Evidence based on Mendelian randomization and colocalization analysis strengthens causal relationships between structural changes in specific brain regions and risk of amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord with a poor prognosis. Previous studies have observed cognitive decline and changes in brain morphometry in ALS patients. However, it remains unclear whether the brain structural alterations contribute to the risk of ALS.

Mendelian randomization study revealed a gut microbiota-neuromuscular junction axis in myasthenia gravis.

A growing number of studies have implicated that gut microbiota abundance is associated with myasthenia gravis (MG). However, the causal relationship underlying the associations is still unclear. Here, we aim to investigate the causal effect of gut microbiota on MG using Mendelian randomization (MR) method.

Nonsense suppression induces read-through of a novel BMPR1A variant in a Chinese family with hereditary colorectal cancer.

Background: BMPR1A-mediated signaling transduction plays an essential role in intestinal growth. Variations of BMPR1A lead to a rare autosomal dominant inherited juvenile polyposis syndrome (JPS) with high probability of developing into colorectal cancer (CRC). Nonsense and frameshift variations, generating premature termination codons (PTCs), are the most pathogenic variants in the BMPR1A gene.

Mouse promotes spermatogonia proliferation through enhancing -mediated DNA replication.

Context: The human TSPY1 (testis-specific protein, Y-linked 1) gene is critical for spermatogenesis and male fertility. However, there have been difficulties with studying the mechanism underlying its function, partly due to the presence of the Tspy1 pseudogene in mice.

Aims: TSPYL5 (TSPY-like 5), an autosomal homologous gene of TSPY1 showing a similar expression pattern in both human and mouse testes, is also speculated to play a role in male spermatogenesis.

SCN5A-L256del and L1621F exhibit loss-of-function properties related to autosomal recessive congenital cardiac disorders presenting as sick sinus syndrome, dilated cardiomyopathy, and sudden cardiac death.

Pathogenic mutations in SCN5A could result in dysfunctions of Na1.5 and consequently lead to a wide range of inherited cardiac diseases. However, the presence of numerous SCN5A-related variants with unknown significance (VUS) and the comprehensive genotype-phenotype relationship pose challenges to precise diagnosis and genetic counseling for affected families.

NR0B1 suppresses ferroptosis through upregulation of NRF2/c-JUN-CBS signaling pathway in lung cancer cells.

Ferroptosis has demonstrated significant potential in treating radiochemotherapy-resistant cancers, but its efficacy can be affected by recently discovered ferroptosis suppressors. In this study, we discovered that NR0B1 protects against erastin- or RSL3-induced ferroptosis in lung cancer cells. Transcriptomic analysis revealed that NR0B1 significantly interfered with the expression of 12 ferroptosis-related genes, and the expression level of NR0B1 positively correlated with that of c-JUN, NRF2, and CBS.

NR0B1 augments sorafenib resistance in hepatocellular carcinoma through promoting autophagy and inhibiting apoptosis.

NR0B1 is frequently activated in hepatocellular carcinoma (HCC). However, the role of NR0B1 is controversial in HCC. In this study, we observed that NR0B1 was an independent poor prognostic factor, negatively correlated with the overall survival of HCC and the relapse-free survival of patients treated with sorafenib.

Integration and deconvolution methodology deciphering prognosis-related signatures in lung adenocarcinoma.

Purpose: This study aims to establish a risk prediction model based on prognosis-related genes (PRGs) and clinicopathological factors, and investigate the biological activities of PRGs in lung adenocarcinoma (LUAD).

Methods: Risk score signatures were developed by employing multiple algorithms and their amalgamations. A predictive model for overall survival was established through the integration of risk score signatures and several clinicopathological parameters.

[Analysis of a patient with early-onset retinitis pigmentosa due to novel variants of CRB1 gene].

Objective: To explore the genetic basis for a patient with early-onset retinitis pigmentosa (RP).

Methods: A patient who had presented at the West China Hospital of Sichuan University on March 10, 2020 was selected as the study subject. The patient and his parents were subjected to whole exome sequencing (WES).

Primary azoospermia factor C duplication associated with spermatogenic impariment: a case-control study based on Y-chromosome haplogrouping in a Han Chinese population.

Background: Azoospermia factor C (AZFc) in the male-specific region of Y-chromosome (MSY) presents wide structure variation mainly due to frequent non-allele homologous recombination, leading to significant copy number variation of the AZFc-linked coding sequences involving in spermatogenesis. A large number of studies had been conducted to investigate the association between AZFc deletions and male infertility in certain Y chromosome genetic backgrounds, however, the influence of primary AZFc duplication on spermatogenesis remained controversial and the cause of the discrepant outcomes is unknown.

Methods: In the present study, a total of 1,102 unrelated Han Chinese males without any detectable AZF deletions were recruited from 2014 to 2019, including 411 controls with normozoospermia and 691 patients with idiopathic spermatogenic failure.

[A novel splicing acceptor variant of the FBN2 gene contributes to a case of congenital contractural arachnodactyly].

Objective: To identify the pathogenic variants from a patient with suspected congenital contractural arachnodactyly, and to explore the possible molecular genetic pathogenesis, so as to provide evidence for clinical diagnosis.

Methods: Whole exome sequencing was performed for the patient. The splicing site variation of candidate pathogenic genes was verified by Sanger sequencing, and the new transcript sequence was determined by RT-PCR and TA-cloning sequencing.

