scholarly journals Duplication of 17q11.2 and Features of Albright Hereditary Osteodystrophy Secondary to Methylation Defects within the GNAS Cluster: Coincidence or Causal?

2013 ◽  
Vol 2013 ◽  
pp. 1-3 ◽  
Author(s):  
M. White ◽  
J. Conroy ◽  
H. Bullman ◽  
M. Lever ◽  
E. Daly ◽  
...  
Keyword(s):  
De Novo ◽  
Uniparental Disomy ◽  
Neurofibromatosis Type ◽  
Secretory Protein ◽  
Epigenetic Mechanism ◽  
Guanine Nucleotide Binding Protein ◽  
Albright Hereditary Osteodystrophy ◽  
Chromosome 20 ◽  
Nf1 Gene ◽  
Guanine Nucleotide Binding

We report a case of Albright hereditary osteodystrophy (AHO) in a three-year-old girl with a microduplication at 17q11.2. The child developed obesity within the first 6 months of life. A diagnosis of Albright was made at age 2 years when biochemical evidence of parathyroid resistance was found. No mutations were identified in guanine nucleotide-binding protein G (s) subunit alpha (GNAS1). Subsequent investigations revealed methylation disturbance at GNAS1A, neuroendocrine secretory protein antisense (NESPAS) and neuroendocrine secretory protein 55 (NESP55) confirming a diagnosis of pseudohypothyroidism type 1B. A deletion of NESP55 and uniparental disomy chromosome 20 were excluded which suggested that the features of AHO arose through a purely epigenetic mechanism. Further investigation revealed ade novomicroduplication at 17q11.2 encompassing the neurofibromatosis type 1 (NF1) gene. The combination of two rarede novoevents in the same child raises the possibility that duplication of a gene within the 17q11.2 region may have triggered abnormal methylation in the GNAS cluster region on chromosome 20.

Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1

2003 ◽  
Vol 112 (1) ◽  
pp. 12-17 ◽  
Author(s):  
Meena Upadhyaya ◽  
Elisa Majounie ◽  
Peter Thompson ◽  
Song Han ◽  
Claudia Consoli ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
De Novo ◽  
Neurofibromatosis Type ◽  
Pathological Lesions ◽  
Nf1 Gene

scholarly journals Genetic and Epigenetic Causes of Pituitary Adenomas

2021 ◽  
Vol 11 ◽  
Author(s):  
Mengqi Chang ◽  
Chengxian Yang ◽  
Xinjie Bao ◽  
Renzhi Wang
Keyword(s):  
Pituitary Adenomas ◽  
Neurofibromatosis Type ◽  
Carney Complex ◽  
Hormone Production ◽  
Guanine Nucleotide Binding Protein ◽  
Interacting Protein ◽  
Von Hippel Lindau ◽  
Aryl Hydrocarbon ◽  
Guanine Nucleotide Binding

Pituitary adenomas (PAs) can be classified as non-secreting adenomas, somatotroph adenomas, corticotroph adenomas, lactotroph adenomas, and thyrotroph adenomas. Substantial advances have been made in our knowledge of the pathobiology of PAs. To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and X-LAG syndromes. PAs have also been described in association with succinate dehydrogenase-related familial PA, neurofibromatosis type 1, and von Hippel–Lindau, DICER1, and Lynch syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the deubiquitinase gene USP8, USP48, and BRAF mutations are associated with adrenocorticotropic hormone production. In this review, we describe the genetic and epigenetic landscape of PAs and summarize novel insights into the regulation of pituitary tumorigenesis.

