Recurrent<i>PRKAR1A</i>Mutation in Acrodysostosis with Hormone Resistance

Linglart, Agnès; Menguy, Christine; Couvineau, Alain; Auzan, Colette; Güneş, Yasemin; Cancel, Mathilde; Motte, Emmanuelle; Pinto, Graziella; Chanson, Philippe; Bougnères, Pierre; Clauser, Éric; Silve, Caroline

doi:10.1056/nejmoa1012717

Cited by 167 publications

(235 citation statements)

References 24 publications

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“…23 Consistent with the observed gain-of-function effect and due to the resulting increased cAMPhydrolytic activity, expression of all six PDE3A mutations decreased luciferase expression compared to wildtype ( Supplementary Fig. 6a-g).…”

supporting

confidence: 79%

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

et al. 2015

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All Mendelian hypertension syndromes described to date involve increased sodium reabsorption in the distal nephron. 5 The sole exception is autosomal-dominant hypertension with BDE (HTNB, OMIM #112410), first reported in a Turkish kindred. 2,6 HTNB was linked to chromosome 12p in six unrelated families. 2,7,8 The locus accounts for a ~50 mm Hg mean blood pressure difference at age 50 years. 2 The penetrance is 100% (Fig. 1a). Previously, we reported a rearrangement on chromosome 12p common to all families. 8,9 A linkage study in Chinese hypertensive families without BDE coincided with the HTNB locus, supporting relevance to essential hypertension. 10 Whole-genome sequencing of Turkish family members revealed a heterozygous missense mutation in PDE3A (Gene ID: 5139), a gene encoding a cGMP/cAMP phosphodiesterase with a prominent role in the heart, VSMC, oocytes and platelets. 11 Resequencing of all 48 affected persons in six unrelated families identified six independently clustered heterozygous missense mutations in exon 4 (Fig. 1a, b Supplementary Fig. 1).We detected none of the previously described chromosomal breakpoints on chromosome 12p12.2-12.1, perhaps due to high repetitive content in the breakpoint regions Fig. 2a-c). 4 A haplotype analysis identified a novel recombination that reduced the linkage interval and eliminated an inversion common to all affected individuals in the six families (Fig. 2c). 9 In contrast, the affected mother's haplotype showed co-segregation with the more severe brachydactyly phenotype.PDEs are involved during early stages of osteogenesis. 12 PDE4D mutations have been associated with severe brachydactyly in acrodysostosis. 13,14 In mice, Pde3a was expressed in the developing limbs, consistent with a role during chondrogenesis (Fig. 2d, Supplementary Fig. 3a, b). Chondrogenic downregulation of PTHLH encoding PTHrP was associated with BDE. 15 We also observed PTHLH downregulation in chondrogenically induced fibroblasts from affected persons (Fig. 2e, Supplementary Fig. 3c).We addressed the functional consequences of the identified PDE3A mutations in HeLa cells expressing the six mutations. Forskolin or L-arginine stimulated the adenylate or guanylate cyclases to enhance cellular cAMP or cGMP levels, respectively. 16,17 We detected significantly reduced cAMP levels, consistent with gain-of-function mutations with no change in cGMP levels for the PDE3A mutations ( Supplementary Fig. 4a, b). Three PDE3A isoforms, PDE3A1 (microsomal), PDE3A2 and PDE3A3 (microsomal and cytosolic), have been identified in human myocardium. 18,19 PDE3A3 does not contain the sequence harboring the detected mutations. The predominant isoform in VSMC is PDE3A2. 18,20 To directly elucidate the mutations' effects, we compared the Michaelis-Menten kinetics of cAMPhydrolytic activity for recombinant T445N FLAG-tagged PDE3A1 and PDE3A1-WT and the tagged A2 isoforms purified from transfected cells (Fig. 3a, b, Supplementary Fig. 4d-k). The T445N mutation increased the affinity of both enzyme's isoforms for cAM...

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supporting

confidence: 79%

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

et al. 2015

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“…Our findings are further supported by previous studies demonstrating that PRKAR1A mutations discovered in patients cause a defect in PKA activation by cAMP, associated with a decreased responsiveness of PKA to cAMP, and their dominant negative effect on PKA function. (10,13) Recently, Kaname and colleagues performed functional studies to analyze PDE4D mutants and generated Pde4d knockout rats, demonstrating that PDE4D loss results in the skeletal dysplasia phenotype observed in acrodysostosis. (18) Meanwhile, the functional consequences of the PDE4D coding changes was also confirmed in zebrafish, suggesting a dominant negative effect.…”

Section: Discussionmentioning

confidence: 99%

“…The Ellsworth-Howard test was performed only in 1 PRKAR1A-mutated patient (pt PHP4), showing a blunted cAMP and phosphaturic urinary response, as previously described by Linglart and colleagues. (10) Twentyfour of the patients also showed an elevated TSH, documented by raised serum TSH levels, absence of antithyroid antibodies, and presence of normal thyroid scan. Clinical details of mutated patients and the whole investigated series are resumed in Table 1 and Supplemental Table S1, respectively.…”

