Genetic and Functional Analysis of Renal Tubular Disorders: from Clinical to Bench Study

• Main Authors: Tseng, Min-Hua, 曾敏華
• Other Authors: Lin, Shih-Hua
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/w98be6

博士 === 國防醫學院 === 醫學科學研究所 === 106 === Inherited renal tubular disorders are characterized by muscle weakness, exertional intolerance, polyuria, convulsion, short stature, and rickets during childhood. The main biochemical abnormalities include dysnatremia, dyskalemia, dyscalcemia, metabolic acidosis and metabolic alkalosis. The modes of inheritance could be autosomal recessive, autosomal dominant, X-linked recessive or X-linked dominant. Because the major inheritance is autosomal recessive and the initial presentations are insidious, it is difficult to make an early diagnosis of inherited renal tubular disorders. However, it leads to growth retardation, renal failure and even death from delayed diagnosis or treatment. In recent years, we have diagnosed several inherited renal tubular disorders including Gitelman’s syndrome, Bartter’s syndrome, renal fanconi syndrome results from LOWE syndrome, Dent’s disease, and mitochondrial disorder, familial hypomagnesemia hypercalciuria nephrocalcinosis, nephrogenic diabetes insipidus, and autosomal recessive renal tubular dysgenesis by molecular analysis. The improvement of clinical conditions of most of our patients was achieved after timely diagnosis and appropriate treatment. In chapter 1, we presented a child with hereditary vitamin D-resistant rickets (HVDRR) caused by a novel mutation on RXR domain of vitamin D receptor gene. This child exhibited hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, increased serum 1,25-dihydroxyvitamin D3, rickets and alopecia. Although patients with mutations in different binding domains have been shown to exhibit distinct and variable severity of phenotypes, the study of the VDR mutant on RXR-binding domains remains limited. Therefore, we conducted a functional study was performed to explore the molecular mechanism in vitro to aid in understanding the pathogenesis of HVDRR. In chapter 2, mutations in SLC12A3 encoding the thiazide-sensitive sodium chloride cotransporter on the apical membrane of distal convoluted tubule lead to Gitelman’s syndrome. We attempted to investigate the genotype, phenotype and follow-up of Taiwanese with Gitelman syndrome. In chapter 3, Autosomal recessive renal tubular dysgenesis is caused by genetic defects on AGT, REN, ACE or AT1R and is characterized by absence or poor-differentiated proximal convoluted tubules. Recently, we firstly identified five patients of ARRTD caused by identical homozygous large deletion of AGT gene from four unrelated families within 3 year in Taiwan. We will explore the pathogenic role of roles of our defected AGT on the development of renal tubular dysgenesis.