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


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.


CONCLUSIONS
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.
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. auryans@hadassah.org.il.
Auryan
A
Szalat
Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Shoshana
S
Shpitzen
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Anat
A
Tsur
Pediatric Endocrinology, Armon Child Center, Carmel Hospital, Clalit Health Service, Haifa, Israel.
Ilana
I
Zalmon Koren
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Shmuel
S
Shilo
Endocrinology Department, Chaim Sheba Medical Center, Tel Ha Shomer, Ramat Gan, Israel.
Liana
L
Tripto-Shkolnik
Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Ronen
R
Durst
Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Eran
E
Leitersdorf
Department of Genetics and Metabolic diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Vardiella
V
Meiner
D033962:Adaptor Protein Complex 2 / Q000235:genetics*; D034002:Adaptor Protein Complex sigma Subunits / Q000235:genetics*; D000328:Adult; D002675:Child, Preschool; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D006801:Humans; D006934:Hypercalcemia / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D055815:Young Adult
C510065:AP2S1 protein, human; D033962:Adaptor Protein Complex 2; D034002:Adaptor Protein Complex sigma Subunits; C095550:CASR protein, human; C554062:GNA11 protein, human; D044385:GTP-Binding Protein alpha Subunits; D044169:Receptors, Calcium-Sensing
AP2S1; Calcium-sensing receptor; Cognitive impairment; Familial hypocalciuric hypercalcemia; Parathyroid