Tsuji Tomoya, Hiroyuki Ariyasu, Uraki Shinsuke, Doi Asako, Morita Shuhei, Iwakura Hiroshi, Nishi Masahiro, Furuta Hiroto, Akamizu Takashi
First Department of Medicine, Wakayama Medical University, Wakayama, Wakayama Prefecture, Japan.
Internal Medicine, Kuma Hospital, Chuo-ku, Kobe, Hyogo Prefecture, Japan.
J Endocr Soc. 2020 Dec 4;5(3):bvaa190. doi: 10.1210/jendso/bvaa190. eCollection 2021 Mar 1.
Autosomal dominant hypocalcemia (ADH) is caused by gain-of-function mutations of the calcium sensing receptor (CaSR). It is characterized by hypercalciuria in spite of hypocalcemia. Vitamin D deficiency increases calcium reabsorption in the distal tubules of the kidneys, resulting in hypocalciuria.
A 38-year-old female proband had hypocalcemia, hypocalciuria, and vitamin D deficiency. Her father and brother also had hypocalcemia, but her mother was normocalcemic. We analyzed the gene abnormality in this family. Polymerase chain reaction (PCR) and sequence analysis were performed to explore the gene mutation. Mutagenesis, transfection, and functional analysis were performed on the discovered genetic abnormalities.
PCR and sequence analysis revealed that the proband, her father, and brother had a novel heterozygous mutation of the genes that causes threonine to asparagine substitution at codon 186 (T186N). Using HEK293 cells transfected with wild-type or T186N complementary DNA, we assessed the intracellular Ca concentration in response to changes in the extracellular Ca concentration. The cells transfected mutant gene had higher activity than that of wild-type. Therefore, we determined our patient had ADH with a novel mutation of the gene and hypocalciuria resulting from a vitamin D deficiency. We administered vitamin D to the proband, which caused elevation of her urinary calcium level, a typical finding of ADH.
Vitamin D deficiency was suggested to potentially mask hypercalciuria in ADH. Hypocalcemia with vitamin D deficiency should be diagnosed with care.
常染色体显性遗传性低钙血症（ADH）由钙敏感受体（CaSR）功能获得性突变引起。其特征是尽管存在低钙血症，但尿钙排泄增多。维生素D缺乏会增加肾脏远端小管对钙的重吸收，导致尿钙减少。
一名38岁女性先证者存在低钙血症、尿钙减少及维生素D缺乏。她的父亲和哥哥也有低钙血症，但母亲血钙正常。我们分析了该家族的基因异常情况。采用聚合酶链反应（PCR）和序列分析来探寻基因突变。对发现的基因异常进行了诱变、转染及功能分析。
PCR和序列分析显示，先证者及其父亲和哥哥存在一种新的基因杂合突变，导致第186位密码子的苏氨酸被天冬酰胺取代（T186N）。利用转染了野生型或T186N互补DNA的HEK293细胞，我们评估了细胞内钙浓度对细胞外钙浓度变化的反应。转染了突变基因的细胞活性高于野生型细胞。因此，我们确定该患者患有ADH，存在新的基因突变，且尿钙减少是由维生素D缺乏所致。我们给先证者补充了维生素D，这导致其尿钙水平升高，这是ADH的典型表现。
维生素D缺乏可能会掩盖ADH患者的高尿钙症状。对于伴有维生素D缺乏的低钙血症患者，诊断时应谨慎。