Expanding Phenotype of De Novo Mutations in GNAO1: Four New Cases and Review of Literature

2017 ◽  
Vol 48 (05) ◽  
pp. 371-377 ◽  
Author(s):  
Tobias Dietel ◽  
Christina Evers ◽  
Katrin Hinderhofer ◽  
Rudolf Korinthenberg ◽  
Daniel Ezzo ◽  
...  
Keyword(s):  
De Novo ◽  
Involuntary Movement ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation ◽  
Guanine Nucleotide ◽  
Review Of Literature ◽  
De Novo Mutations ◽  
Guanine Nucleotide Binding Protein ◽  
Guanine Nucleotide Binding ◽  
Severe Epilepsy

AbstractMutations in GNAO1 (guanine nucleotide-binding protein, alpha-activating activity polypeptide O) were recently identified as being causative for early epileptic encephalopathy. Since then approximately 27 patients with severe developmental delay and different neurological phenotypes for epilepsy and involuntary movement disorder have been reported. We report four additional patients with mutations in GNAO1 including a report of siblings of different sex harboring the same de novo mutation (c.736G > A, p.Glu246Lys) but showing differences in phenotype with pronounced dystonia in the boy and epilepsy in his sister. Another de novo mutation in GNAO1 (c.607G > A, p.Gly203Arg) was identified in two unrelated girls with severe epilepsy. Both girls later also developed severe dystonia with severe nonepileptic spasms. An extensive review of published cases revealed that epilepsy was reported in only one male patient so far. Thus it appears possible that epilepsy is a sex-dependent phenotypic feature of GNAO1-related diseases.

A de novo nonsense mutation in exon 28 of the neurofibromatosis type l (NF1) gene

1993 ◽  
Vol 92 (4) ◽  
pp. 410-412 ◽  
Author(s):  
Ming Hong Shen ◽  
Meena Upadhyaya
Keyword(s):  
Nonsense Mutation ◽  
De Novo ◽  
Neurofibromatosis Type ◽  
Nf1 Gene

scholarly journals One NF1 Mutation may Conceal Another

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 633
Author(s):  
Laurence Pacot ◽  
Cyril Burin des Roziers ◽  
Ingrid Laurendeau ◽  
Audrey Briand-Suleau ◽  
Audrey Coustier ◽  
...  
Keyword(s):  
De Novo ◽  
Mapk Pathway ◽  
Neurofibromatosis Type ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Complete Penetrance ◽  
Pathogenic Variants ◽  
Legius Syndrome ◽  
Nf1 Gene ◽  
Dominant Disease

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but high variable expressivity. NF1 is caused by loss-of-function mutations in the NF1 gene, a negative regulator of the RAS-MAPK pathway. The NF1 gene has one of the highest mutation rates in human disorders, which may explain the outbreak of independent de novo variants in the same family. Here, we report the co-occurrence of pathogenic variants in the NF1 and SPRED1 genes in six families with NF1 and Legius syndrome, using next-generation sequencing. In five of these families, we observed the co-occurrence of two independent NF1 variants. All NF1 variants were classified as pathogenic, according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines. In the sixth family, one sibling inherited a complete deletion of the NF1 gene from her mother and carried a variant of unknown significance in the SPRED1 gene. This variant was also present in her brother, who was diagnosed with Legius syndrome, a differential diagnosis of NF1. This work illustrates the complexity of molecular diagnosis in a not-so-rare genetic disease.

scholarly journals Guanine Nucleotide Binding Protein (GNAS Complex Locus) Gene Produces Biallelically Expressed and Paternally Expressed Transcripts in Pigs

2015 ◽  
Vol 15 (4) ◽  
pp. 867-877 ◽  
Author(s):  
Maria Oczkowicz ◽  
Agata Piestrzyńska-Kajtoch ◽  
Katarzyna Ropka-Molik
Keyword(s):  
Binding Protein ◽  
Nucleotide Binding ◽  
Secretory Protein ◽  
Paternal Allele ◽  
Kidney Cortex ◽  
Guanine Nucleotide ◽  
Guanine Nucleotide Binding Protein ◽  
Complex Locus ◽  
Guanine Nucleotide Binding ◽  
Nucleotide Binding Protein

