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Recurrent Familial Hypocalcemia Due to Germline Mosaicism for an Activating Mutation of the Calcium-Sensing Receptor Gene

Departments of Medicine, Human Genetics, and Physiology, McGill University and Calcium Research Laboratory, Royal Victoria Hospital (G.N.H., L.C., S.P., B.Y., Z.N.), Montréal, Québec, Canada H3A 1A1; Department of Pediatrics, Mayo Clinic (C.M., D.Z.), Rochester, Minnesota 55905; and Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics, University of Toronto and The Banting Institute (C.W., D.E.C.C.), Toronto, Ontario, Canada M5G 1L5

Address all correspondence and requests for reprints to: Dr. G. N. Hendy, Calcium Research Laboratory Royal Victoria Hospital, Room H4.67, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1. E-mail: geoffrey.hendy{at}mcgill.ca.

De novo activating mutations in the calcium-sensing receptor (CASR) gene are a common cause of sporadic isolated hypoparathyroidism. Here, we describe a family in which two affected siblings were found to be heterozygous for a novel F788L mutation in the fifth transmembrane domain encoded by exon 7 of the CASR. Both parents and the third sibling were clinically unaffected and genotypically normal by direct sequencing of their leukocyte exon 7 PCR amplicons. However, the mother was revealed to be a mosaic for the mutation by sequence analysis of multiple subclones as well as denaturing HPLC of the CASR exon 7 leukocyte PCR product. A functional analysis of the mutation was performed by transiently transfecting wild-type and mutant CASRs tagged with a c-Myc epitope in human embryonic kidney (HEK293) cells. The mutant CASR was expressed at a similar level as the wild type. The F788L mutant produced a significant shift to the left relative to the wild-type CASR in the MAPK response to increasing extracellular calcium concentrations. This is the first report of mosaicism for an activating CASR mutation and suggests that care should be exercised in counseling for risks of recurrence in a situation where a de novo mutation appears likely.

This work was supported in part by the Canadian Institutes of Health Research (Grant MOP-57730), the Kidney Foundation of Canada (to G.N.H.), and the Natural Sciences and Engineering Research Council and Dairy Farmers of Canada (to D.E.C.C.). We also acknowledge doctoral fellowships from the Canadian Institutes of Health Research and the NCI of Canada (to L.C.) and a studentship from The Royal Victoria Hospital Research Institute (to S.P.).

Abbreviations: ADH, Autosomal dominant hypocalcemia; CASR, calcium-sensing receptor; DHPLC, denaturing HPLC; EC₅₀, half-maximal response.

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