title: Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains.
abstract: The predominant variety of familial benign hypocalciuric hypercalcemia (FBHH) is FBHH(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 Ca2+-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 NH2-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.
authors.affiliation: Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, 84132, USA.
authors.forename: H
authors.initials: H
authors.lastname: Heath
authors.forename: S
authors.initials: S
authors.lastname: Odelberg
authors.forename: C E
authors.initials: CE
authors.lastname: Jackson
authors.forename: B T
authors.initials: BT
authors.lastname: Teh
authors.forename: N
authors.initials: N
authors.lastname: Hayward
authors.forename: C
authors.initials: C
authors.lastname: Larsson
authors.forename: N R
authors.initials: NR
authors.lastname: Buist
authors.forename: K J
authors.initials: KJ
authors.lastname: Krapcho
authors.forename: B C
authors.initials: BC
authors.lastname: Hung
authors.forename: I V
authors.initials: IV
authors.lastname: Capuano
authors.forename: J E
authors.initials: JE
authors.lastname: Garrett
authors.forename: M F
authors.initials: MF
authors.lastname: Leppert
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D004251:DNA Transposable Elements; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics* / Q000652:urine; D008297:Male; D005810:Multigene Family; D009865:Oocytes / Q000502:physiology; D010280:Parathyroid Glands / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000378:metabolism; D014981:Xenopus
chemical_list: D002135:Calcium-Binding Proteins; D004251:DNA Transposable Elements; D011994:Recombinant Proteins