Faerch Mia, Corydon Thomas J, Rittig Søren, Christensen Jane H, Hertz Jens Michael, Jendle Johan
Department of Human Genetics, Aarhus University, Aarhus University Hospital, Aarhus N, Denmark.
Scand J Urol Nephrol. 2010 Nov;44(5):324-30. doi: 10.3109/00365599.2010.482946. Epub 2010 May 12.
To establish the clinical phenotype and genetic background in a family with diabetes insipidus.
The subjects were a sister and brother, aged 34 and 27 years, respectively, with a history of polyuria since infancy. Clinical testing confirmed a diagnosis of congenital nephrogenic diabetes insipidus (CNDI) in both. Samples of purified genomic DNA were analysed.
The sequence of the entire coding region of the AQP2 gene as well as the AVPR2 gene was determined. Sequence analysis revealed no variations in the AQP2 gene. A missense variation in exon 2 of the AVPR2 gene (g.685G>A), predicting a p.Asp85Asn substitution, was identified in the X-chromosome of the affected male and one allele in the sister and the asymptomatic mother. The p.Asp85Asn variation in AVPR2 is known to cause CNDI, and has previously been described as inducing a partial phenotype treatable with dDAVP. However, in this family dDAVP had no influence on urine osmolality, whereas combination therapy with indomethacin and hydrochlorothiazide increased urine osmolality to 299 mosm/l in the proband. A skewed X-inactivation pattern (93%) occurring in the normal X allele was recognized in the sister.
This study demonstrates the effect of skewed X-chromosome inactivation associated with X-linked CNDI. Polydipsia in early childhood could be due to X-linked CNDI despite affecting both genders. The significant heterogeneity in the clinical phenotype in CNDI carries a risk of diagnostic misinterpretation and emphasizes the need for genetic characterization. Treatment combining indomethacin and hydrochlorothiazide results in a marked response on both urine output and urine osmolality.
确定一个尿崩症家族的临床表型和遗传背景。
研究对象为分别34岁和27岁的姐弟，自婴儿期起就有多尿病史。临床检查确诊两人均为先天性肾性尿崩症（CNDI）。对纯化的基因组DNA样本进行了分析。
测定了水通道蛋白2（AQP2）基因以及血管加压素2型受体（AVPR2）基因整个编码区的序列。序列分析显示AQP2基因无变异。在患病男性的X染色体以及其姐姐和无症状母亲的一个等位基因中，发现了AVPR2基因第2外显子的一个错义变异（g.685G>A），预测为p.Asp85Asn替代。已知AVPR2基因中的p.Asp85Asn变异会导致CNDI，此前曾被描述为可诱导部分表型且可用去氨加压素（dDAVP）治疗。然而，在这个家族中，dDAVP对尿渗透压没有影响，而吲哚美辛和氢氯噻嗪联合治疗使先证者的尿渗透压升高至299 mosm/l。在姐姐中发现正常X等位基因存在X染色体失活偏斜模式（93%）。
本研究证明了与X连锁CNDI相关的X染色体失活偏斜的影响。尽管男女均受影响，但儿童早期的烦渴可能归因于X连锁CNDI。CNDI临床表型的显著异质性存在诊断误解的风险，并强调了进行基因特征分析的必要性。吲哚美辛和氢氯噻嗪联合治疗对尿量和尿渗透压均有显著反应。
