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

Qian Li,Jing Cen,Dan Tian,Weibo Xia,Lian Duan

doi:10.3389/fendo.2021.686818

Abstract

ObjectiveMutations in AQP2 (aquaporin-2) lead to rare congenital nephrogenic diabetes insipidus (NDI), which has been limitedly studied in Chinese population.MethodsTwenty-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.ResultsWe 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.ConclusionIn 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.

Highlights

Congenital Nephrogenic Diabetes Insipidus (NDI) is characterized by impaired water resorption in the collecting duct due to insensitivity to arginine vasopressin (AVP) of principal cells, leading to polyuria and polydipsia (1)
Missense mutations were the most common mutation type, followed by splicing mutations, frameshift mutations caused by small deletion or insertion
Of these AQP2 mutations, 3 were novel mutations (p.G165D, p.Q255RfsTer[72] and IVS3-3delC) (Table 1), which were predicted to be pathogenic according to ACMG guidelines

Summary

Introduction

Congenital Nephrogenic Diabetes Insipidus (NDI) is characterized by impaired water resorption in the collecting duct due to insensitivity to arginine vasopressin (AVP) of principal cells, leading to polyuria and polydipsia (1). Mutations in the two key genes-AQP2 (aquaporin-2) and AVPR2 (vasopressin V2 receptor) were identified in most patients with a clear phenotype of NDI (2). 10% of patients with inherited NDI have a mutation in AQP2 with an autosomal recessive or dominant pattern (OMIM 125800, 107777)) (3). Infants with congenital NDI may suffer from hypernatremic dehydration, intermittent fever, irritaility, poor feeding and constipation (4). Repeated episodes of hypernatraemic dehydration and rehydration may cause brain tissue damage, seizure and even impair mental development (5, 6). Current therapeutic methods for NDI focus on relieving symptoms, which are limited and only partially beneficial (8)

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