<i>PRKAR1A</i>and<i>PDE4D</i>Mutations Cause Acrodysostosis but Two Distinct Syndromes with or without GPCR-Signaling Hormone Resistance

Linglart, Agnès; Fryssira, Helena; Hiort, Olaf; Holterhus, Paul Martin; Nanclares, Guiomar Perez de; Argente, Jesús; Heinrichs, Claudine; Kuechler, Alma; Mantovani, Giovanna; Leheup, Bruno; Wicart, Philippe; Chassot, Virginie; Schmidt, D.; Rubio-Cabezas, Óscar; Richter‐Unruh, Annette; Berrade, Sara; Pereda, Arrate; Boros, Emese; Muñoz-Calvo, M.T.; Castori, Marco; Güneş, Yasemin; Bertrand, Guylène; Bougnères, Pierre; Clauser, Éric; Silve, Caroline

doi:10.1210/jc.2012-2326

Cited by 102 publications

(177 citation statements)

References 32 publications

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“…Because the association between PRKAR1A defects and ACRDYS represents a recent discovery, the number of recurrent mutations will likely increase because some mutations, affecting key amino acids, were found to recur in unrelated subjects. (11,14,16,19) Although most of known PRKAR1A mutations alter the NBD-B (76.5%), our findings support the previous observation that mutations also affecting the NBD-A (23.5%) may be associated with ACRDYS. (13,16,pt A1) We also cross-referenced mutations associated with ACRDYS with those associated to Carney Complex, and we did not find any molecular overlap, suggesting that different substitutions lead to different and opposite effects on protein function, with consequent different clinical phenotypes.…”

Section: Prkar1a Mutation Spectrumsupporting

confidence: 89%

“…(14,19) In addition, our analysis highlighted the presence of 2 amino acid residues, arginine 335 and tyrosine 373, that may be considered as putative mutational hot spots, being mutated in 5 unrelated patients through 5 different genetic variations (c.1003C>T, c.1004G>C, c.1004G>T, c.1117T>C, and c.1118A>G) changing Arg to Cys/Pro/Leu and Tyr to His/Cys (Table 2). (11,14,16) These amino acids are located in highly Fig. 2.…”

Section: Prkar1a Mutation Spectrummentioning

confidence: 82%

“…Bone growth is regulated by the PTHrp/PTH receptor type 1 (PTH1R) activation that stimulates slow chondrocyte differentiation into hypertrophic cells; thus, it was proposed that skeletal abnormalities derive from a general impairment of the cAMP/PKA pathway. (14) Conversely, other clinical features seem to be more frequently associated with a specific subgroup, like intrauterine growth restriction and hormonal resistance in PRKAR1A-mutated patients and mental retardation in patients with PDE4D defects. Although both genes are involved in the GPCR-Gsa-cAMP-PKA pathway, PRKAR1A ubiquitous expression compared with PDE4D isoforms tissue-specific distribution may account for these observed phenotypic differences.…”

Section: Discussionmentioning

confidence: 99%

“…2). (11,12,14,15,17,18,20) Considering the distribution of these mutations, exon 5 is the most affected site (36%), followed by exon 15 (16%), exons 8 and 17 (12% each), exon 9 (8%), and exons 4, 6, 13, and 16 (4% each). No mutation has been observed to date in other exons, acceptor-donor splice sites, and introns.…”

Section: Pde4d Mutation Spectrummentioning

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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Section: Prkar1a Mutation Spectrumsupporting

confidence: 89%

Section: Prkar1a Mutation Spectrummentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Pde4d Mutation Spectrummentioning

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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“…Acrodysostosis is uncommon; the prevalence of the disease is unknown, and clinical, biochemical and radiological features overlap with those of PHP1A and PPHP 6,[11][12][13][14][15] .…”

mentioning

confidence: 99%

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Mantovani¹,

Lecumberri²,

Baştepe³

et al. 2018

EJEA

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Pseu do hy popar ath yroi dism (PHP) and related disorders are associated with a spectrum of abnormal physical characteristics as well as neurocognitive and endocrine abnormalities that are caused primarily by molecular defects that impair hormonal signalling via receptors that are coupled, through the α-subunit of the stimulatory G protein (G s α), to activation of adenylyl cyclase (Fig. 1). 6,7,20,48 * Abstract | This Consensus Statement covers recommendations for the diagnosis and management of patients with pseu do hy popar ath yroi dism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency , hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

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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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PRKAR1AandPDE4DMutations Cause Acrodysostosis but Two Distinct Syndromes with or without GPCR-Signaling Hormone Resistance

Cited by 102 publications

References 32 publications

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

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

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Genetics of Carney Complex

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