Supplementary Material for: The Novel Ser18del AVP Variant Causes Inherited Neurohypophyseal Diabetes Insipidus by Mechanisms Shared with Other Signal Peptide Variants
Toustrup L.B.
Kvistgaard H.
Palmfeldt J.
Bjerre C.K.
Gregersen N.
Rittig S.
Corydon T.J.
Christensen J.H.
10.6084/m9.figshare.5107561.v1
https://karger.figshare.com/articles/dataset/Supplementary_Material_for_The_Novel_Ser18del_AVP_Variant_Causes_Inherited_Neurohypophyseal_Diabetes_Insipidus_by_Mechanisms_Shared_with_Other_Signal_Peptide_Variants/5107561
<p><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.</p>
2017-06-14 14:01:43
Arginine vasopressin
Diabetes insipidus
Signal peptide
Quantitative RT-PCR
Mass spectrometry
Heterologous expression
SH-SY5Y cells