The Clinical Characteristics Of Hereditary Diabetes Insipidus, Gene Mutation Detection And Cell Function Research

[Objectives]To identify gene mutations and clinical characteristics of patients with familial diabetes insipidus for clarifying the specific hereditary features and improving the diagnostics and targeted treatment. To explore the cellular function and potential mechanism of abnormal and normal vasopressin receptors encoded by the mutant and wild types of A VPR2gene.[Methods]Patients with familial diabetes insipidus diagnosed and treated in Peking Union Medical College Hospital from2008to2012were investigated in our research, including5cases of familial neurohypophyseal diabetes insipidus (FNDI) index (13cases of family member in total) and20cases of inherited nephrogenic diabetes insipidus (NDI) index (66cases of family member in total). Firstly, clinical presentations of patients with familial diabetes insipidus were retrospectively analyzed. Secondly, mutations of AVP, AVPR2and AQP2genes responsible for family diabetes insipidus were analyzed by PCR and sequencing. Female carriers with AVPR2gene mutations presented with NDI symptoms were further investigated by skewed X chromosome inactivation (SXCI). The function of AVPR2gene mutations were further analyzed via eukaryon expression vector in vitro.[Results]Patients with inherited NDI were characterized by early onset of polyuria and polydipsia, which could be partially relieved by the combination treatment of hydrochlorothiazide and amiloride. The24-hour urine output could be reduced by1/3-1/2after treatment. FNDI was a rare disease characterized by postnatal development of severe polyuria and polydipsia, while effectively recovered by the replacement of AVP analogues such as DDAVP. Serious complications could be developed because of late diagnosis and treatment. We diagnosed14cases of X-linked NDI with13types of AVPR2gene mutations (2types were firstly reported),2cases of autosomal recessive NDI with3forms of AQP2gene mutations (2forms were firstly reported) and4cases of FNDI with4types of AVP gene mutations (4types were firstly reported). The relationship between the genotypes and the clinical phenotypes of familial diabetes insipidus revealed that mutations resulting in the truncated protein may play a role in the NDI patients with severe clinical symptoms. Female carriers with AVPR2gene mutations presented with symptoms of NDI could be attributed to SXCI. Functional analysis in vitro revealed that HEK293T cells transfected with targeted plasmids of missense mutations (M123K, C192R, L313R and P322S) resulted in the decreased level of cytoplasma cAMP, which is one of the main features of abnormal receptor function.[Conclusions]Familial diabetes insipidus is a rare group of monogenetic diseases and clinical presentation may vary considerably. The diagnosis of familial diabetes insipidus should be taken into consideration when young patients presented with unexplained clinical symptoms such as identified polyuria, polydipsia, failure to thrive, short stature and severe urine complications. Genetic testing is helpful for further diagnosis and tailored treatment. The decreased level of cellular cAMP caused by AVPR2gene mutations may play an important role in the pathogenesis of X-linked NDI.