scholarly journals A novel rasopathy caused by recurrent de novo missense mutations inPPP1CBclosely resembles Noonan syndrome with loose anagen hair

2016 ◽  
Vol 170 (9) ◽  
pp. 2237-2247 ◽  
Author(s):  
Karen W. Gripp ◽  
Kimberly A. Aldinger ◽  
James T. Bennett ◽  
Laura Baker ◽  
Jessica Tusi ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
De Novo ◽  
Missense Mutations ◽  
Anagen Hair

scholarly journals On the Need to Tell Apart Fraternal Twins eEF1A1 and eEF1A2, and Their Respective Outfits

2021 ◽  
Vol 22 (13) ◽  
pp. 6973
Author(s):  
Alberto Mills ◽  
Federico Gago
Keyword(s):  
De Novo ◽  
Elongation Factor ◽  
Missense Mutations ◽  
Developmentally Regulated ◽  
High Sequence Identity ◽  
80S Ribosome ◽  
Cellular Effects ◽  
Cellular Processes ◽  
Eukaryotic Elongation Factor ◽  
A Site

eEF1A1 and eEF1A2 are paralogous proteins whose presence in most normal eukaryotic cells is mutually exclusive and developmentally regulated. Often described in the scientific literature under the collective name eEF1A, which stands for eukaryotic elongation factor 1A, their best known activity (in a monomeric, GTP-bound conformation) is to bind aminoacyl-tRNAs and deliver them to the A-site of the 80S ribosome. However, both eEF1A1 and eEF1A2 are endowed with multitasking abilities (sometimes performed by homo- and heterodimers) and can be located in different subcellular compartments, from the plasma membrane to the nucleus. Given the high sequence identity of these two sister proteins and the large number of post-translational modifications they can undergo, we are often confronted with the dilemma of discerning which is the particular proteoform that is actually responsible for the ascribed biochemical or cellular effects. We argue in this review that acquiring this knowledge is essential to help clarify, in molecular and structural terms, the mechanistic involvement of these two ancestral and abundant G proteins in a variety of fundamental cellular processes other than translation elongation. Of particular importance for this special issue is the fact that several de novo heterozygous missense mutations in the human EEF1A2 gene are associated with a subset of rare but severe neurological syndromes and cardiomyopathies.

An intronic variant disrupts mRNA splicing and causes FGFR3-related skeletal dysplasia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ting Xu ◽  
Liang Shi ◽  
Weiqian Dai ◽  
Xuefan Gu ◽  
Yongguo Yu ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Findings ◽  
Recurrent Mutation ◽  
Mrna Splicing ◽  
Additional Patient ◽  
Missense Mutations ◽  
Splicing Variant ◽  
Amino Acid Insertion ◽  
Whole Exome ◽  
Minigene Assay

Abstract Objectives Achondroplasia and hypochondroplasia are the most common forms of disproportionate short stature, of which the vast majority of cases can be attributed to the hotspot missense mutations in the gene FGFR3. Here we presented cases with a novel cryptic splicing variant of FGFR3 gene and aimed to interrogate the variant pathogenicity. Case presentaiton In whole exome sequencing of two patients with hypochondroplasia-like features, a de novo intronic variant c.1075 + 95C>G was identified, predicted to alter mRNA splicing. Minigene assay showed that this intronic variant caused retention of a 90-nucleotide segment of intron 8 in mRNA, resulting in a 30-amino acid insertion at the extracellular domain of the protein. This is the first likely pathogenic splicing variant identified in the FGFR3 gene and was detected in one additional patient among 26 genetically unresolved patients. Conclustions Our results strongly suggest that c.1075 + 95C>G is a recurrent mutation and should be included in genetic testing of FGFR3 especially for those patients with equivocal clinical findings and no exonic mutations identified.

scholarly journals The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway

2018 ◽  
Vol 39 (5) ◽  
pp. 676-700 ◽  
Author(s):  
Mylène Tajan ◽  
Romain Paccoud ◽  
Sophie Branka ◽  
Thomas Edouard ◽  
Armelle Yart
Keyword(s):  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Genetic Disorders ◽  
Mapk Signaling ◽  
Mendelian Inheritance ◽  
Disease Genes ◽  
Type I ◽  
Future Directions ◽  
Legius Syndrome ◽  
Anagen Hair

