Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains

Journal Article · Mon Apr 01 04:00:00 EST 1996 · Journal of Clinical Endocrinology and Metabolism

DOI:https://doi.org/10.1210/jc.81.4.1312· OSTI ID:530763

Heath, H III; Odelberg, S; Leppert, M F ^[1]

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1. Univ. of Utah School of Medicine, Salt Lake City, UT (United States); and others

The predominant variety of familial benign hypocalciuric hypercalcamia (FBHH) is FBHH{sub 3q}, which is associated with presumed inactivating mutations of the cell surface calcium receptor (CaR) gene on chromosome 3q13.3-q21. We sought mutations of the CaR gene in FBHH by direct sequencing of PCR-amplified genomic DNA from 14 affected families: 8 mapped to 3q13, 1 mapped to chromosome 19p, and 5 unmapped. We sequenced the entire coding region of the gene (exons 2-7) in one or two affected members of each family and found six point mutations that altered one amino acid, cosegregated with hypercalcemia, and were absent in more than 100 unaffected persons. Four mutations were unique (S53P, D215G, S657Y, and P748R), and two had been reported previously (P55L and R185Q). Of four mutant CaR proteins expressed in Xenopus oocytes, three were deficient in extracellular Ca{sup 2+}-induced signaling. No CaR mutations were found in eight families, including the one mapped to chromosome 19p. Three benign polymorphisms occurred in the COOH-terminal region of the CaR protein in 10%, 15%, and 30% of more than 100 unaffected persons. Thus, FBHH-causing CaR mutations were clustered in the NH{sub 2}-terminal extracellular and membrane-spanning regions of the receptor protein. We suggest that these are important functional domains, probably for calcium binding and signal transduction, respectively. Finally, mutations in regulatory or intronic regions of the CaR gene may also underlie many cases of FBHH. 39 refs., 2 figs., 3 tabs.

• OSTI ID: 530763
• Journal Information: Journal of Clinical Endocrinology and Metabolism, Journal Name: Journal of Clinical Endocrinology and Metabolism Journal Issue: 4 Vol. 81; ISSN JCEMAZ; ISSN 0021-972X
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACID SEQUENCE
CALCIUM
DNA SEQUENCING
ETIOLOGY
GENE MUTATIONS
GENETIC MAPPING
GENETICS
HEREDITARY DISEASES
HUMAN CHROMOSOME 19
HUMAN CHROMOSOME 3
METABOLIC DISEASES
PATIENTS
POLYMERASE CHAIN REACTION
RECEPTORS
STRUCTURE-ACTIVITY RELATIONSHIPS