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Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia

  • Endocrine Genetics/Epigenetics
  • Published:
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Abstract

Purpose

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.

Subjects and methods

Selected patients were recruited for genetic evaluation. After informed consent was signed, blood for DNA extraction was obtained and genetic sequencing of CaSR was done. In negative cases, we further performed sequencing of AP2S1 and GNA11.

Results

A total of 10 index cases were recruited. CaSR sequencing 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 AP2S1 gene. No GNA11 mutation was found. Clinically, patients with AP2S1 mutations had significant cognitive and behavioral disorders, and higher blood calcium and magnesium levels than patients with FHH1.

Conclusion

CaSR and AP2S1 sequencing is worthwhile in patients with familial hyperparathyroidism and phenotype suggesting FHH as it can diagnose up to 50% of cases. GNA11 mutations seem much rarer. Learning disabilities in these patients, associated with higher serum calcium and magnesium levels may suggest the presence of AP2S1 rather than CaSR mutation and may guide the first step in the genetic evaluation.

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Acknowledgements

This study was supported by the Research Foundation of the Chief Scientist at the Israel Ministry of Health and  by the Israel Endocrine Society.

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Authors and Affiliations

  1. Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Auryan Szalat, Anat Tsur & Shmuel Shilo

  2. Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Shoshana Shpitzen, Ronen Durst & Eran Leitersdorf

  3. Pediatric Endocrinology, Armon Child Center, Carmel Hospital, Clalit Health Service, Haifa, Israel

    Ilana Zalmon Koren

  4. Endocrinology Department, Chaim Sheba Medical Center, Tel Ha Shomer, Ramat Gan, Israel

    Liana Tripto-Shkolnik

  5. Department of Genetics and Metabolic diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Vardiella Meiner

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  1. Auryan Szalat
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Correspondence to Auryan Szalat.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Szalat, A., Shpitzen, S., Tsur, A. et al. Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia. Endocrine 55, 741–747 (2017). https://doi.org/10.1007/s12020-017-1241-5

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