In:
Neuroendocrinology, S. Karger AG, Vol. 106, No. 2 ( 2018), p. 167-186
Abstract:
〈 b 〉 〈 i 〉 Background/Aim: 〈 /i 〉 〈 /b 〉 Variability in the severity and age at onset of autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) may be associated with certain types of variants in the arginine vasopressin ( 〈 i 〉 AVP 〈 /i 〉 ) gene. In this study, we aimed to describe a large family with an apparent predominant female occurrence of polyuria and polydipsia and to determine the underlying cause. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 The family members reported their family demography and symptoms. Two subjects were diagnosed by fluid deprivation and dDAVP challenge tests. Eight subjects were tested genetically. The identified variant along with 3 previously identified variants in the 〈 i 〉 AVP 〈 /i 〉 gene were investigated by heterologous expression in a human neuronal cell line (SH-SY5Y). 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Both subjects investigated clinically had a partial neurohypophyseal diabetes insipidus phenotype. A g.276_278delTCC variant in the 〈 i 〉 AVP 〈 /i 〉 gene causing a Ser18del deletion in the signal peptide (SP) of the AVP preprohormone was perfectly co-segregating with the disease. When expressed in SH-SY5Y cells, the Ser18del variant along with 3 other SP variants (g.227G 〉 A, Ser17Phe, and Ala19Thr) resulted in reduced 〈 i 〉 AVP 〈 /i 〉 mRNA, impaired AVP secretion, and partial AVP prohormone degradation and retention in the endoplasmic reticulum. Impaired SP cleavage was demonstrated directly in cells expressing the Ser18del, g.227G 〉 A, and Ala19Thr variants, using state-of-the-art mass spectrometry. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 Variants affecting the SP of the AVP preprohormone cause adFNDI with variable phenotypes by a mechanism that may involve impaired SP cleavage combined with effects at the mRNA, protein, and cellular level.
Type of Medium:
Online Resource
ISSN:
0028-3835
,
1423-0194
Language:
English
Publisher:
S. Karger AG
Publication Date:
2018
detail.hit.zdb_id:
1483028-0
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