Abstract Imprinted loci are a subset of genes expressed only from one parental allele. Guanine nucleotide binding protein (GNAS complex locus) produces a few different proteins and noncoding RNAs. It is imprinted in mice and humans, while in pigs imprinting status of only one of them - NESP55 (neuroendocrine secretory protein-55) has been established. In the present study we aimed to establish imprinting status of the other two GNAS transcripts. We collected a panel of tissues (muscle, liver, kidney cortex, heart, fat, ovary, brain, blood) from the animals (aged 40-210 days) heterozygous in rs#333005482 polymorphism. We performed several RT -PCRs (Reverse Transcription Polymerase Chain Reactions) with variant specific primers and sequenced the cDNA products obtained. We observed only paternal allele in all tissues at all developmental stages after sequencing with primers specific to variant 8 of GNAS gene and both alleles when sequencing with primers specific to variant 6. Our results show for the first time that, in pigs, GNAS complex locus produces biallelically expressed and paternally expressed transcripts, in the same way as previously demonstrated in mice and humans

scholarly journals Hybrid Minigene Assay: An Efficient Tool to Characterize mRNA Splicing Profiles of NF1 Variants

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 999
Author(s):  
Valeria Morbidoni ◽  
Elisa Baschiera ◽  
Monica Forzan ◽  
Valentina Fumini ◽  
Dario Seif Ali ◽  
...  
Keyword(s):  
De Novo ◽  
Neurofibromatosis Type ◽  
Diagnostic Process ◽  
Fast Method ◽  
Loss Of Function ◽  
Clinical Criteria ◽  
Nf1 Gene ◽  
Set Up ◽  
Next Generation Sequencing Ngs ◽  
Minigene Assay

Neurofibromatosis type 1 (NF1) is caused by heterozygous loss of function mutations in the NF1 gene. Although patients are diagnosed according to clinical criteria and few genotype-phenotype correlations are known, molecular analysis remains important. NF1 displays allelic heterogeneity, with a high proportion of variants affecting splicing, including deep intronic alleles and changes outside the canonical splice sites, making validation problematic. Next Generation Sequencing (NGS) technologies integrated with multiplex ligation-dependent probe amplification (MLPA) have largely overcome RNA-based techniques but do not detect splicing defects. A rapid minigene-based system was set up to test the effects of NF1 variants on splicing. We investigated 29 intronic and exonic NF1 variants identified in patients during the diagnostic process. The minigene assay showed the coexistence of multiple mechanisms of splicing alterations for seven variants. A leaky effect on splicing was documented in one de novo substitution detected in a sporadic patient with a specific phenotype without neurofibromas. Our splicing assay proved to be a reliable and fast method to validate novel NF1 variants potentially affecting splicing and to detect hypomorphic effects that might have phenotypic consequences, avoiding the requirement of patient’s RNA.

Mapping the Heart

2010 ◽  
Vol 18 (4) ◽  
pp. 6-8
Author(s):  
Stephen W. Carmichael
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
G Protein Coupled Receptors ◽  
Receptor Subtypes ◽  
Cardiac Muscle Cells ◽  
Guanine Nucleotide Binding Protein ◽  
The Common ◽  
Guanine Nucleotide Binding ◽  
First Time ◽  
G Protein Coupled

Some of the receptors on the surface of cardiac muscle cells (cardiomyocytes) mediate the response of these cells to catecholamines by causing the production of the common second messenger cyclic adenosine monophosphate (cAMP). An example of such receptors are the β1- and β2-adrenergic receptors (βARs) that are heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. Selective stimulation of these two receptor subtypes leads to distinct physiological and pathophysiological responses, but their precise location on the surface of cardiomyocytes has not been correlated with these responses. In an ingenious combination of techniques, Viacheslav Nikolaev, Alexey Moshkov, Alexander Lyon, Michele Miragoli, Pavel Novak, Helen Paur, Martin Lohse, Yuri Korchev, Sian Harding, and Julia Gorelik have mapped the function of these receptors for the first time.

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