Abstract Noonan syndrome [NS; Mendelian Inheritance in Men (MIM) #163950] and related syndromes [Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome; MIM #151100), Noonan-like syndrome with loose anagen hair (MIM #607721), Costello syndrome (MIM #218040), cardio-facio-cutaneous syndrome (MIM #115150), type I neurofibromatosis (MIM #162200), and Legius syndrome (MIM #611431)] are a group of related genetic disorders associated with distinctive facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was clinically described more than 50 years ago, and disease genes have been identified throughout the last 3 decades, providing a molecular basis to better understand their physiopathology and identify targets for therapeutic strategies. Most of these genes encode proteins belonging to or regulating the so-called RAS/MAPK signaling pathway, so these syndromes have been gathered under the name RASopathies. In this review, we provide a clinical overview of RASopathies and an update on their genetics. We then focus on the functional and pathophysiological effects of RASopathy-causing mutations and discuss therapeutic perspectives and future directions.

scholarly journals Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

2017 ◽  
Vol 101 (3) ◽  
pp. 478-484 ◽  
Author(s):  
Stefan H. Lelieveld ◽  
Laurens Wiel ◽  
Hanka Venselaar ◽  
Rolph Pfundt ◽  
Gerrit Vriend ◽  
...  
Keyword(s):  
De Novo ◽  
Spatial Clustering ◽  
Neurodevelopmental Disorder ◽  
Missense Mutations

scholarly journals Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate

2020 ◽  
Vol 8 (7) ◽  
Author(s):  
Alba Sanchis‐Juan ◽  
Marcia A. Hasenahuer ◽  
James A. Baker ◽  
Amy McTague ◽  
Katy Barwick ◽  
...  
Keyword(s):  
Structural Analysis ◽  
De Novo ◽  
Missense Mutations ◽  
De Novo Variant

scholarly journals Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

2017 ◽  
Vol 48 (03) ◽  
pp. 166-184 ◽  
Author(s):  
Gillian Rice ◽  
Naoki Kitabayashi ◽  
Magalie Barth ◽  
Tracy Briggs ◽  
Annabel Burton ◽  
...  
Keyword(s):  
Neurological Disease ◽  
De Novo ◽  
Phenotypic Variability ◽  
Spastic Paraparesis ◽  
Dominant Negative ◽  
Compound Heterozygous ◽  
Motor Disorder ◽  
Type I ◽  
Missense Mutations ◽  
Dominant Negative Mutation

AbstractWe investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.

scholarly journals In vivo, in vitro and in silico correlations of four de novo SCN1A missense mutations

PLoS ONE ◽  
2019 ◽  
Vol 14 (2) ◽  
pp. e0211901 ◽  
Author(s):  
Andreea Nissenkorn ◽  
Yael Almog ◽  
Inbar Adler ◽  
Mary Safrin ◽  
Marina Brusel ◽  
...  
Keyword(s):  
In Silico ◽  
De Novo ◽  
Missense Mutations

Non-Inversion Factor VIII Mutations in 80 Hemophilia A Families Including 24 with Alloimmune Responses

2002 ◽  
Vol 87 (02) ◽  
pp. 273-276 ◽  
Author(s):  
Miao-Liang Liu ◽  
Shelley Nakaya ◽  
Arthur Thompson
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
De Novo ◽  
High Titer ◽  
Direct Sequencing ◽  
Normal Variant ◽  
Missense Mutations ◽  
Gene Deletions ◽  
Intron Splice ◽  
Splice Junctions

SummaryHeteroduplex screening identified 74 small mutations in the factor VIII genes of 72 families with hemophilia A. In addition, patients from 3 families with high titer inhibitors had partial gene deletions and 5 unrelated families that were negative for heteroduplex formation had a mutation on direct sequencing. The latter had mild hemophilia A with an inhibitor, and sequencing their exon 23 fragments found a transition predicting a recurrent Arg2150 to His. Of 69 distinct mutations (including the 3 partial gene deletions), 47 are novel. Of small mutations, 51 were missense (one possibly a normal variant and two that could also alter splicing) at 39 sites, 13 were small deletions or insertions (3 inframe and one a normal variant in an intron), 13 were nonsense at 12 sites and 2 altered intron splice junctions. In 24 families, at least one affected member had evidence for an alloimmune response to factor VIII; of these, 11 were associated with missense mutations. In 14 families, de novo origin was demonstrated.

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