Involvement of the bone morphogenic protein/SMAD signaling pathway in the etiology of congenital anomalies of the kidney and urinary tract accompanied by cryptorchidism

Background

Congenital anomalies of the kidney and urinary tract (CAKUT), such as renal dysplasia, hydronephrosis, or vesicoureteral reflux, are the most common causes of end-stage renal disease. However, the genetic etiology of CAKUT remains unclear. In this study, we performed whole exome sequencing (WES) to elucidate the genetic etiology of symptomatic CAKUT and CAKUT accompanied by cryptorchidism.

Methods

Three patients with unilateral renal dysplasia accompanied by ipsilateral cryptorchidism were included in this analysis. Genomic DNA was extracted from peripheral blood, and WES was performed. Disease-specific single nucleotide polymorphisms (SNPs) were determined by comparison with the human genome reference sequence (hg19). Additionally, we searched for SNPs that were common to all three patients, with a particular focus on the coding regions of the target genes.

Results

In total, 8710 SNPs were detected. Of the genes harboring these SNPs, 32 associated with renal or testicular development were selected for further analyses. Of these, eight genes (i.e., SMAD4, ITGA8, GRIP1, FREM1, FREM2, TNXB, BMP8B, and SALL1) carried a single amino acid substitution that was common to all three patients. In particular, SNPs in SMAD4 (His290Pro and His291Pro) have not been reported previously in patients with symptomatic CAKUT. Of the candidate genes, four genes (i.e., ITGA8, GRIP1, FREM1, and FREM2) were Fraser syndrome-related genes, encoding proteins that functionally converged on the glial cell-derived neurotrophic factor/RET/bone morphogenic protein (BMP) signaling pathways. As another candidate gene, the protein encoded by BMP8B activates the nuclear translocation of SMAD4, which regulates the expression of genes associated with the differentiation of primordial germ cells or testicular development. Additionally, BMP4, a member of the BMP family, regulates the interaction between metanephric mesenchyme and ureteric buds by suppressing GDNF.

Conclusions

Taken together, our findings suggested that the development of the kidney and urinary tract is intimately linked with that of male reproductive organs via BMP/SMAD signaling pathways.

     

Immunoglobulin G4-related gastrointestinal diseases,are they immunoglobulin G4-related diseases?

In immunoglobulin G4(IgG4)-related disease(RD),organ enlargement or nodular lesions consisting of abundant infiltration of lymphocytes and IgG4-positive plasma cells and fibrosis are seen in various organs.Although infiltration of many IgG4-positive plasma cells is detected in the gastric and colonic mucosa and major duodenal papilla of patients with autoimmune pancreatitis,it cannot be diagnosed as a gastrointestinal lesion involved in IgG4-RD,because none of the following is observed in these lesions:a mass-like formation;dense fibrosis;or obliterative phlebitis.Based on our review of the literature,there appear to be two types of IgG4-related gastrointestinal disease.One is a gastrointestinal lesion showing marked thickening of the wall of the esophagus and stomach,consisting of dense fibrosis with abundant infiltration of IgG4-positive plasma cells,which usually show submucosal spreading.The other is an IgG4-related pseudotumor occurring in gastrointestinal regions such as the stomach,colon,and major duodenal papilla,showing polypoid or mass-like lesions.Most solitary IgG4-related gastrointestinal lesions that are not associated with other IgG4-RD appear to be difficult to diagnose.It is of utmost importance to rule out malignancy.However,these lesions may respond to steroid therapy.To avoid unnecessary resection,IgG4-related gastrointestinal diseases should be considered in the differential diagnosis.     

Renal oncocytoma with bilateral synchronous renal cell carcinoma in a patient undergoing long-term hemodialysis

Abstract:   We report a case of bilateral synchronous renal cell carcinoma and renal oncocytoma in a 56-year-old male who had been treated with hemodialysis for 32 years. Because anemia gradually worsened, computed tomography and magnetic resonance imaging were carried out and revealed bilateral renal tumors within acquired cystic disease of the kidney. Bilateral nephrectomy was carried out, and the patient was diagnosed with multiple renal cell carcinomas and a single renal oncocytoma. To our knowledge, this is the first reported case of renal oncocytoma with synchronous renal cell carcinoma in a patient undergoing long-term hemodialysis.     

