquitination of mitochondrial Parkin substrates. This study was conducted to evaluate the roles of USP30 and Parkin in myocardial cell senescence and mitophagy. Initially, myocardial cells were isolated from neonatal SD rats and subjected to D-gal treatment to induce cell senescence, after which the effects of D-gal on mitochondria damage, ROS production, cell senescence, and mitophagy were assessed. The myocardial cells were infected with lentiviruses bearing overexpression plasmids or shRNA targeting Parkin or USP30 to elucidate the effects of Parkin and USP30 on D-gal-induced mitophagy damage and cell senescence. Finally, aging was induced in rats by subcutaneous injection of D-gal to determine the role of Parkin and USP30 on cell senescence in vivo. D-gal was found to trigger mitochondria damage, ROS production, and cell senescence in myocardial cells. The overexpression of Parkin or silencing of USP30 reduced D-gal-induced mitochondrial damage and relieved D-gal-induced myocardial cell senescence. Moreover, the in vivo experiments validated that either elevation of Parkin or silencing USP30 could alleviate D-gal-induced myocardial cell senescence in rats. Silencing USP30 alleviates D-gal-induced mitochondrial damage and consequently suppresses myocardial cell senescence by activating Parkin. Our study highlights the potential of USP30 as a novel target against myocardial cell senescence.

Objective: Intellectual disability (ID) is one of the most common developmental disabilities. To identify the genetic etiology of IDs in Chongqing, we conducted a multistage study in Chinese Han patients. Methods: We collected the clinical and etiological data of 1665 ID patients, including 1,604 from the disabled children evaluation center and 61 from the pediatric rehabilitation unit. Routine genetic screening results were obtained, including karyotype and candidate gene analysis. Then 105 idiopathic cases with syndromic and severe ID/developmental delay (DD) were selected and tested by chromosomal microarray (CMA) and whole exome sequencing (WES) sequentially. The pathogenicity of the CNVs and SNVs were evaluated according to ACMG guidelines. Results: Molecular diagnosis was made by routine genetic screening in 216 patients, including 196 chromosomal syndromes. Among the 105 idiopathic patients, 49 patients with pathogenic/likely pathogenic CNVs and 21 patients with VUS were identified by CMA. Twenty-six pathogenic CNVs underlying well-known syndromic cases, such as Williams-Beuren syndrome, were confirmed by multiplex ligation-dependent probe amplification (MLPA). Nine novel mutations were identified by WES in thirty-fix CNV-negative ID cases. Conclusions: The study illustrated the genetic aberrations distribution of a large ID cohort in Chongqing. Compared with conventional or single methods, a tiered high-throughput diagnostic strategy was developed to greatly improve the diagnostic yields and extend the variation spectrum for idiopathic syndromic ID cases.