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

Szalat, Auryan; Shpitzen, Shoshana; Tsur, Anat; Zalmon, Ilana Rosental; Shilo, Shmuel; Tripto-Shkolnik, Liana; Durst, Ronen; Leitersdorf, Eran; Meiner, Vardiella

doi:10.1007/s12020-017-1241-5

Cited by 28 publications

(26 citation statements)

References 30 publications

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“…Moreover, we did not test for GNA11 variants in this series. We and others have previously shown that GNA11 variants are an extremely rare cause of hypercalcemia, 5,6,22 thus the probability of finding an FHH individual caused by a GNA11 variant is low. Additionally, information on family history of hypercalcemia and previous unsuccessful parathyroidectomy could have been of advantage.…”

Section: Discussionmentioning

confidence: 90%

“…The genes responsible for FHH types 2 and 3 (OMIM #145981 and #600740, respectively) were identified recently by Nesbit and colleagues, revealing that variants of the GNA11 and AP2S1 genes caused phenotypes marginally distinct from FHH type 1 . It was later shown that AP2S1 and especially GNA11 variants were rare causes of hypercalcemia …”

Section: Introductionmentioning

confidence: 99%

“…3,4 It was later shown that AP2S1 and especially GNA11 variants were rare causes of hypercalcemia. 5,6 Primary hyperparathyroidism (PHPT) is a common endocrine disorder and the most common cause of hypercalcemia. The disorder is caused by excessive secretion of parathyroid hormone (PTH) Abstract Objective: Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominantly inherited disorder with overlapping biochemistry profile with primary hyperparathyroidism (PHPT), making the correct diagnosis a challenge.…”

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confidence: 99%

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Expanding the spectrum of genetic variants in the calcium‐sensing receptor (CASR) gene in hypercalcemic individuals

Nissen

Rejnmark

2019

Clinical Endocrinology

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Objective Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominantly inherited disorder with overlapping biochemistry profile with primary hyperparathyroidism (PHPT), making the correct diagnosis a challenge. The objective of the study was to evaluate the results of the clinical work‐up of a large group of hypercalcemic individuals. Design Cross‐sectional study. Patients Patients undergoing clinical work‐up of hypercalcemia. Measurements Molecular genetic analysis of the CASR gene and exon 2 of the AP2S1 gene. Plasma levels of ionized calcium and PTH as well as calcium creatinine clearance ratio (CCCR). Results A rare CASR variant was identified in 38 of 624 index patients (6.1%). A total of 18 CASR variants identified in this study were novel. No variants were identified in exon 2 of the AP2S1 gene. The majority of the variants (N = 16) were classified as likely pathogenic. The level of plasma calcium, plasma PTH and the CCCR was not affected by the type of variant (ie nonsense vs missense) (all P‐values >.05). The CCCR was found to be significantly lower for variants in the transmembrane domain compared with variants located in the extracellular domain (P < .05). Plasma levels of calcium and PTH were not associated with the location of the variant (P > .05). Conclusions We expanded the spectrum of CASR variants in hypercalcemia with 18 novel variants, and suggest that the location of the CASR variant may affect calcium excretion as determined by the CCCR.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Expanding the spectrum of genetic variants in the calcium‐sensing receptor (CASR) gene in hypercalcemic individuals

Nissen

Rejnmark

2019

Clinical Endocrinology

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“…We confirmed the diagnosis of FHH Type 3 in our proband with WES at the age of 2 years 8 months, and we had followed him regularly and had him evaluated for his ADHD features and developmental and speech delay. We have reported his laboratory investigations and clinical features to further add to the reports, showing FHH-3 and its association with cognitive impairment [10][11][12].…”

Section: Discussionmentioning

confidence: 70%

“…In addition, they reported that individuals with FHH-3 were more likely to have cognitive impairment when compared with individuals with FHH-1, raising the possibility of an association between AP2S1 mutation and cognitive impairment [11]. is possibility was also highlighted by Szalat et al in their series, where two of their patients with FHH-3 had cognitive disorder, depression, severe ADHD, and language skill deficiency [12].…”

Section: Discussionmentioning

confidence: 89%

Clinical and Biochemical Features in a Case of Familial Hypocalciuric Hypercalcemia Type 3 with AP2S1 Gene Mutation in Codon Arg15His

Aashiq

Malallah

Khan

et al. 2020

Case Reports in Pediatrics

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Familial hypocalciuric hypercalcemia (FHH) is usually a benign condition divided into three types. FHH-3 occurs in about 20% of the cases and is caused due to missense mutations in AP2S1 (adaptor-related protein complex 2 subunit sigma 1) involving the codon Arg15 (p.R15). We report a case of FHH-3 with a heterozygous mutation in the AP2S1 gene on chr19_47349359 C>T, c.44G>A, p.Arg15His. There are a handful of reports describing the clinical features in patients diagnosed with FHH-3. Herein, we describe the laboratory and clinical features associated with a case of FHH-3 with mutation in the Arg15His codon of the AP2S1 gene.

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GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia

Howles

Gorvin

Cranston

et al. 2020

Journal of Bone and Mineral Research

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Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss-and gainof-function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calciumsensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline GNA11 variants in >1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 noncoding, and 11 nonsynonymous variants. The synonymous and noncoding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcemic and hypocalcemic individuals. Nine of the nonsynonymous variants (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands have been reported to be FHH2-or ADH2-causing. Of the remaining nonsynonymous variants, Ala65Thr was predicted to be benign, and Met87Val, identified in a hypercalcemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it was likely benign, and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two noncoding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in GNA11 mRNA or Gα11 protein levels in cells from the patient and no abnormality in splicing of the GNA11 mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease-causing GNA11 variants in <1% of probands with hypercalcemia or hypocalcemia and highlights the occurrence of GNA11 rare variants that are benign polymorphisms.

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

Cited by 28 publications

References 30 publications

Expanding the spectrum of genetic variants in the calcium‐sensing receptor (CASR) gene in hypercalcemic individuals

Expanding the spectrum of genetic variants in the calcium‐sensing receptor (CASR) gene in hypercalcemic individuals

Clinical and Biochemical Features in a Case of Familial Hypocalciuric Hypercalcemia Type 3 with AP2S1 Gene Mutation in Codon Arg15His

GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia

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