PDF(Pubmed)
Abstract：
BACKGROUND: Nephrogenic diabetes insipidus (NDI) is a rare genetic disease that causes water imbalance. The kidneys play a crucial role in regulating body fluids by controlling water balance through urine excretion. This highlights their essential function in managing the body\'s water levels, but individuals with NDI may have excess urine production (polyuria), that leads to excessive thirst (polydipsia). Untreated affected individuals may exhibit poor feeding and failure to thrive. This disease is caused by mutations in the AVPR2 and the AQP2 genes which have the X-linked and autosomal recessive/dominant inheritance, respectively. Both of these genes are expressed in the kidney.
METHODS: Twelve Iranian patients from 10 consanguineous families were studied in this project. DNA was extracted from the whole blood samples of the patients and their parents. All coding exons and exon-intron boundaries of the AVPR2 and AQP2 genes were sequenced in the affected individuals, and the identified variants were investigated in the parents. All variants were analyzed according to the ACMG (American College of Medical Genetics and Genomics) guidelines.
RESULTS: In this study, 6 different mutations were identified in the patients, including 5 in the AQP2 gene (c.439G>A, c.538G>A, c.140C>T, c.450T>A, and the novel c.668T>C) and 1 in the AVPR2 gene (c.337C>T) in the present study.
CONCLUSIONS: As expected, all the detected mutations in this study were missense. According to the ACMG guideline, the identified mutations were categorized as pathogenic or likely pathogenic. Unlike previous studies which showed more than 90% of mutations were in the AVPR2 gene, and only less than 10% of the mutations were in the AQP2 gene, it was found that more than 90% of our identified mutations located in the AQP2 gene, and only one mutation was observed in the AVPR2 gene, which seems it may be a result of the high rate of consanguineous marriages in the Iranian population. We observed genotype-phenotype correlation in some of our affected individuals, and some of the mutations were observed in unrelated families from same ethnicity which could be suggestive of a founder mutation.
METHODS: Twelve Iranian patients from 10 consanguineous families were studied in this project. DNA was extracted from the whole blood samples of the patients and their parents. All coding exons and exon-intron boundaries of the AVPR2 and AQP2 genes were sequenced in the affected individuals, and the identified variants were investigated in the parents. All variants were analyzed according to the ACMG (American College of Medical Genetics and Genomics) guidelines.
RESULTS: In this study, 6 different mutations were identified in the patients, including 5 in the AQP2 gene (c.439G>A, c.538G>A, c.140C>T, c.450T>A, and the novel c.668T>C) and 1 in the AVPR2 gene (c.337C>T) in the present study.
CONCLUSIONS: As expected, all the detected mutations in this study were missense. According to the ACMG guideline, the identified mutations were categorized as pathogenic or likely pathogenic. Unlike previous studies which showed more than 90% of mutations were in the AVPR2 gene, and only less than 10% of the mutations were in the AQP2 gene, it was found that more than 90% of our identified mutations located in the AQP2 gene, and only one mutation was observed in the AVPR2 gene, which seems it may be a result of the high rate of consanguineous marriages in the Iranian population. We observed genotype-phenotype correlation in some of our affected individuals, and some of the mutations were observed in unrelated families from same ethnicity which could be suggestive of a founder mutation.
摘要：
背景：肾源性尿崩症（NDI）是一种罕见的遗传性疾病，可导致水分失衡。肾脏通过尿液排泄控制水平衡，在调节体液中起着至关重要的作用。这突出了它们在管理身体水位方面的基本功能，但是患有NDI的人可能有过量的尿液产生（多尿），导致过度口渴（多饮）。未经治疗的受影响个体可能表现出不良的喂养和无法茁壮成长。这种疾病是由具有X连锁和常染色体隐性/显性遗传的AVPR2和AQP2基因突变引起的，分别。这两种基因都在肾脏中表达。
方法：本项目研究了来自10个近亲家庭的12名伊朗患者。从患者及其父母的全血样本中提取DNA。在受影响的个体中，对AVPR2和AQP2基因的所有编码外显子和外显子-内含子边界进行了测序，并在父母中对鉴定出的变异进行了调查。根据ACMG(美国医学遗传学和基因组学学院)指南分析所有变体。
结果：在这项研究中，在患者中发现了6种不同的突变，在AQP2基因中包括5个（c.439G>A，c.538G>A，c.140℃>T，c.450T>A，和本研究中AVPR2基因中的新型c.668T>C）和1（c.333C>T）。
结论：如预期的那样，本研究中检测到的所有突变均为错义.根据ACMG指南,鉴定出的突变分为致病性或可能致病性.与以前的研究显示超过90％的突变发生在AVPR2基因不同，只有不到10%的突变在AQP2基因中，我们发现超过90%的突变位于AQP2基因，在AVPR2基因中只观察到一个突变，这似乎可能是伊朗人口中近亲结婚率很高的结果。我们在一些受影响的个体中观察到基因型-表型相关性，并且在来自同一种族的无关家庭中观察到一些突变，这可能暗示了创始人突变。
方法：本项目研究了来自10个近亲家庭的12名伊朗患者。从患者及其父母的全血样本中提取DNA。在受影响的个体中，对AVPR2和AQP2基因的所有编码外显子和外显子-内含子边界进行了测序，并在父母中对鉴定出的变异进行了调查。根据ACMG(美国医学遗传学和基因组学学院)指南分析所有变体。
结果：在这项研究中，在患者中发现了6种不同的突变，在AQP2基因中包括5个（c.439G>A，c.538G>A，c.140℃>T，c.450T>A，和本研究中AVPR2基因中的新型c.668T>C）和1（c.333C>T）。
结论：如预期的那样，本研究中检测到的所有突变均为错义.根据ACMG指南,鉴定出的突变分为致病性或可能致病性.与以前的研究显示超过90％的突变发生在AVPR2基因不同，只有不到10%的突变在AQP2基因中，我们发现超过90%的突变位于AQP2基因，在AVPR2基因中只观察到一个突变，这似乎可能是伊朗人口中近亲结婚率很高的结果。我们在一些受影响的个体中观察到基因型-表型相关性，并且在来自同一种族的无关家庭中观察到一些突变，这可能暗示了创始人突变。