Patency of the accessory pancreatic duct in relation to its course and shape: a dye-injection endoscopic retrograde pancreatography study

Objective: The accessory pancreatic duct (APD) exhibits several appearances on pancreatography. We examined the patency of the APD by dye-injection endoscopic retrograde pancreatography (ERP), and studied the relationship between patency and duct course and shape.
Methods: There were 213 patients with satisfactory imaging of the entire normal APD who also underwent dye-injection ERP. The length and maximum diameter of the APD and the length of the main pancreatic duct (MPD) from its orifice to the junction with the APD were measured.
Results: The caliber of the patent APD was 1.6 ± 0.6 mm. This was significantly larger than the caliber (1.1 ± 0.4 mm) of the nonpatent APD (   p < 0.01  ). The length of the MPD from its orifice to the junction with the patent APD was 32.7 ± 12.5 mm. This was significantly longer than the length to the junction with the nonpatent APD (22.5 ± 8.1 mm) (   p < 0.01  ). The APD was classified according to duct course: long type, intermediate type, short type, or ansa type. Patency was most common in the long type APD (74.5%). The terminal shape of the APD was also used to classify the ducts: stick type, branch type, saccular type, cudgel type, or spindle type. Patency was most frequently observed in the spindle and cudgel type ducts.
Conclusions: Patency of the APD might be dependent on duct caliber, course, and terminal shape of the duct.     

Effects of nizatidine and itopride hydrochloride on esophageal motor function

Background and Aim

Nizatidine and itopride hydrochloride inhibit cholinesterase activity and increase acetylcholine in the cholinergic nervous systems. The effect of nizatidine and itopride hydrochloride on esophageal motor function has not been determined, although these drugs are reported to increase gastric motility. Esophageal peristalsis between the upper esophageal sphincter and lower esophageal sphincter (LES) has been shown to be composed of three segments (segments 1?C3) using high-resolution manometry. The aim of this study was to clarify the effects of nizatidine and itopride on esophageal motor function using high-resolution manometry.

Methods

Seven healthy male volunteers (mean age 37.8?years) were examined three times: without medication, treated with 150?mg of nizatidine, or treated with 50?mg of itopride. LES pressure (LESP) and peak peristaltic pressures in the three esophageal segments upon swallowing 5?ml of water were examined using high-resolution manometry 1?h after drug administration.

Results

The mean LESP after administration of nizatidine or itopride hydrochloride tended to be higher than that without medication. There was no significant difference between the peak contraction pressure in the first (uppermost) esophageal segment with drug administration and that without. On the other hand, both nizatidine and itopride hydrochloride significantly augmented the peak contraction pressure in the second and third segments.

Conclusion

Administration of nizatidine and itopride hydrochloride is suggested to augment peristaltic contraction in the second and third segments of the esophageal body.     

M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan

Mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) tumor suppressor- gene mutation is an early event in human hepatocellular carcinoma (HCC) formation in the United States, but its role in hepatocarcinogenesis in Japan is unclear. We therefore determined M6P/IGF2R mutation frequency in HCCs from patients who resided in the southern, central, and northern regions of Japan. Ten single nucleotide polymorphisms were used to identify HCCs and dysplastic liver nodules with M6P/IGF2R loss of heterozygosity. The retained allele in these tumors was also assessed for point mutations and deletions in the M6P/IGF2R ligand binding domains by direct sequencing of polymerase chain reaction (PCR) amplified DNA products. Fifty-eight percent (54 of 93) of the patients were heterozygous at the M6P/IGF2R locus, and 67% (43 of 64) of the HCCs and 75% (3 of 4) of the dysplastic nodules had loss of heterozygosity. The remaining allele in 21% of the HCCs contained either M6P/IGF2R missense mutations or deletions, whereas such mutations were not found in the dysplastic lesions. In conclusion, M6P/IGF2R is mutated in HCCs from throughout Japan with a frequency similar to that in the United States. Loss of heterozygosity in dysplastic liver nodules provides additional evidence that M6P/IGF2R haploid insufficiency is an early event in human hepatocarcinogenesis.