Autosomal recessive familial neurohypophyseal diabetes insipidus with continued secretion of mutant weakly active vasopressin.
Autosomal recessive familial neurohypophyseal diabetes insipidus with continued secretion of mutant weakly active vasopressin.
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DOI：
10.1093/hmg/8.7.1303
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发表时间：
1999-07
影响因子：
3.5
通讯作者：
M. Willcutts;E. Felner;P. White
中科院分区：
文献类型：
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作者：
M. Willcutts;E. Felner;P. White
家族性神经垂体性尿崩症是一种常染色体显性遗传疾病，其特征是由于精氨酸加压素（AVP）基因突变导致的出生后发育缺乏。所有已发表的突变影响信号肽或neurophysin-II载体蛋白，并被推测干扰前激素原的加工，导致神经元损伤。我们研究了一个不寻常的巴勒斯坦家庭组成的无症状的堂兄弟姐妹的父母和三个孩子患有神经垂体尿崩症，这表明常染色体隐性遗传。所有三个受影响的儿童都是纯合子，父母是外显子1中单一新突变（C301->T）的杂合子，用Leu取代成熟AVP的Pro 7（Leu-AVP）。Leu-AVP是一种弱激动剂，与人V2受体的结合减少约30倍。通过放射免疫测定法与合成Leu-AVP标准，血清Leu-AVP水平升高，在所有三个孩子，并进一步增加，在水剥夺高达正常的30倍。最小的孩子（2岁）仅受到轻度影响，但Leu-AVP水平与她受到严重影响的8岁弟弟相似，这表明未知的机制可能部分弥补了幼儿活性AVP的不足。
Familial neurohypophyseal diabetes insipidus is an autosomal dominant disorder characterized by post-natal development of arginine vasopressin (AVP) deficiency due to mutations in the AVP gene. All published mutations affect the signal peptide or the neurophysin-II carrier protein and are presumed to interfere with processing of the preprohormone, leading to neuronal damage. We studied an unusual Palestinian family consisting of asymptomatic first cousin parents and three children affected with neurohypophyseal diabetes insipidus, suggesting autosomal recessive inheritance. All three affected children were homozygous and the parents heterozygous for a single novel mutation (C301->T) in exon 1, replacing Pro7 of mature AVP with Leu (Leu-AVP). Leu-AVP was a weak agonist with approximately 30-fold reduced binding to the human V2 receptor. Measured by radioimmunoassay with a synthetic Leu-AVP standard, serum Leu-AVP levels were elevated in all three children and further increased during water deprivation to as high as 30 times normal. The youngest child (2 years old) was only mildly affected but had Leu-AVP levels similar to her severely affected 8-year-old brother, suggesting that unknown mechanisms may partially compensate for a deficiency of active AVP in very young children.