A novel AVPR2 splice site mutation leads to partial X-linked nephrogenic diabetes insipidus in two brothers

Marie Helene Schernthaner-Reiter, David Adams, Giampaolo Trivellin, Mary Scott Ramnitz, Margarita Raygada, Gretchen Golas, Fabio R. Faucz, Ola Nilsson, Aikaterini A. Nella, Kavitha Dileepan, Maya Lodish, Paul Lee, Cynthia Tifft, Thomas Markello, William Gahl, Constantine A. Stratakis

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


X-linked nephrogenic diabetes insipidus (NDI, OMIM#304800) is caused by mutations in the arginine vasopressin (AVP, OMIM*192340) receptor type 2 (AVPR2, OMIM*300538) gene. A 20-month-old boy and his 8-year-old brother presented with polyuria, polydipsia, and failure to thrive. Both boys demonstrated partial DDAVP (1-desamino-8-D AVP or desmopressin) responses; thus, NDI diagnosis was delayed. While routine sequencing of AVPR2 showed a potential splice site variant, it was not until exome sequencing confirmed the AVPR2 splice site variant and did not reveal any more likely candidates that the patients’ diagnosis was made and proper treatment was instituted. Both patients were hemizygous for two AVPR2 variants predicted in silico to affect AVPR2 messenger RNA (mRNA) splicing. A minigene assay revealed that the novel AVPR2 c.276A>G mutation creates a novel splice acceptor site leading to 5′ truncation of AVPR2 exon 2 in HEK293 human kidney cells. Both patients have been treated with high-dose DDAVP with a remarkable improvement of their symptoms and accelerated linear growth and weight gain. Conclusion: We present here a unique case of partial X-linked NDI due to an AVPR2 splice site mutation; patients with diabetes insipidus of unknown etiology may harbor splice site mutations that are initially underestimated in their pathogenicity on sequence analysis.What is Known:• X-linked nephrogenic diabetes insipidus is caused by AVPR2 mutations, and disease severity can vary depending on the functional effect of the mutation.What is New:• We demonstrate here that a splice site mutation in AVPR2 leads to partial X-linked NDI in two brothers.• Treatment with high-dose DDAVP led to improvement of polyuria and polydipsia, weight gain, and growth.

Original languageEnglish (US)
Pages (from-to)727-733
Number of pages7
JournalEuropean Journal of Pediatrics
Issue number5
StatePublished - May 1 2016
Externally publishedYes


  • Arginine vasopressin receptor type 2
  • Partial nephrogenic diabetes insipidus
  • Pathogenic splice site mutation
  • X-linked nephrogenic diabetes insipidus

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health


Dive into the research topics of 'A novel AVPR2 splice site mutation leads to partial X-linked nephrogenic diabetes insipidus in two brothers'. Together they form a unique fingerprint.

Cite this