High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme

2014 ◽  
Vol 15 (3) ◽  
pp. 288-292 ◽  
Author(s):  
M Apellániz-Ruiz ◽  
L Inglada-Pérez ◽  
M E G Naranjo ◽  
L Sánchez ◽  
V Mancikova ◽  
...  
Keyword(s):  
Founder Effect ◽  
High Frequency ◽  
Spanish Population ◽  
Loss Of Function

scholarly journals High frequency of inactivating tetraspanin CD37 mutations in diffuse large B-cell lymphoma at immune-privileged sites

Blood ◽  
2019 ◽  
Vol 134 (12) ◽  
pp. 946-950 ◽  
Author(s):  
Suraya Elfrink ◽  
Charlotte M. de Winde ◽  
Michiel van den Brand ◽  
Madeleine Berendsen ◽  
Margaretha G. M. Roemer ◽  
...  
Keyword(s):  
B Cell ◽  
High Frequency ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Loss Of Function ◽  
Large B Cell Lymphoma ◽  
Key Points ◽  
Surface Localization ◽  
Cell Surface Localization ◽  
Large B Cell

Key Points Loss-of-function mutations in CD37 occur predominantly in diffuse large B-cell lymphoma at immune-privileged sites. CD37-mutated lymphoma B cells show impaired CD37 cell-surface localization, which may have implications for anti-CD37 therapies.

The High Frequency of the Hb B2Variant in the Herero Population: A Founder Effect?

Hemoglobin ◽  
1994 ◽  
Vol 18 (4-5) ◽  
pp. 317-323 ◽  
Author(s):  
A. B. Spurdle ◽  
A. Krause ◽  
M. Ransay ◽  
T. Jenkins
Keyword(s):  
Founder Effect ◽  
High Frequency

scholarly journals Highly efficient CRISPR gene editing in yeast enabled by double selection

2018 ◽  
Author(s):  
Philippe C Després ◽  
Alexandre K Dubé ◽  
Lou Nielly-Thibault ◽  
Nozomu Yachie ◽  
Christian R Landry
Keyword(s):  
High Frequency ◽  
Large Scale ◽  
Gene Editing ◽  
Chromosomal Translocations ◽  
Selection Strategy ◽  
Loss Of Function ◽  
Base Editing ◽  
Fitness Effects ◽  
Genetics And Genomics ◽  
Selection For

AbstractCRISPR-Cas9 loss of function (LOF) and base editing screens are powerful tools in genetics and genomics. Yeast is one of the main models in genetics and genomics, yet large-scale approaches remain to be developed in this species because of low mutagenesis rates without donor DNA. We developed a double selection strategy based on co-selection that increases LOF mutation rates, both for CRISPR-Cas9 and the Target-AID base editor. We constructed the pDYSCKO vector, which is amenable to high throughput double selection for both approaches. Using modeling, we show that this improvement provides the required increased in detection power to measure the fitness effects of thousands of mutations in typical yeast pooled screens. We also show that multiplex genome editing with Cas9 causes programmable chromosomal translocations at high frequency, suggesting that multiplex editing should be performed with caution and that base-editors could be preferable tools for LOF screens.

scholarly journals Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells

2021 ◽  
Author(s):  
Perry W.E. Spratt ◽  
Roy Ben-Shalom ◽  
Atehsa Sahagun ◽  
Caroline M. Keeshen ◽  
Stephan J. Sanders ◽  
...  
Keyword(s):  
Sodium Channel ◽  
High Frequency ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Autism Spectrum ◽  
Dynamic Clamp ◽  
Loss Of Function ◽  
Intrinsic Mechanism ◽  
Channel Loss

Loss-of-function variants in the gene SCN2A, which encodes the sodium channel NaV1.2, are strongly associated with autism spectrum disorder and intellectual disability. An estimated 20-30% of children with these variants are co-morbid for epilepsy, with altered neuronal activity originating in neocortex, a region where NaV1.2 channels are expressed predominantly in excitatory pyramidal cells. This is paradoxical, as sodium channel loss in excitatory cells would be expected to dampen neocortical activity rather than promote seizure. Here, we examined pyramidal neurons lacking NaV1.2 channels and found that they were intrinsically hyperexcitable, firing high-frequency bursts of action potentials (APs) despite decrements in AP size and speed. Compartmental modeling and dynamic clamp recordings revealed that NaV1.2 loss prevented potassium channels from properly repolarizing neurons between APs, increasing overall excitability by allowing neurons to reach threshold for subsequent APs more rapidly. This cell-intrinsic mechanism may therefore account for why SCN2A loss-of-function can paradoxically promote seizure.

