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Stepwise CaSR, AP2S1, and GNA11sequencing in patients with suspected familial hypocalciuric hypercalcemia
- Source :
- Endocrine; March 2017, Vol. 55 Issue: 3 p741-747, 7p
- Publication Year :
- 2017
-
Abstract
- Patients with familial hyperparathyroidism and low urinary calcium excretion may have familial hypocalciuric hypercalcemia (FHH) with mutations in one of three genes: the calcium-sensing receptor (CaSR) defining FHH-type 1, the adaptor-related protein complex 2 (AP2S1) related to FHH-type 3 or the G-protein subunit alpha11 (GNA11) associated with FHH-type 2. We aimed to evaluate the presence of mutations in these genes and to identify phenotypic specificities and differences in these patients. Selected patients were recruited for genetic evaluation. After informed consent was signed, blood for DNA extraction was obtained and genetic sequencing of CaSRwas done. In negative cases, we further performed sequencing of AP2S1and GNA11. A total of 10 index cases were recruited. CaSRsequencing yielded three missense heterozygous mutations (30%): c.554G > A (p.I32V) previously characterized by our team, c.1394 G > A (p.R465Q) and a novel expected disease-causing mutation c.2479 A > C (p.S827R). We identified 2 additional patients (20%) carrying the deleterious recurrent mutation c.44G > T (p.R15L) in the AP2S1gene. No GNA11mutation was found. Clinically, patients with AP2S1mutations had significant cognitive and behavioral disorders, and higher blood calcium and magnesium levels than patients with FHH1. CaSRand AP2S1sequencing is worthwhile in patients with familial hyperparathyroidism and phenotype suggesting FHH as it can diagnose up to 50% of cases. GNA11mutations seem much rarer. Learning disabilities in these patients, associated with higher serum calcium and magnesium levels may suggest the presence of AP2S1rather than CaSRmutation and may guide the first step in the genetic evaluation.
Details
- Language :
- English
- ISSN :
- 1355008x and 15590100
- Volume :
- 55
- Issue :
- 3
- Database :
- Supplemental Index
- Journal :
- Endocrine
- Publication Type :
- Periodical
- Accession number :
- ejs41278804
- Full Text :
- https://doi.org/10.1007/s12020-017-1241-5