Genotype/Phenotype Analysis And Follow-Up In 67 Chinese Patients With Gitelman's Syndrome

Objective: Gitelman's syndrome?GS?is an autosomal recessive renal tubular disorder,which is caused by the mutations in the SLC12A3 gene.The aim of this study was to analyze the characteristics of the genotype,phenotype,and follow-up in the largest group of Chinese patients.In addition,the cause of diabetes mellitus was investigated by a patient with Gitelman's syndrome.Methods: Sixty seven patients with GS underwent SLCl2A3 gene analysis.Clinical characteristics and biochemical findings at the first presentation as well as follow-up were reviewed.Additionally,the association of genotype and phenotype was explored.Evaluate GS patients' insulin sensitivity ability by 3h oral glucose tolerance test,10 healthy volunteers and 10 DM patients serve as controls.Results: 1.Forty one different SLC12A3 mutations were identified,including 11 novel ones,and 5 recurrent ones?p.T60M?28.4%?,p.D486N?13.4%?,p.R913Q?8.2%?,c.965-1_c.977 del GCGGACATTTTTGins ACCGAAAATTT?7.5%?,c.2877₂878del AG?5.2%??.The mutant frequency of T60 M is up to 28.8%,and T60 M is the most frequent mutation in our study.Approximately 5.7%of families had triple SLC12A3 mutations.2.Typical hypocalciuria and hypomagnesemia were not found in six?9%?and eight?11.9%?patients,respectively.In addition,male patients had an earlier age of onset and a higher urinary fraction excretion of electrolytes.3.Two patients had CKD?e GFR<60 m L/min?1.73m2?.Among sixty seven patients,thirteen?19.4%?had type2 diabetes,fourteen?20.9%?had impaired glucose tolerance?IGT?,five?7.5%?had impaired fasting glucose?IFG?.4.The patients harboring 2 severe mutations mentioned above in both alleles?severe genotype group?showed significant higher FEK?p < 0.01?,FEMg?p = 0.038?and FECl?p = 0.01?and a borderline significant decreased serum potassium level?p= 0.07?than the others?mild genotype group?;meanwhile,the severe genotype group possessed a greater proportion of patients with severe phenotype.5.OGTT result indicated that GS patients with diabetes manifested abnormal glucose metabolism and insulin function when she did not receive regular potassium and magnesium supplementation.Compared with healthy control,GS patients exhibited glucose peak and insulin peak delay,increased area under curve of glucose and insulin sensitivity index?HOMA-IR?and decreased area under curve of insulin and insulin sensitivity index?QUICKI and ISI?.While no significant differences of the insulin resistant indexes?ISI,QUICKI and HOMA-IR?were found between healthy control and GS patients which have normal level of blood glucose and have stopped taking hypoglycemic agents by receiving regular potassium and magnesium supplementation.Conclusions: We found 41 mutations,including 11 novel variants and 5 high-frequency ones,in 67 Chinese patients with GS.Fraction excretion of electrolyte in urine may be more sensitive in the evaluation of phenotype compared with those of blood.Hypokalemia and hypomagnesemia in GS is difficult to correct.Patients with GS are at higher risk of the development of type 2 diabetes than ordinary people.It is speculated that hypokalemia and hypomagnesemia may be the main cause.