Autosomal dominant pseudohypoaldosteronism type 1 with a novel splice site mutation in MR gene

<p>Abstract</p> <p>Background</p> <p>Autosomal dominant pseudohypoaldosteronism type 1 (PHA1) is a rare inherited condition that is characterized by renal resistance to aldosterone as well as salt wasting, hyperkalemia, and metabolic acidosis. Renal PHA1 is caused by mutations of the human mineralcorticoid receptor gene (<it>MR</it>), but it is a matter of debate whether <it>MR </it>mutations cause mineralcorticoid resistance via haploinsufficiency or dominant negative mechanism. It was previously reported that in a case with nonsense mutation the mutant mRNA was absent in lymphocytes because of nonsense mediated mRNA decay (NMD) and therefore postulated that haploinsufficiency alone can give rise to the PHA1 phenotype in patients with truncated mutations.</p> <p>Methods and Results</p> <p>We conducted genomic DNA analysis and mRNA analysis for familial PHA1 patients extracted from lymphocytes and urinary sediments and could detect one novel splice site mutation which leads to exon skipping and frame shift result in premature termination at the transcript level. The mRNA analysis showed evidence of wild type and exon-skipped RT-PCR products.</p> <p>Conclusion</p> <p>mRNA analysis have been rarely conducted for PHA1 because kidney tissues are unavailable for this disease. However, we conducted RT-PCR analysis using mRNA extracted from urinary sediments. We could demonstrate that NMD does not fully function in kidney cells and that haploinsufficiency due to NMD with premature termination is not sufficient to give rise to the PHA1 phenotype at least in this mutation of our patient. Additional studies including mRNA analysis will be needed to identify the exact mechanism of the phenotype of PHA.</p

Endovascular Treatment May Be Effective in Preventing Recurrence of Ischemic Stroke in Vertebral Artery Stump Syndrome: A Case Series

Vertebral artery stump syndrome (VASS) is a rare condition that can cause posterior circulation ischemic stroke due to occlusion of the ipsilateral vertebral artery (VA) orifice, resulting in blood flow stagnation and embolus formation. Although there is no established treatment for this condition, we observed 3 cases of VASS out of 326 acute ischemic stroke cases at a single institution from April 2021 to October 2022. Despite the best possible antithrombotic treatment, all 3 patients had recurrent ischemic strokes. One patient underwent drug-eluting stenting of the VA orifice to relieve occlusive flow. The other 2 patients received coil embolization, which resulted in the disappearance of their culprit collateral flow. None of the patients had recurrent ischemic strokes after endovascular intervention. Based on our observations, stenting and coil embolization are effective methods for preventing future recurrences of VASS

Natural history of genetically proven autosomal recessive Alport syndrome

BackgroundAutosomal recessive Alport syndrome (ARAS) is a rare hereditary disease caused by homozygous or compound heterozygous mutations in either the COL4A3 or COL4A4 genes. Failure to diagnose ARAS cases is common, even if detailed clinical and pathological examinations are carried out. As the mutation detection rate for ARAS is unsatisfactory, we sought to develop more reliable diagnostic methods and provide a better description of the clinicopathological characteristics of this disorder.MethodsA retrospective analysis of 30 genetically diagnosed patients with ARAS in 24 pedigrees was conducted. The mutation detection strategy comprised three steps: (1) genomic DNA analysis using polymerase chain reaction (PCR) and direct sequencing; (2) mRNA analysis using reverse transcription (RT)-PCR to detect RNA processing abnormalities; (3) semi-quantitative PCR using capillary electrophoresis to detect large heterozygous deletions.ResultsUsing the three-step analysis, we identified homozygous or compound heterozygous mutations in all patients. Interestingly, 20 % of our ARAS patients showed normal expression of ?5 in kidney tissue. The median age of developing end-stage renal disease was 21 years.ConclusionsThe strategy described in this study improves the diagnosis for ARAS families. Although immunohistochemical analysis of ?5 can provide diagnostic information, normal distribution does not exclude the diagnosis of ARAS