Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism

Cavaco, Branca; Canaff, Lucie; Nolin-Lapalme, Alexis; Vieira, Margarida; Silva, Tiago N; Saramago, Ana; Domingues, Rita; Rutter, Meilan M.; Hudon, Jonathan; Gleason, James L.; Leite, Valeriano; Hendy, Geoffrey N.

doi:10.1210/jc.2017-02407

Cited by 20 publications

(19 citation statements)

References 35 publications

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“…It is also interesting that NLRP1 GOF can underlie an AR phenotype, as human GOF mutations underlying a recessive phenotype are extremely rare. To our knowledge, this has only been described in CASR mutations in hypocalcemic hypoparathyroidism, where GOF mutations may underlie both AD and AR patterns of inheritance (55). Interestingly, the AR and AD inherited mutations lead to the same disease, although like NLRP1, the AD and AR mutations localize to different regions of the protein (55).…”

Section: Discussionmentioning

confidence: 93%

“…To our knowledge, this has only been described in CASR mutations in hypocalcemic hypoparathyroidism, where GOF mutations may underlie both AD and AR patterns of inheritance (55). Interestingly, the AR and AD inherited mutations lead to the same disease, although like NLRP1, the AD and AR mutations localize to different regions of the protein (55). Recent findings suggest that familial Mediterranean fever (FMF) caused by mutations in the MEFV gene and long thought to be exclusively AR, can also be AD, as evidenced by knock-in mice engineered to express the human B30.2 domain of MEFV harboring mutations found in patients with AR FMF (56).…”

Section: Discussionmentioning

confidence: 98%

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Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

Drutman

Haerynck

Zhong

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

Drutman

Haerynck

Zhong

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Historically, the study of inborn errors of human immunity has provided invaluable insight into the intricate regulation of the immune system. (Cavaco et al, 2018), and most recently in recurrent respiratory papillomatosis caused by homozygous mutations in NLRP1 . Identification of homozygous GOF mutation in STAT2 was surprising, given that STAT2 is a positive regulator of the IFN-I pathway by its essential role in the transcription factor complex that induces hundreds of ISGs.…”

Section: Discussionmentioning

confidence: 99%

HomozygousSTAT2gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

Gruber

Martín-Fernández

Ailal

et al. 2019

Preprint

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Type I interferonopathies are monogenic disorders characterized by enhanced Type I interferon (IFN-I) activity. Inherited ISG15 and USP18 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, ISG15/USP18 are induced by IFN-I and sterically hinder JAK1 from binding to the IFNAR2 subunit of IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is gain-offunction (GOF) for ISGF3-dependent induction of late but not early response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic transcriptional activity of ISGF3. Rather, the STAT2 R148Q variant is GOF because it fails to appropriately interact with and traffic USP18 to IFNAR2, preventing USP18 from negatively regulating responses to IFN-I. Overall, a STAT2 missense mutation that fails to facilitate USP18-mediated signal termination in the homozygous state underlies a novel genetic etiology of type I interferonopathy.

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“…ADH2 (OMIM 615361) (Table 2) has been reported in seven probands (Mannstadt et al, 2013;Nesbit et al, 2013a;Li et al, 2014a;Piret et al, 2016;Tenhola et al, 2016). Patients with ADH2 generally have mild-tomoderate hypocalcemia, in keeping with the serum May occasionally be caused by homozygous CASR mutations (Lietman et al, 2009;Cavaco et al, 2018 biochemical phenotype of ADH1 (Hannan et al, 2016). However, ADH2 is associated with a milder urinary phenotype, with significantly reduced urinary calcium excretion compared with ADH1 (Li et al, 2014a).…”

Section: Autosomal Dominant Hypocalcemia and Bartter Syndrome Type Vmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, g-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca 2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca 2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca 2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca 2+ o , an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G q/11 , G i/o , potentially G 12/13 , and even G s in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. Significance Statement-The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

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Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism

Abstract: The patient's hypoparathyroidism is due to homozygosity of a variant in the CASR that normally has weak or no phenotypic expression in heterozygosity. Although rare, this has important implications for genetic counseling and clinical management.

Cited by 20 publications

References 35 publications

Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

HomozygousSTAT2gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

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