ESPE Abstracts (2015) 84 P-2-530

Nephrogenic Diabetes Insipidus with Partial Response to Ddavp Caused by a Novel AVPR2 Splice Site Mutation

Marie Helene Schernthaner-Reitera, David Adamsb, Ola Nilssona, Giampaolo Trivellinb, Mary Scott Ramnitza, Margarita Raygadaa, Gretchen Golasb, Fabio R. Faucza, Kavitha Dileepanc, Maya B. Lodisha, Paul R. Leeb, Thomas C. Markellob, Cynthia J. Tifftb, William A. Gahlb & Constantine A. Stratakisa


aPDEGEN, NICHD, National Institutes of Health, Bethesda. MD, USA; bMGB, NHGRI, National Institutes of Health, Bethesda, MD, USA; cChildrens Mercy Hospital, Kansas City, MO, USA


Background: Congenital diabetes insipidus (DI) can be due to mutations in the arginine vasopressin (AVP) gene (familial neurohypophyseal DI), the AVP receptor type 2 (AVPR2) or aquaporin 2 (AQP2) genes (congenital nephrogenic DI, NDI). The clinical manifestation of congenital NDI, especially the response to AVP, can vary greatly depending on the functional effect of the AVPR2 mutation. Here we present two male siblings with NDI and partial response to ddAVP.

Objective and hypotheses: To identify the genetic cause of the condition.

Method: Whole exome sequencing was performed in selected family members. A minigene splicing assay was used to evaluate the effect of two splice site variants in AVPR2.

Results: Two male siblings presented with failure to thrive, polyuria, and polydipsia. Laboratory evaluation showed hypernatremia, elevated serum osmolality, and low urine osmolality. During water deprivation urine osmolality remained low. Subcutaneous ddAVP administration (1 mcg) increased urine osmolality modestly to 250–350 mOsm/kg, consistent with partial NDI. The two parents, a sister, and a brother were unaffected. Initial Sanger Sequencing reported no pathogenic variants in AVPR2 or AQP2, with mention of a possible splice site variant of unknown significance. We performed exome sequencing and found the same variant. In fact, we confirmed that both the patient and brother were hemizygous for two AVPR2 variants with in silico predicted effects on mRNA splicing. A minigene assay revealed that only one, the novel AVPR2 c.276 A>G mutation created a cryptic splice acceptor site that led to 5’ truncation of AVPR2 exon 2 when tested in HEK293 cells. This truncation leads to a frameshift and premature stop codon, which is likely to be the cause for these familial cases of NDI with partial responsiveness to AVP. Both patients were treated with high dose ddAVP and showed improvement of DI symptoms as well as improved growth and weight gain.

Conclusions: A novel AVPR2 splice site mutation as a cause of X-linked NDI was identified. Patients with DI of unknown etiology can harbor splice site mutations whose pathogenicity may be underestimated on routine sequence analysis. In NDI with partial response to ddAVP, high dose ddAVP treatment may be considered.

Funding information: “The work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Human Genome Research Institute, National Institutes of Health.”