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.
N1 - Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg (outside the USA).
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
KW - Arginine vasopressin receptor type 2
KW - Partial nephrogenic diabetes insipidus
KW - Pathogenic splice site mutation
KW - X-linked nephrogenic diabetes insipidus
UR - http://www.scopus.com/inward/record.url?scp=84955278670&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84955278670&partnerID=8YFLogxK
U2 - 10.1007/s00431-015-2684-4
DO - 10.1007/s00431-015-2684-4
M3 - Article
C2 - 26795631
AN - SCOPUS:84955278670
SN - 0340-6199
VL - 175
SP - 727
EP - 733
JO - European Journal of Pediatrics
JF - European Journal of Pediatrics
IS - 5
ER -