PMID- 28176280
OWN - NLM
STAT- MEDLINE
DCOM- 20170817
LR  - 20181113
IS  - 1559-0100 (Electronic)
IS  - 1355-008X (Linking)
VI  - 55
IP  - 3
DP  - 2017 Mar
TI  - Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial 
      hypocalciuric hypercalcemia.
PG  - 741-747
LID - 10.1007/s12020-017-1241-5 [doi]
AB  - 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.
FAU - Szalat, Auryan
AU  - Szalat A
AD  - Endocrinology and Metabolism Service, Department of Internal Medicine, 
      Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 
      auryans@hadassah.org.il.
FAU - Shpitzen, Shoshana
AU  - Shpitzen S
AD  - Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Tsur, Anat
AU  - Tsur A
AD  - Endocrinology and Metabolism Service, Department of Internal Medicine, 
      Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
FAU - Zalmon Koren, Ilana
AU  - Zalmon Koren I
AD  - Pediatric Endocrinology, Armon Child Center, Carmel Hospital, Clalit Health 
      Service, Haifa, Israel.
FAU - Shilo, Shmuel
AU  - Shilo S
AD  - Endocrinology and Metabolism Service, Department of Internal Medicine, 
      Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
FAU - Tripto-Shkolnik, Liana
AU  - Tripto-Shkolnik L
AD  - Endocrinology Department, Chaim Sheba Medical Center, Tel Ha Shomer, Ramat Gan, 
      Israel.
FAU - Durst, Ronen
AU  - Durst R
AD  - Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Leitersdorf, Eran
AU  - Leitersdorf E
AD  - Center for Research, Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew 
      University Medical Center, Jerusalem, Israel.
FAU - Meiner, Vardiella
AU  - Meiner V
AD  - Department of Genetics and Metabolic diseases, Hadassah-Hebrew University Medical 
      Center, Jerusalem, Israel.
LA  - eng
PT  - Journal Article
DEP - 20170207
PL  - United States
TA  - Endocrine
JT  - Endocrine
JID - 9434444
RN  - 0 (AP2S1 protein, human)
RN  - 0 (Adaptor Protein Complex 2)
RN  - 0 (Adaptor Protein Complex sigma Subunits)
RN  - 0 (CASR protein, human)
RN  - 0 (GNA11 protein, human)
RN  - 0 (GTP-Binding Protein alpha Subunits)
RN  - 0 (Receptors, Calcium-Sensing)
RN  - Hypocalciuric hypercalcemia, familial, type 1
SB  - IM
MH  - Adaptor Protein Complex 2/*genetics
MH  - Adaptor Protein Complex sigma Subunits/*genetics
MH  - Adult
MH  - Child, Preschool
MH  - Female
MH  - GTP-Binding Protein alpha Subunits/*genetics
MH  - Humans
MH  - Hypercalcemia/*congenital/diagnosis/genetics
MH  - Infant, Newborn
MH  - Male
MH  - *Mutation
MH  - Oligonucleotide Array Sequence Analysis
MH  - Pedigree
MH  - Receptors, Calcium-Sensing/*genetics
MH  - Young Adult
OTO - NOTNLM
OT  - AP2S1
OT  - Calcium-sensing receptor
OT  - Cognitive impairment
OT  - Familial hypocalciuric hypercalcemia
OT  - Parathyroid
EDAT- 2017/02/09 06:00
MHDA- 2017/08/18 06:00
CRDT- 2017/02/09 06:00
PHST- 2016/10/11 00:00 [received]
PHST- 2017/01/17 00:00 [accepted]
PHST- 2017/02/09 06:00 [pubmed]
PHST- 2017/08/18 06:00 [medline]
PHST- 2017/02/09 06:00 [entrez]
AID - 10.1007/s12020-017-1241-5 [pii]
AID - 10.1007/s12020-017-1241-5 [doi]
PST - ppublish
SO  - Endocrine. 2017 Mar;55(3):741-747. doi: 10.1007/s12020-017-1241-5. Epub 2017 Feb 
      7.