Novel AQP2 Mutations and Clinical Characteristics in Seven Chinese Families With Congenital Nephrogenic Diabetes Insipidus

Abstract

Objective: Mutations in AQP2 (aquaporin-2) lead to rare congenital nephrogenic diabetes insipidus (NDI), which has been limitedly studied in Chinese population.

Methods: Twenty-five subjects from seven families with NDI in a department (Beijing, PUMCH) were screened for AQP2 mutations. Clinical characteristics were described and genotype-phenotype correlation analysis was performed.

Results: We identified 9 AQP2 mutations in 13 patients with NDI, including 3 novel AQP2 mutations (p.G165D, p.Q255RfsTer72 and IVS3-3delC). Missense mutations were the most common mutation type, followed by splicing mutations, and frameshift mutations caused by small deletion or insertion. The onset-age in our patients was younger than 1 year old. Common manifestations included polydipsia, polyuria (7/7) and intermittent fever (6/7). Less common presentations included short stature (3/7) and mental impairment (1/7). High osmotic hypernatremia and low osmotic urine were the main biochemical features. Dilation of the urinary tract was a common complication of NDI (3/6). Level of serum sodium in NDI patients with compound het AQP2 mutations was higher than non-compound het mutations.

Conclusion: In the first and largest case series of NDI caused by AQP2 mutation in Chinese population, we identified 9 AQP2 mutations, including 3 novel mutations. Phenotype was found to correlate with genotypes, revealed by higher level of serum sodium in patients with compound het AQP2 mutations than non-compound het mutations. This knowledge broadens genotypic and phenotypic spectrum for rare congenital NDI and provided basis for studying molecular biology of AQP2.

Keywords: Nephrogenic diabetes insipidus; aquaporin-2; mutation; vasopressin V2 receptor; water resorption.

Figure 1

Pedigrees of the 7 families detected to carry pathogenic AQP2 mutations. The question mark indicates AQP2 mutation analysis of the individual was not performed.

Figure 2

Distribution of AQP2 mutations detected in our patients with NDI. (A) Distribution of the nine mutations in AQP2 gene. (B) Schematic diagram of the primary structure of AQP2, showing the location of changed amino acid. The black rectangles indicate DNA coding sequence; the empty circles indicate amino acid of AQP2; the grey half-filled circles indicate amino acid alterations found in our study.