PMID- 27666534
OWN - NLM
STAT- MEDLINE
DCOM- 20170206
LR  - 20220330
IS  - 1479-683X (Electronic)
IS  - 0804-4643 (Linking)
VI  - 175
IP  - 5
DP  - 2016 Nov
TI  - Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: 
      function, inheritance and phenotype.
PG  - 421-31
LID - 10.1530/EJE-16-0223 [doi]
AB  - BACKGROUND: Homozygous inactivating mutations of the calcium-sensing receptor 
      (CaSR) lead to neonatal severe hyperparathyroidism (NSHPT), whereas heterozygous 
      inactivating mutations result in familial hypocalciuric hypercalcemia (FHH). It 
      is unknown why in some cases heterozygous CaSR mutations cause neonatal 
      hyperparathyroidism (NHPT) clinically similar to NSHPT but with only moderately 
      elevated serum calcium. METHODS: A literature survey was conducted to identify 
      patients with heterozygous CaSR mutations and NHPT. The common NHPT CaSR mutants 
      R185Q and R227L were compared with 15 mutants causing only FHH in the 
      heterozygous state. We studied in vitro calcium signaling including the 
      functional consequences of co-expression of mutant and wild-type (wt) CaSR, 
      patients' phenotype, age of disease manifestation and mode of inheritance. 
      RESULTS: All inactivating CaSR mutants impaired calcium signaling of wt-CaSR 
      regardless of the patients' clinical phenotype. The absolute intracellular 
      calcium signaling response to physiologic extracellular calcium concentrations in 
      vitro showed a high correlation with patients' serum calcium concentrations in 
      vivo, which is similar in NHPT and FHH patients with the same genotype. Pedigrees 
      of FHH families revealed that paternal inheritance per se does not necessarily 
      lead to NHPT but may only cause FHH. CONCLUSIONS: There is a significant 
      correlation between in vitro functional impairment of the CaSR at physiologic 
      calcium concentrations and the severity of alterations in calcium homeostasis in 
      patients. Whether a particular genotype leads to NHPT or FHH appears to depend on 
      additional predisposing genetic or environmental factors. An individual 
      therapeutic approach appears to be warranted for NHPT patients.
CI  - (c) 2016 European Society of Endocrinology.
FAU - Glaudo, Markus
AU  - Glaudo M
AD  - Division of Endocrinology and DiabetesDepartment of Medicine I, 
      Universitatsklinikum Erlangen, Erlangen, Germany.
FAU - Letz, Saskia
AU  - Letz S
AD  - Division of Endocrinology and DiabetesDepartment of Medicine I, 
      Universitatsklinikum Erlangen, Erlangen, Germany.
FAU - Quinkler, Marcus
AU  - Quinkler M
AD  - Endokrinologie in CharlottenburgBerlin, Germany.
FAU - Bogner, Ulrich
AU  - Bogner U
AD  - Endokrinologie in CharlottenburgBerlin, Germany.
FAU - Elbelt, Ulf
AU  - Elbelt U
AD  - Department of EndocrinologyDiabetes and Nutrition.
FAU - Strasburger, Christian J
AU  - Strasburger CJ
AD  - Department of EndocrinologyDiabetes and Nutrition.
FAU - Schnabel, Dirk
AU  - Schnabel D
AD  - Center for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charite - 
      Universitatsmedizin Berlin, Berlin, Germany.
FAU - Lankes, Erwin
AU  - Lankes E
AD  - Center for Chronic Sick ChildrenPediatric Endocrinology and Diabetes, Charite - 
      Universitatsmedizin Berlin, Berlin, Germany.
FAU - Scheel, Sandra
AU  - Scheel S
AD  - Endocrinology and DiabetologyKlinikum Bielefeld, Bielefeld, Germany.
FAU - Feldkamp, Joachim
AU  - Feldkamp J
AD  - Endocrinology and DiabetologyKlinikum Bielefeld, Bielefeld, Germany.
FAU - Haag, Christine
AU  - Haag C
AD  - Endocrine PracticeHeidelberg, Germany.
FAU - Schulze, Egbert
AU  - Schulze E
AD  - Endocrine PracticeHeidelberg, Germany.
FAU - Frank-Raue, Karin
AU  - Frank-Raue K
AD  - Endocrine PracticeHeidelberg, Germany.
FAU - Raue, Friedhelm
AU  - Raue F
AD  - Endocrine PracticeHeidelberg, Germany.
FAU - Mayr, Bernhard
AU  - Mayr B
AD  - Division of Endocrinology and DiabetesDepartment of Medicine I, 
      Universitatsklinikum Erlangen, Erlangen, Germany bernhard.mayr@uk-erlangen.de.
FAU - Schofl, Christof
AU  - Schofl C
AD  - Division of Endocrinology and DiabetesDepartment of Medicine I, 
      Universitatsklinikum Erlangen, Erlangen, Germany.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Eur J Endocrinol
JT  - European journal of endocrinology
JID - 9423848
RN  - 0 (CASR protein, human)
RN  - 0 (Receptors, Calcium-Sensing)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium/metabolism
MH  - Calcium Signaling/*genetics
MH  - Female
MH  - Genotype
MH  - *Heterozygote
MH  - Homeostasis/genetics
MH  - Humans
MH  - Hyperparathyroidism/congenital/*genetics
MH  - Infant, Newborn
MH  - Infant, Newborn, Diseases/*genetics
MH  - Male
MH  - *Mutation
MH  - Phenotype
MH  - Receptors, Calcium-Sensing/*genetics
EDAT- 2016/09/27 06:00
MHDA- 2017/02/07 06:00
CRDT- 2016/09/27 06:00
PHST- 2016/03/14 00:00 [received]
PHST- 2016/08/30 00:00 [accepted]
PHST- 2016/09/27 06:00 [entrez]
PHST- 2016/09/27 06:00 [pubmed]
PHST- 2017/02/07 06:00 [medline]
AID - 175/5/421 [pii]
AID - 10.1530/EJE-16-0223 [doi]
PST - ppublish
SO  - Eur J Endocrinol. 2016 Nov;175(5):421-31. doi: 10.1530/EJE-16-0223.