A novel NPHS2 mutation (c.865A > G) identified in a Chinese family with steroid-resistant nephrotic syndrome alters subcellular localization of nephrin.

Background: NPHS2 is the causative gene of nephrotic syndrome type 2 (MIM 600995) which often clinically manifests as steroid-resistant nephrotic syndrome (SRNS). The NPHS2 gene encodes a slit diaphragm (SD) associated protein podocin.

Objective: This study reported a novel disease-causing mutation of NPHS2 in a Chinese family with SRNS.

[Genetic analysis of a recurrent abnormal pregnancy case caused by a cryptic reciprocal autosomal translocation].

Objective: To provide genetic counseling for a couple with recurrent detection of fetal structural abnormality during second trimester pregnancy.

Methods: The fetal tissue and peripheral blood samples of the couple were subjected to G banded chromosomal analysis, copy number variation sequencing (CNV-seq) and fluorescence in situ hybridization (FISH) assays.

Results: CNV-seq has detected a 6.

Is BRD7 associated with spermatogenesis impairment and male infertility in humans? A case-control study in a Han Chinese population.

Background: Bromodomain-containing protein 7 (BRD7), a member of the bromodomain-containing protein family, plays important roles in chromatin modification and transcriptional regulation. A recent model of Brd7-knockout mice presented azoospermia and male infertility, implying the potential role of BRD7 in spermatogenic failure in humans. This case-control study aimed to explore the association of the BRD7 gene with spermatogenic efficiency and the risk of spermatogenic defects in humans.

Identification of novel single-nucleotide variants altering RNA splicing of PKD1 and PKD2.

The development of sequencing techniques identified numerous genetic variants, and accurate evaluation of the clinical significance of these variants facilitates the diagnosis of Mendelian diseases. In the present study, 549 rare single- nucleotide variants of uncertain significance were extracted from the ADPKD and ClinVar databases. MaxEntScan scoresplice is an in silico splicing prediction tool that was used to analyze rare PKD1 and PKD2 variants of unknown significance.

[Genetic analysis of two couples with a history of multiple fetal malformations].

Objective: To explore the genetic basis for a couple with recurrent conceptions of fetus with abnormal longbones, and another couple with a history of omphalocele.

Methods: Genomic DNA was extracted from the peripheral blood samples from both couples. All exons and flanking regions were analyzed with next generation sequencing.

PIWIL2 interacting with IKK to regulate autophagy and apoptosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies and cause of death from cancer in China. Previous studies showed that autophagy and apoptosis inhibition are critical for the survival of ESCC cells. However, the underlying mechanisms remain to be clarified.

Epigenetic modification-dependent androgen receptor occupancy facilitates the ectopic TSPY1 expression in prostate cancer cells.

Testis-specific protein Y-encoded 1 (TSPY1), a Y chromosome-linked oncogene, is frequently activated in prostate cancers (PCa) and its expression is correlated with the poor prognosis of PCa. However, the cause of the ectopic transcription of TSPY1 in PCa remains unclear. Here, we observed that the methylation status in the CpG islands (CGI) of the TSPY1 promoter was negatively correlated with its expression level in different human samples.

Identification of two rare mutations c.1318G>A and c.6438+2T>G in a Chinese DMD family as genetic markers.

Background: Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disorder with no effective treatment, which underscores the importance of avoiding the birth of children with DMD by identifying pathogenic mutations and obtaining an accurate prenatal diagnosis.

Objective: The objective of this study was to analyze the genetic defect of a Chinese family where all male patients have died of DMD.

Methods: Multiplex ligation dependent probe analysis (MLPA) and next-generation sequencing (NGS) were employed to detect DMD mutations.

PIWIL2 stabilizes β-catenin to promote cell cycle and proliferation in tumor cells.

PIWIL2 belongs to the PIWI protein subfamily and is widely expressed in a variety of tumors. Previous studies have shown that PIWIL2 has the characteristics of oncogene. Recently we reported that PIWIL2 suppresses GSK3β activity to regulate circadian rhythms through SRC-PI3K-AKT pathway.

Testis-specific protein, Y-linked 1 activates PI3K/AKT and RAS signaling pathways through suppressing IGFBP3 expression during tumor progression.

The testis-specific protein, Y-linked 1 (TSPY1), a newly recognized cancer/testis antigen, has been suggested to accelerate tumor progression. However, the mechanisms underlying TSPY1 cancer-related function remain limited. By mining the RNA sequencing data of lung and liver tumors from The Cancer Genome Atlas, we found frequent ectopic expression of TSPY1 in lung adenocarcinoma (LUAD) and liver hepatocellular carcinoma (LIHC), and the male-specific protein was associated with higher mortality rate and worse overall survival in patients with LUAD and LIHC.

RAE1 promotes BMAL1 shuttling and regulates degradation and activity of CLOCK: BMAL1 heterodimer.

Circadian rhythm is an autoregulatory rhythm, which is sustained by various mechanisms. The nucleocytoplasmic shuttling of BMAL1 is essential for CLOCK translocation between cytoplasm and nucleus and maintenance of the correct pace of the circadian clock. Here we showed that RAE1 and NUP98 can promote the degradation of BMAL1 and CLOCK.