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A novel AVPR2 splice site mutation leads to partial X-linked nephrogenic diabetes insipidus in two brothers.
Eur J Pediatr. 2016 May; 175(5):727-33.EJ

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.

Authors+Show Affiliations

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.Division of Endocrinology and Diabetes, Children's Mercy Hospital, Kansas City, MO, USA.Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. lodishma@mail.nih.gov.NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

26795631

Citation

Schernthaner-Reiter, Marie Helene, et al. "A Novel AVPR2 Splice Site Mutation Leads to Partial X-linked Nephrogenic Diabetes Insipidus in Two Brothers." European Journal of Pediatrics, vol. 175, no. 5, 2016, pp. 727-33.
Schernthaner-Reiter MH, 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. 2016;175(5):727-33.
Schernthaner-Reiter, M. H., Adams, D., Trivellin, G., Ramnitz, M. S., Raygada, M., Golas, G., Faucz, F. R., Nilsson, O., Nella, A. A., Dileepan, K., Lodish, M., Lee, P., Tifft, C., Markello, T., Gahl, W., & Stratakis, C. A. (2016). A novel AVPR2 splice site mutation leads to partial X-linked nephrogenic diabetes insipidus in two brothers. European Journal of Pediatrics, 175(5), 727-33. https://doi.org/10.1007/s00431-015-2684-4
Schernthaner-Reiter MH, et al. A Novel AVPR2 Splice Site Mutation Leads to Partial X-linked Nephrogenic Diabetes Insipidus in Two Brothers. Eur J Pediatr. 2016;175(5):727-33. PubMed PMID: 26795631.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel AVPR2 splice site mutation leads to partial X-linked nephrogenic diabetes insipidus in two brothers. AU - Schernthaner-Reiter,Marie Helene, AU - Adams,David, AU - Trivellin,Giampaolo, AU - Ramnitz,Mary Scott, AU - Raygada,Margarita, AU - Golas,Gretchen, AU - Faucz,Fabio R, AU - Nilsson,Ola, AU - Nella,Aikaterini A, AU - Dileepan,Kavitha, AU - Lodish,Maya, AU - Lee,Paul, AU - Tifft,Cynthia, AU - Markello,Thomas, AU - Gahl,William, AU - Stratakis,Constantine A, Y1 - 2016/01/21/ PY - 2015/08/04/received PY - 2015/12/17/accepted PY - 2015/12/15/revised PY - 2016/1/23/entrez PY - 2016/1/23/pubmed PY - 2017/1/14/medline KW - Arginine vasopressin receptor type 2 KW - Partial nephrogenic diabetes insipidus KW - Pathogenic splice site mutation KW - X-linked nephrogenic diabetes insipidus SP - 727 EP - 33 JF - European journal of pediatrics JO - Eur J Pediatr VL - 175 IS - 5 N2 - UNLABELLED: 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. SN - 1432-1076 UR - https://www.unboundmedicine.com/medline/citation/26795631/A_novel_AVPR2_splice_site_mutation_leads_to_partial_X_linked_nephrogenic_diabetes_insipidus_in_two_brothers_ L2 - https://dx.doi.org/10.1007/s00431-015-2684-4 DB - PRIME DP - Unbound Medicine ER -