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

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Abstract

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.

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Abbreviations

AQP2:

aquaporin 2

AVP:

arginine vasopressin

AVPR2:

arginine vasopressin receptor type 2

DDAVP:

1-desamino-8-D AVP or desmopressin

DI:

diabetes insipidus

mRNA:

messenger RNA

NDI:

nephrogenic diabetes insipidus

RT-PCR:

reverse transcription PCR

References

  1. Babey M, Kopp P, Robertson GL (2011) Familial forms of diabetes insipidus: clinical and molecular characteristics. Nat Rev Endocrinol 7:701–714

    Article  CAS  PubMed  Google Scholar 

  2. Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloglu A, Ozen S, Sanjad S, Nelson-Williams C, Farhi A, Mane S, Lifton RP (2009) Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A 106:19096–19101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Faerch M, Christensen JH, Corydon TJ, Kamperis K, de Zegher F, Gregersen N, Robertson GL, Rittig S (2008) Partial nephrogenic diabetes insipidus caused by a novel mutation in the AVPR2 gene. Clin Endocrinol 68:395–403

    Article  CAS  Google Scholar 

  4. Gahl WA, Markello TC, Toro C, Fajardo KF, Sincan M, Gill F, Carlson-Donohoe H, Gropman A, Pierson TM, Golas G, Wolfe L, Groden C, Godfrey R, Nehrebecky M, Wahl C, Landis DM, Yang S, Madeo A, Mullikin JC, Boerkoel CF, Tifft CJ, Adams D (2012) The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. Genet Med 14:51–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gahl WA, Tifft CJ (2011) The NIH Undiagnosed Diseases Program: lessons learned. JAMA 305:1904–1905

    Article  CAS  PubMed  Google Scholar 

  6. 1000 Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491:56–65

  7. Juul KV, Bichet DG, Nielsen S, Norgaard JP (2014) The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am J Physiol Renal Physiol 306:F931–F940

    Article  CAS  PubMed  Google Scholar 

  8. Kamperis K, Siggaard C, Herlin T, Nathan E, Hertz JM, Rittig S (2000) A novel splicing mutation in the V2 vasopressin receptor. Pediatr Nephrol 15:43–49

    Article  CAS  PubMed  Google Scholar 

  9. Moeller HB, Rittig S, Fenton RA (2013) Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment. Endocr Rev 34:278–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nakamura K, Fukao T, Perez-Cerda C, Luque C, Song XQ, Naiki Y, Kohno Y, Ugarte M, Kondo N (2001) A novel single-base substitution (380C>T) that activates a 5-base downstream cryptic splice-acceptor site within exon 5 in almost all transcripts in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab 72:115–121

    Article  CAS  PubMed  Google Scholar 

  11. Neocleous V, Skordis N, Shammas C, Efstathiou E, Mastroyiannopoulos NP, Phylactou LA (2012) Identification and characterization of a novel X-linked AVPR2 mutation causing partial nephrogenic diabetes insipidus: a case report and review of the literature. Metabolism 61:922–930

    Article  CAS  PubMed  Google Scholar 

  12. Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68:598–605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Spanakis E, Milord E, Gragnoli C (2008) AVPR2 variants and mutations in nephrogenic diabetes insipidus: review and missense mutation significance. J Cell Physiol 217:605–617

    Article  CAS  PubMed  Google Scholar 

  14. Wesche D, Deen PM, Knoers NV (2012) Congenital nephrogenic diabetes insipidus: the current state of affairs. Pediatr Nephrol 27:2183–2204

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Marie Helene Schernthaner-Reiter (MHSR), David Adams (DA), Giampaolo Trivellin (GT), Mary Scott Ramnitz (MSR), Margarita Raygada (MR), Gretchen Golas (GG), Fabio R. Faucz (FRF), Ola Nilsson (ON), Aikaterini A. Nella (AAN), Kavitha Dileepan (KD), Maya Lodish (ML), Paul Lee (PL), Cynthia Tifft (CT), Thomas Markello (TM), William Gahl (WG), Constantine A. Stratakis (CAS).

Clinical data were acquired by DA, MSR, MR, GG, ON, AAN, KD, ML, PL, CT, TM, WG and CAS. Functional studies were performed by MHSR, GT and FRF. MHSR, GT, ML and CAS were responsible for the study design and drafted the manuscript, which was subsequently critically revised by all authors. Data interpretation was performed by all authors. All authors approved the final version of the manuscript.

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Correspondence to Maya Lodish.

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All authors declare no conflict of interest.

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Communicated by Beat Steinmann

Marie Helene Schernthaner-Reiter and David Adams are sharing first authorship.

William Gahl and Constantine A. Stratakis are sharing senior authorship.

Revisions received: 1 December 2015; 16 December 2015

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Schernthaner-Reiter, M.H., Adams, D., Trivellin, G. et al. A novel AVPR2 splice site mutation leads to partial X-linked nephrogenic diabetes insipidus in two brothers. Eur J Pediatr 175, 727–733 (2016). https://doi.org/10.1007/s00431-015-2684-4

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  • DOI: https://doi.org/10.1007/s00431-015-2684-4

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