Different mutations in<i>PDE4D</i>associated with developmental disorders with mirror phenotypes

Wedell, Anna; Grigelioniené, Giedré; Nilsson, Daniel; Pettersson, Maria; Hofmeister, Wolfgang; Anderlid, Britt‐Marie; Kant, Sarina G.; Ruivenkamp, Claudia; Gustavsson, Peter; Valta, Helena; Geiberger, Stefan; Topa, Alexandra; Lagerstedt‐Robinson, Kristina; Taylan, Fulya; Wincent, Josephine; Laurell, Tobias; Pekkinen, Minna; Nordenskjöld, Magnus; Mäkitie, Outi; Nordgren, Ann

doi:10.1136/jmedgenet-2013-101937

Cited by 61 publications

(78 citation statements)

References 28 publications

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“…(15,18,pts P1/P2) Interestingly, structural variants of chromosome 5q12.1 determining haploinsufficiency of PDE4D resulted in a novel intellectual disability syndrome, but several opposing features compared with acrodysostosis (characteristic faces with prominent nasal bridge and maxillary hyperplasia, low body mass index [BMI], and long extremities and fingers). (17) The review of published mutations associated to ACRDYS (summarized in Tables 2 and 3) demonstrated that PRKAR1A/ PDE4D genetic variants may affect different functional domains and are mainly private mutations. Only few variants recurred in more than one unrelated case, but because ACRDYS-associated genes have been recently discovered, the number of recurrent mutations is likely to increase.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…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%

“…(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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Section: Discussionmentioning

confidence: 99%

Section: Prkar1a Mutation Spectrummentioning

confidence: 99%

Section: Pde4d Mutation Spectrummentioning

confidence: 99%

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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“…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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Pseudohypoparathyroidism

Linglart¹,

Levine²,

Jüppner³

2018

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Different mutations inPDE4Dassociated with developmental disorders with mirror phenotypes

Cited by 61 publications

References 28 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

Pseudohypoparathyroidism

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