Two Novel Mutations in the Aquaporin 2 Gene in a Girl with Congenital Nephrogenic Diabetes Insipidus

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder characterized by insensitivity of the kidney to the antidiuretic effect of vasopressin. There are three inheritance patterns of CNDI: the X-linked recessive form associated with vasopressin V2 receptor gene mutations, and the autosomal recessive and dominant forms associated with aquaporin-2 gene (AQP2) mutations. The evaluation for polyuria and polydipsia in a one-month-old Korean girl revealed no response to vasopressin and confirmed the diagnosis of CNDI. Because the child was female without family history of CNDI, her disease was thought to be an autosomal recessive form. We analyzed the AQP2 gene and detected a compound heterozygous missense point mutation: (70)Ala (GCC) to Asp (GAC) in exon 1 inherited from her father and (187)Arg (CGC) to His (CAC) in exon 3 inherited from her mother. The first mutation is located within the first NPA motif of the AQP2 molecule and the second one right after the second NPA motif. This is the first report to characterize AQP2 mutations in Korean patients with autosomal recessive CNDI, and expands the spectrum of AQP2 mutations by reporting two novel mutation, (70)Ala (GCC) to Asp (GAC) and (187)Arg (CGC) to His (CAC).

Angiotensin I Converting Enzyme Polymorphism and the Progression of IgA Nephropathy / 대한신장학회잡지

IgA nephropathy(IgAN) is the most common glomerulonephritis(GN) in worldwide, and accounts for 20% to 40% of all patients with primary GN in Korea. IgAN has diverse clinical courses, but the risk factors affecting the deterioration of renal function are not established. Recently, there were some suggestions that systemic or local expression of peptides of angiotensin system exerts several effects on the progression of renal disease, and the genetic polymorphisms may associated with peptide expression. To evaluate the role of genetic polymorphism of angiotensin I converting enzyme(ACE) polymorphism in the progression of IgAN, the genotypic distributions in 278 biopsy-proven cases of IgAN were studied, which had undergone a renal biopsy at Seoul National University Hospital, between 1979 and 2000. We also compared the genotypes with clinical manifestations to evaluate the clinical implications of genetic polymorphism. The study shows that there was no difference in the ACE genotype frequencies between the patients (II : 26.6%, ID : 55.0%, DD : 18.4%) and normal controls(II : 31.4%, ID : 57.4%, and DD : 11.2%). Seventy- two percent and 48% of patients maintained renal function for 10 years and 20 years after the initial diagnosis in 278 patients, respectively. However, in 153 patients who were followed more than 5 years, the DD genotype was more prevalent in patients with deteriorating renal function than in those with stable renal function(31.8% vs. 13.8%; p=0.0146). Presence of systemic hypertension increased the risk of renal disease progression(OR=3.3), and it was showed 7.4 fold risk whenever the creatinine was increased by 1 mg/dL. Renal disease progression is not associated with DD genotype among normotensive patients at the biopsy. But, in patients with hypertension, II and DD/ID genotypes have an increased risk for disease progression when compared with II genotype of normotensive patients(OR=1.4, OR=7.8; respectively). ACE polymorphisms did not have any interaction with the levels of serum creatinine at the time of biopsy in our patients. Our results suggested that ACE genotypes(D allele) affected the progression of IgAN, especially in hypertensive patients. One of the prospects of the present study is the potential for screening high risk individuals, thus helping to develop a practical application of the molecular findings in clinical practice.

The Effect of Uteroglobin Exon 1, 5' Untranslated Region Polymorphism on the Progression of IgA Nephropathy / 대한신장학회잡지

Uteroglobin(UG) is an anti-inflammatory/immunomodulatory protein secreted by the epithelial cells of vertebrates. Targeted disruption of UG rendered mouse glomerulonephritis resembling IgA nephropathy(IgAN). Sequence analysis on exon 1 of UG showed several putative binding sites for transcription factors, and genetic polymorphisms in this site might influence the expression level of UG as a competitive protein. We speculated that the single nucleotide polymorphism at the 38th nucleotide from the transcription initiation site of UG exon 1 would impact the progression of IgAN. PCR-RFLP was instituted to determine the genetic polymorphism in 60 patients with IgAN. Other measures like SSCP and direct sequencing were also adopted for the verification of polymorphic sites. Seventeen patients with IgAN(28%) were homozygous for adenine at position 38(38AA), 26 patients(43%) were heterozygous(38AG), and 17 patients(28%) were homozygous for the polymorphism(38GG), which was similar to the pattern obtained from the 60 normal controls. The amount of daily proteinuria, presence of hypertension, the level of IgA, and the amount of IgA-fibronectin(FN) complexes was similar between the genotypes. Serum IgA-FN level did not influence the progression of disease. However, 8 out of 17 patients (47%) with the AA genotype had progressive disease(PD), 10 of 26 patients(38%) with the AG genotype had PD, and only 1 of 17 patients(6%) with GG homozygocity had PD after 94+/-30.1 months of follow-up(mean+/-S.D.). The odds ratio for the progression of renal disease in patients with the AA genotype was 14.93(p=0.0355) and in patients with AG genotype was 12.94(p=0.0496) compared with patients have the GG genotype. Moreover, serum creatinine at the time of kidney biopsy was higher in patients with AA and AG genotypes than in patients with the GG genotype(1.5+/-0.69 : 1.3+/-0.53 : 1.0+/-0.31mg/dL; AA : AG : GG; p=0.0137 AA vs. GG; p=0.0269 AG vs. GG). Our results suggest that polymorphism at the 5' UTR region of UG exon 1 is an important marker for the progression of IgAN.