Distinct phenotypic expression of two de novo missense mutations affecting the dimer interface of glucose-6-phosphate dehydrogenase

2004 ◽  
Vol 32 (1) ◽  
pp. 112-117 ◽  
Author(s):  
R VANWIJK ◽  
E HUIZINGA ◽  
I PRINS ◽  
A KORS ◽  
G RIJKSEN ◽  
...  
Keyword(s):  
De Novo ◽  
Phenotypic Expression ◽  
Missense Mutations ◽  
Dimer Interface ◽  
Glucose 6 Phosphate Dehydrogenase

scholarly journals Glucose-6-phosphate dehydrogenase Aveiro: a de novo mutation associated with chronic nonspherocytic hemolytic anemia

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1499-1501 ◽  
Author(s):  
Elı́sio Costa ◽  
José Manuel Cabeda ◽  
Emilia Vieira ◽  
Rui Pinto ◽  
Susana Aires Pereira ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Phenotype ◽  
Class I ◽  
De Novo Mutation ◽  
Dimer Interface ◽  
New Class ◽  
Disease Cluster ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Exon 10 ◽  
Lesion Class

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked enzyme abnormality. The clinical phenotype is variable but often predictable from the molecular lesion. Class I variants (the most severe forms of the disease) cluster within exon 10, in a region that, at the protein level, is believed to be involved in dimerization. Here we describe a de novo mutation (C269Y) of a new class I variant (G6PD Aveiro) that maps to exon 8. Mutant and normal alleles were found in both hematopoietic and buccal cells, indicating the presence of mosaicism. The available model of the protein predicts that this lesion lies in proximity to the dimer interface of the molecule. A possible mechanism to explain the severity of the defect is proposed.

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 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 Attenuated enzootic (pestoides) isolates of Yersinia pestis express active aspartase

Microbiology ◽  
2009 ◽  
Vol 155 (1) ◽  
pp. 198-209 ◽  
Author(s):  
Scott W. Bearden ◽  
Christopher Sexton ◽  
Joshua Pare ◽  
Janet M. Fowler ◽  
Cindy G. Arvidson ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Yersinia Pseudotuberculosis ◽  
Amino Acid Position ◽  
Enzymic Activity ◽  
Broad Host Range ◽  
Missense Mutations ◽  
Tissue Invasion ◽  
Muroid Rodents ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Reduced Activity

It is established that Yersinia pestis, the causative agent of bubonic plague, recently evolved from enteropathogenic Yersinia pseudotuberculosis by undergoing chromosomal degeneration while acquiring two unique plasmids that facilitate tissue invasion (pPCP) and dissemination by fleabite (pMT). Thereafter, plague bacilli spread from central Asia to sylvatic foci throughout the world. These epidemic isolates exhibit a broad host range including man as opposed to enzootic (pestoides) variants that remain in ancient reservoirs where infection is limited to muroid rodents. Cells of Y. pseudotuberculosis are known to express glucose-6-phosphate dehydrogenase (Zwf) and aspartase (AspA); these activities are not detectable in epidemic Y. pestis due to missense mutations (substitution of proline for serine at amino position 155 of Zwf and leucine for valine at position 363 of AspA). In this study, functional Zwf was found in pestoides strains E, F and G but not seven other enzootic isolates; enzymic activity was associated with retention of serine at amino acid position 155. Essentially, full AspA activity occurred in pestoides isolates where valine (pestoides A, B, C and D) or serine (pestoides E, F, G and I) occupied position 363. Reduced activity occurred in strains Angola and A16, which contained phenylalanine at this position. The k cat but not K m of purified AspA from strain Angola was significantly reduced. In this context, aspA of the recently described attenuated enzootic microtus biovar encodes active valine at position 363, further indicating that functional AspA is a biomarker for avirulence of Y. pestis in man.

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 Glucose-6-phosphate dehydrogenase deficiency in the Han Chinese population: molecular characterization and genotype–phenotype association throughout an activity distribution

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ying He ◽  
Yinhui Zhang ◽  
Xionghao Chen ◽  
Qiong Wang ◽  
Lifen Ling ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
G6pd Deficiency ◽  
National Level ◽  
Gene Mutations ◽  
Single Mutation ◽  
Missense Mutations ◽  
Severe Deficiency ◽  
Compound Mutation ◽  
Normal Males ◽  
Glucose 6 Phosphate Dehydrogenase

Abstract Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common hereditary disorder in China. The existing prevalence and molecular epidemiology of G6PD deficiency in China were geographically limited. In this study, the spectrum of G6PD gene mutations was well characterized in a large and diverse population all over the country; and the correlation of genotype and enzyme activity phenotype was explored for the first time. The results showed that the overall prevalence of G6PD deficiency in China was 2.10% at the national level. The top six common mutations were c.1388 G>A, c.1376 G>T, c.95 A>G, c.392 G>T, c.871 G>A and c.1024 C>T, accounting for more than 90% of G6PD deficient alleles. Compound mutation patterns were frequently observed in females with severe deficiency. The distribution of G6PD activities depended on the type of mutation patterns and genders. Hemizygote, homozygote, and compound heterozygote were predominantly associated with severe G6PD deficiency, whereas heterozygotes with single mutation mainly presented moderate enzyme deficiency. A significant gap between G6PD activities in hemizygous and normal males was observed, and yet, the overall distribution of that in females carrying missense mutations was a continuum from G6PD severely deficient to normal. This is the first report of discussing the association between G6PD genetic variants in the Chinese and enzyme activity phenotypes.

scholarly journals A New Case of 13q12.2q13.1 Microdeletion Syndrome Contributes to Phenotype Delineation

2014 ◽  
Vol 2014 ◽  
pp. 1-5
Author(s):  
Giorgia Mandrile ◽  
Eleonora Di Gregorio ◽  
Alessandro Calcia ◽  
Alessandro Brussino ◽  
Enrico Grosso ◽  
...  
Keyword(s):  
Clinical Features ◽  
Critical Region ◽  
Array Cgh ◽  
De Novo ◽  
Genetic Disorder ◽  
Phenotypic Expression ◽  
Microdeletion Syndrome ◽  
Complex Rearrangement

A recently described genetic disorder has been associated with 13q12.3 microdeletion spanning three genes, namely,KATNAL1, LINC00426, andHMGB1. Here, we report a new case with similar clinical features that we have followed from birth to 5 years old. The child carried a complex rearrangement with a double translocation: 46,XX,t(7;13)(p15;q14),t(11;15)(q23;q22). Array-CGH identified ade novomicrodeletion at 13q12.2q13.1 spanning 3–3.4 Mb and overlapping 13q12.3 critical region. Clinical features resembling those reported in the literature confirm the existence of a distinct 13q12.3 microdeletion syndrome and provide further evidence that is useful to characterize its phenotypic expression during the 5 years of development.

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
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