Pathogenesis of hypokalemia in autosomal dominant hypocalcemia type 1.
BACKGROUND
Autosomal dominant hypocalcemia type 1 (ADH1) is a relatively rare endocrine disorder characterized by hypocalcemia and inadequate parathyroid hormone secretion. ADH is caused by activating mutations in the calcium-sensing receptor (CaSR) gene, CASR. CaSR plays a crucial role in calcium and magnesium homeostasis in the kidney. ADH may be accompanied by hypokalemia and metabolic alkalosis when it is classified as type V Bartter syndrome. However, the mechanism underlying hypokalemia in this disease is unclear.


METHODS
We investigated a 33-year-old woman with hypocalcemia and hypoparathyroidism since childhood, whose mother also had hypocalcemia and hypoparathyroidism, but with no clinical symptoms. Blood examinations showed hypokalemia and metabolic alkalosis in the patient, but not her mother. We conducted mutation analysis and diuretic tests to clarify the patient's and her mother's diagnosis and to investigate the onset mechanism of hypokalemia in ADH1. We also determined the localization of CaSR in the kidney by immunohistochemistry.


RESULTS
We detected a known gain-of-function mutation in CASR in both the patient and her mother. Diuretic tests revealed a response to furosemide and no reaction to thiazide in the patient, although the mother responded well to both diuretics. CaSR co-localized with the Na(+)-Cl(-) cotransporter (NCCT) on distal tubular epithelial cells.


CONCLUSIONS
These results indicate that the NCCT in the distal convoluted tubule was secondarily affected in this patient. We conclude that the main pathogenesis of secondary hypokalemia in ADH1 in this patient was secondary NCCT dysfunction.
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 6500017, Japan.
Naohiro
N
Kamiyoshi
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 6500017, Japan. nozu@med.kobe-u.ac.jp.
Kandai
K
Nozu
Department of Nephrology, Komaki City Hospital, Komaki, Aichi, Japan.
Yoshimichi
Y
Urahama
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 6500017, Japan.
Natsuki
N
Matsunoshita
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 6500017, Japan.
Tomohiko
T
Yamamura
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 6500017, Japan.
Shogo
S
Minamikawa
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 6500017, Japan.
Takeshi
T
Ninchoji
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 6500017, Japan.
Naoya
N
Morisada
Department of Pediatrics, Wakayama Medical College, Wakayama, Japan.
Koichi
K
Nakanishi
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 6500017, Japan.
Hiroshi
H
Kaito
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, 6500017, Japan.
Kazumoto
K
Iijima
D000328:Adult; D005260:Female; D006801:Humans; D053565:Hypercalciuria / Q000150:complications*; D006996:Hypocalcemia / Q000150:complications*; D007008:Hypokalemia / Q000209:etiology*; D007011:Hypoparathyroidism / Q000150:complications / Q000151:congenital*
Calcium-sensing receptor; Hypocalcemia; Hypoparathyroidism; Na+–Cl− cotransporter