scholarly journals High frequency of a splice mutation in intron 2 of the 21-hydroxylase gene in Russia could be partly explained by a founder effect

1998 ◽  
Vol 11 (S1) ◽  
pp. S53-S54
Author(s):  
Alexander Vladimirovich Polyakov ◽  
Irina Genrikhovna Dzenis ◽  
Vladimir Anatol'Evich Baharev ◽  
Oleg Vadimovich Evgrafov
Keyword(s):  
Founder Effect ◽  
High Frequency ◽  
Splice Mutation ◽  
Hydroxylase Gene ◽  
Intron 2

scholarly journals Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion

PLoS ONE ◽  
2017 ◽  
Vol 12 (11) ◽  
pp. e0176181 ◽  
Author(s):  
Lee A. Albacker ◽  
Jeremy Wu ◽  
Peter Smith ◽  
Markus Warmuth ◽  
Philip J. Stephens ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Immune Evasion ◽  
High Frequency ◽  
Loss Of Function

The high frequency of the — 6G → A factor IX promoter mutation is the result both of a founder effect and recurrent mutation at a CpG dinucleotide

1995 ◽  
Vol 89 (3) ◽  
pp. 672-674 ◽  
Author(s):  
G. E. Morgan ◽  
M. S. Figueiredo ◽  
P. R. Winship ◽  
R. Baker ◽  
P. H. B. Bolton-Maggs ◽  
...  
Keyword(s):  
Founder Effect ◽  
High Frequency ◽  
Recurrent Mutation ◽  
Factor Ix ◽  
Promoter Mutation ◽  
Cpg Dinucleotide

scholarly journals Founding mutations explains hot spots of polycystic kidney disease in Southern Spain

2020 ◽  
Author(s):  
Carmen García Rabaneda ◽  
Francisco Perea ◽  
María Luz Bellido Díaz ◽  
Ana I Morales García ◽  
Margarita Morales Atienza ◽  
...  
Keyword(s):  
Health Care ◽  
Kidney Disease ◽  
Founder Effect ◽  
Hot Spots ◽  
High Frequency ◽  
Common Ancestor ◽  
Common Haplotype ◽  
Chromosome 16 ◽  
Polycystic Kidney ◽  
Pathogenic Variants

Abstract Our group identified two pathogenic variants on the PKD1 gene, c.10527_10528delGA and c.7292T>A from unrelated families. They came from two small counties in Granada, with 61 and 26 ADPKD individuals affected. To determine a common ancestor, healthy and ADPKD individuals from these families were genotyped by analyzing four microsatellites located on chromosome 16. Our study identified a common haplotype in all ADPKD individuals. These findings underpin our hypothesis of the founder effect and explains why there is a high frequency of ADPKD in small regions. Determining hot spots of ADPKD will help to better plan health care in the future.

scholarly journals The CDH1 c.1901C>T Variant: A Founder Variant in the Portuguese Population with Severe Impact in mRNA Splicing

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4464
Author(s):  
Rita Barbosa-Matos ◽  
Rafaela Leal Silva ◽  
Luzia Garrido ◽  
Ana Cerqueira Aguiar ◽  
José Garcia-Pelaez ◽  
...  
Keyword(s):  
Splice Site ◽  
Founder Effect ◽  
Age Of Onset ◽  
Clinical Information ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Allelic Expression Imbalance ◽  
Pcr Cloning ◽  
Bona Fide ◽  
The Impact

Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C>T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers’ RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C>T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C>T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445–10,900). Among 58 carriers (27 males (M)–31 females (F); 13–83 years), DGC occurred in 11 (18.9%; 4M–7F; average age 33 ± 12) and LBC in 6 females (19.4%; average age 50 ± 8). Herein, we demonstrated that the c.1901C>T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum.

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