A case of primary selective hypoaldosteronism carrying three mutations in the aldosterone synthase (Cyp11b2) gene

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• 作者：Anna Taranta^a ; ¹ ; Carla Bizzarri^b ; ¹ ; ^{bizzarri@opbg.net} ; Andrea Masotti^c ; Giuseppe Sciré ; ^d ; Valentina Pampanini^d ; Marco Cappa^b
• 关键词：CYP11B2 ; Cytochrome P45011B2 or Aldosterone synthase ; DOC ; 11-deoxycorticosterone ; B ; Corticosterone ; 18OHB ; 18-hydroxycortisterone ; CYP11B1 ; Cytochrome P45011B1 or Steroid 11尾-hydroxylase ; SDS ; SD score ; PCR ; Polymerase chain reaction ; CYP11A1 ; Cytochro
• 刊名：Gene
• 出版年：2012
• 期刊代码：73_03781119
• 类别：bio
• 出版时间：25 May, 2012
• 卷：500
• 期：1
• 页码：22-27
• 文件大小：675 K

摘要

An infant with a clinical phenotype of early onset hypoaldosteronism has been screened for mutation analysis of the Cyp11b2 gene encoding aldosterone synthase enzyme. We have described a novel nonsense mutation in exon 3 (c.508 C > T) that gave rise to a shorter protein (Q170X) and two known concurrent missense mutations (c.594A > C in exon 3 and c.1157 T > C in exon 7) that led to substitution of glutamic acid for aspartic acid at amino acid position 198 (E198D) and of valine for alanine at amino acid position 386 (V386A). The father, who carried E198D plus V386A mutations, showed a fractional sodium excretion of 1.25%that was unmodified by dietary salt restriction, suggesting a mild haploinsufficiency.

We examined by in silico analysis the effect of the mutations on the secondary and tertiary structures of aldosterone synthase to explain the inefficient enzymatic activity. The Q170X mutation produced a truncated protein, which was consequently associated with a loss of catalytic activity. As predicted by JPred web system and Dock 6.3 software, the concurrent expression of E198D and V386A mutations induced a significant secondary structure rearrangement and a shift of the heme group and the 18-hydroxycorticosterone substrate from their optimal placement.