Section: Patientsmentioning

confidence: 90%

“…1). (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Considering the distribution of the mutations, exon 11 is the most affected site (52.9%), followed by exon 9 (23.5%), exon 7 (17.6%), and exon 8 (5.9%). No mutations were observed in other exons, acceptor-donor splice sites, and introns.…”

Section: Prkar1a Mutation Spectrummentioning

confidence: 99%

“…(9) Mutations in genes encoding proteins crucial for cAMP-mediated signaling have been recently detected in a small subset of patients negative for GNAS defects, showing a phenotypic overlap between PHP and acrodysostosis. (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) The term acrodysostosis (ACRDYS) describes a group of rare skeletal disorders characterized by severe brachydactyly, nasal, and/or midfacial hypoplasia and variable intellectual/ developmental/behavioral disabilities; resistance to multiple hormones that bind to GPCRs (including PTH and TSH), progressive growth failure with short stature, advanced bone age, and obesity are frequently observed features. (21) Genetic defects affecting PRKAR1A (cAMP-dependent protein kinase type I-a regulatory subunit) and PDE4D (cAMP-specific phosphodiesterase 4D), both crucial for cAMP signaling pathway, were associated with ACRDYS in 2011 and 2012 by different research groups.…”

Section: Introductionmentioning

confidence: 99%

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Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism

Elli

Bordogna

Sanctis

et al. 2016

Journal of Bone and Mineral Research

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The cyclic adenosine monophosphate (cAMP) intracellular signaling pathway mediates the physiological effects of several hormones and neurotransmitters, acting by the activation of G-protein coupled receptors (GPCRs) and several downstream intracellular effectors, including the heterotrimeric stimulatory G-protein (Gs), the cAMP-dependent protein kinase A (PKA), and cAMP-specific phosphodiesterases (PDEs). Defective G-protein-mediated signaling has been associated with an increasing number of disorders, including Albright hereditary osteodistrophy (AHO) and pseudohypoparathyroidism (PHP), a heterogeneous group of rare genetic metabolic disorders resulting from molecular defects at the GNAS locus. Moreover, mutations in PRKAR1A and PDE4D genes have been recently detected in patients with acrodysostosis (ACRDYS), showing a skeletal and endocrinological phenotype partially overlapping with AHO/PHP. Despite the high detection rate of molecular defects by currently available molecular approaches, about 30% of AHO/PHP patients still lack a molecular diagnosis, hence the need to screen patients negative for GNAS epi/genetic defects also for chromosomal regions and genes associated with diseases that undergo differential diagnosis with PHP. According to the growing knowledge on Gsa-cAMP signaling-linked disorders, we investigated our series of patients (n ¼ 81) with a clinical diagnosis of PHP/AHO but negative for GNAS anomalies for the presence of novel genetic variants at PRKAR1A and PDE4D genes. Our work allowed the detection of 8 novel missense variants affecting genes so far associated with ACRDYS in 9 patients. Our data further confirm the molecular and clinical overlap among these disorders. We present the data collected from a large series of patients and a brief review of the literature in order to compare our findings with already published data; to look for PRKAR1A/PDE4D mutation spectrum, recurrent mutations, and mutation hot spots; and to identify specific clinical features associated with ACRDYS surveillance during follow-up.

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Genetics of Carney Complex

Horvath

Stratakis

2013

Encyclopedia of Life Sciences

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Carney complex (CNC) is an autosomal dominant multiple neoplasia and lentiginosis syndrome characterised by spotty skin lesions, cardiac and other myxomas and different types of endocrine tumours. The PRKAR1A gene, which codes for the regulatory subunit type 1‐alpha of the cyclic adenosine monophosphate (cAMP)‐activated protein kinase A, is responsible for more than two‐thirds of the cases of CNC described to date. Currently, more than 120 different disease‐causing PRKAR1A sequence variants have been reported. Other involved genes for adrenal hyperplasias include phosphodiesterases PDE11A and PDE8B . Additional genes are likely to be identified that may expand our understanding on the pathophysiology of the cAMP signalling pathway and how genetic defects cause CNC and its individual components such as adrenal tumours. Key Concepts: Inactivating PRKAR1A mutations cause CNC because PRKAR1A haploinsufficiency leads to uncontrolled PKA activity. The majority (∼80%) of PRKAR1A mutations causing CNC result in an early stop codon generation and degradation of the mutant RNA through nonsense‐mediated RNA decay (NMD). Recently, novel types of PRKAR1A mutations have been described: large gene rearrangements and small indels resulting in an elongated protein through downstream shift of the stop codon. The penetrance of PRKAR1A mutations is more than 95% by the age of 50 years. PDE11A and PDE8B genetic defects contribute to the CNC phenotype, but they may also independently cause forms of adrenal hyperplasia, mainly isolated micronodular adrenocortical disease (iMAD). Genotype–phenotype correlation is limited, but there are certain mutations that cause more frequently certain endocrine manifestations such as isolated Cushing syndrome. The use of new genomic techniques has led to the identification of new genetic defects in PRKAR1A and related genes in CNC.

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RecurrentPRKAR1AMutation in Acrodysostosis with Hormone Resistance

Cited by 167 publications

References 24 publications

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism

Genetics of Carney Complex

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