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Two Novel Missense Mutations in Calcium-Sensing Receptor Gene Associated with Neonatal Severe Hyperparathyroidism¹

Department of Pediatrics, Okayama University Medical School (M.K., H.T., Y.I., K.A., Y.S.), Shikata-cho Okayama 700; the Department of Pediatrics, Social Insurance Chukyo Hospital (K.T., M.T.), 1–1-10 Sanjo-cho Minami-ku, Nagoya 457; and the Department of Surgery, Social Insurance Chukyo Hospital (H.I.), 1–1-10 Sanjo-cho Minami-ku, Nagoya 457, Japan

Address all correspondence and requests for reprints to: Hiroyuki Tanaka, M.D., Department of Pediatrics, Okayama University Medical School, Shikata-cho, Okayama 700, Japan. E-mail: hrtanaka{at}hospital.okayama-u.ac.jp

Familial hypocalciuric hypercalcemia (FHH) is characterized by lifelong asymptomatic hypercalcemia without PTH hypersecretion and is inherited as an autosomal dominant trait with near 100% penetrance. In contrast, neonatal severe hyperparathyroidism (NSHPT) is a life-threatening disorder characterized by marked hypercalcemia and PTH hypersecretion. FHH/NSHPT results from inactivating mutations of the human calcium-sensing receptor (Casr) gene on chromosome 3q13.3–24. Nearly 30 different mutations of the Casr gene associated with FHH/NSHPT have been reported previously. In this report, genetic analysis of 1 Japanese NSHPT family revealed 2 novel mutations at codon 185 (CGATGA/ArgTer) in exon 4 of the Casr gene and at codon 670 (GGGGAG/GlyGlu) in exon 7. The Arg¹⁸⁵Ter change was shown to occur in the proband’s unaffected father and paternal grandmother as well as in the proband. The other mutation in exon 7 was shown in the proband’s unaffected mother of Philippine origin as well as in the proband. This family is the first case of manifestation of more than 1 mutation in a proband’s chromosomes; 1 mutation was obtained from the unaffected father, and the other was from the unaffected mother. Our observations have given us important keys to help elucidate the structure-function relationships of the Casr.

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