title: Recurrent familial hypocalcemia due to germline mosaicism for an activating mutation of the calcium-sensing receptor gene.
abstract: 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.
authors.affiliation: Department of Medicine, McGill University and Calcium Research Laboratory, Royal Victoria Hospital, Montréal, Québec, Canada H3A 1A1. geoffrey.hendy@mcgill.ca
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
authors.forename: Carla
authors.initials: C
authors.lastname: Minutti
authors.forename: Lucie
authors.initials: L
authors.lastname: Canaff
authors.forename: Svetlana
authors.initials: S
authors.lastname: Pidasheva
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.forename: Zaynab
authors.initials: Z
authors.lastname: Nouhi
authors.forename: Donald
authors.initials: D
authors.lastname: Zimmerman
authors.forename: Cuihong
authors.initials: C
authors.lastname: Wei
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
mesh_terms: D000293:Adolescent; D000328:Adult; D002118:Calcium / Q000097:blood / Q000502:physiology; D002648:Child; D002851:Chromatography, High Pressure Liquid; D016172:DNA Fingerprinting; D005091:Exons / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D006996:Hypocalcemia / Q000209:etiology / Q000235:genetics*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009030:Mosaicism / Q000235:genetics*; D009154:Mutation / Q000502:physiology*; D010375:Pedigree; D011489:Protein Denaturation; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics*; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium