Novel Pathogenic Mutation of P209L in TRPC6 Gene Causes Adult Focal Segmental Glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a leading kidney disease, clinically associated with proteinuria and progressive renal failure. The occurrence of this disease is partly related to gene mutations. We describe a single affected family member who presented with FSGS. We used high-throughput sequencing, sanger sequencing to identify the pathogenic mutations, and a systems genetics analysis in the BXD mice was conducted to explore the genetic regulatory mechanisms of pathogenic genes in the development of FSGS. We identified high urinary protein (++++) and creatinine levels (149 µmol/L) in a 29-year-old male diagnosed with a 5-year history of grade 2 hypertension. Histopathology of the kidney biopsy showed stromal hyperplasia at the glomerular segmental sclerosis and endothelial cell vacuolation degeneration. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous missense mutation (c.643C > T) in exon 2 of TRPC6, leading to the substitution of arginine with tryptophan at position 215 (p.Arg215Trp). Systems genetics analysis of the 53 BXD mice kidney transcriptomes identified Pygm as the upstream regulator of Trpc6. Those two genes are jointly involved in the regulation of FSGS mainly via Wnt and Hippo signaling pathways. We present a novel variant in the TRPC6 gene that causes FSGS. Moreover, our data suggested TRPC6 works with PYGM, as well as Wnt and Hippo signaling pathways to regulate renal function, which could guide future clinical prevention and targeted treatment for FSGS outcomes.

Joint analysis of WES and RNA-Seq identify signature genes related to metastasis in prostate cancer.

Prostate cancer (PCa) has a certain degree of heritability, and metastasis occurs as cancer progresses. However, its underlying mechanism remains largely unknown. We sequenced four cases of cancer without metastasis, four metastatic cancer, and four benign hyperplasia tissues as controls. A total of 1839 damaging mutations were identified. Pathway analysis, gene clustering, and weighted gene co-expression network analysis were employed to find characteristics associated with metastasis. Chr19 had the most mutation density and 1p36 had the highest mutation frequency across the genome. These mutations occurred in 1630 genes, including the most frequently mutated genes TTN and PLEC, and dozens of metastasis-related genes, such as FOXA1, NCOA1, CD34, and BRCA2. Ras signalling and arachidonic acid metabolism were uniquely enriched in metastatic cancer. Gene programmes 10 and 11 showed the signatures indicating the occurrence of metastasis better. A module (135 genes) was specifically associated with metastasis. Of them, 67.41% reoccurred in program 10, with 26 genes further retained as the signature genes related to PCa metastasis, including AGR3, RAPH1, SOX14, DPEP1, and UBL4A. Our study provides new molecular perspectives on PCa metastasis. The signature genes and pathways could be served as potential therapeutic targets for metastasis or cancer progression.

[Efficacy of hirudin in treating immunoglobulin A nephropathy with hematuria: a randomized controlled trial].

OBJECTIVE: To investigate the curative effects and side effects of hirudin in treating immunoglobulin A nephropathy (IgAN) with hematuria and minimal proteinuria in a short-term. METHODS: Two hundred and sixty-two histologically confirmed cases of IgAN with hematuria and minimal proteinuria from 1998 to 2007 were randomly divided into hirudin-treated group (peroral administration of Maixuekang capsules) and dipyridamole-treated group (peroral administration of dipyridamole). In the two groups, contrast analysis of conformation and counts of erythrocytes in urine, urine protein quantitation in 24 hours, levels of serum creatinine (Scr) and creatinine clearance rate (Ccr), blood lipid, five items of blood clotting and side effects was performed. RESULTS: After six-month treatment, the anisotrophy rate and the counts of erythrocytes in urine, and the urine protein quantitation in 24 hours in hirudin-treated group were decreased distinctly as compared with pre-treatment (P<0.01) and dipyridamole-treated group (P<0.05). On the other hand, Ccr was increased obviously in hirudin-treated group as compared with pre-treatment and dipyridamole-treated group (P<0.01). The blood lipid was also ameliorated in hirudin-treated group, but there was no significant difference. The anticoagulation effect of hirudin was better than dipyridamole (P<0.01). Efficacy assessment showed that the total response rate, complete remission rate and predominance remission rate in hirudin-treated group were higher than those in dipyridamole-treated group. Few side effects were found in both groups, and the rate of adverse reaction in gastrointestinal tract was lower in hirudin-treated group as compared with that in dipyridamole-treated group (P<0.05). CONCLUSION: Compared with dipyridamole, hirudin has superiority in kidney protection and decreasing the anisotrophy rate, counts of erythrocytes in urine and the urine protein.

Origin and Reticulate Evolutionary Process of Wheatgrass Elymus trachycaulus (Triticeae: Poaceae).

To study origin and evolutionary dynamics of tetraploid Elymus trachycaulus that has been cytologically defined as containing StH genomes, thirteen accessions of E. trachycaulus were analyzed using two low-copy nuclear gene Pepc (phosphoenolpyruvate carboxylase) and Rpb2 (the second largest subunit of RNA polymerase II), and one chloroplast region trnL-trnF (spacer between the tRNA Leu (UAA) gene and the tRNA-Phe (GAA) gene). Our chloroplast data indicated that Pseudoroegneria (St genome) was the maternal donor of E. trachycaulus. Rpb2 data indicated that the St genome in E. trachycaulus was originated from either P. strigosa, P. stipifolia, P. spicata or P. geniculate. The Hordeum (H genome)-like sequences of E. trachycaulus are polyphyletic in the Pepc tree, suggesting that the H genome in E. trachycaulus was contributed by multiple sources, whether due to multiple origins or introgression resulting from subsequent hybridization. Failure to recovering St copy of Pepc sequence in most accessions of E. trachycaulus might be caused by genome convergent evolution in allopolyploids. Multiple copies of H-like Pepc sequence from each accession with relative large deletions and insertions might be caused by either instability of Pepc sequence in H- genome or incomplete concerted evolution. Our results highlighted complex evolutionary history of E. trachycaulus.