Alu element insertion in the MLH1 exon 6 coding sequence as a mutation predisposing to Lynch syndrome

2019 ◽  
Vol 40 (6) ◽  
pp. 716-720
Author(s):  
Jérôme Solassol ◽  
Marion Larrieux ◽  
Julie Leclerc ◽  
Vincent Ducros ◽  
Carole Corsini ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Coding Sequence ◽  
Element Insertion ◽  
Alu Element

scholarly journals Genotype-Phenotype Correlations in RP1-Associated Retinal Dystrophies: A Multi-Center Cohort Study in JAPAN

2021 ◽  
Vol 10 (11) ◽  
pp. 2265
Author(s):  
Kei Mizobuchi ◽  
Takaaki Hayashi ◽  
Noriko Oishi ◽  
Daiki Kubota ◽  
Shuhei Kameya ◽  
...  
Keyword(s):  
Age At Onset ◽  
Japanese Patients ◽  
Clinical Findings ◽  
Cone Dystrophy ◽  
Element Insertion ◽  
Retinal Dystrophies ◽  
Whole Exome ◽  
Novel Variants ◽  
Alu Element ◽  
Frequent Variant

Background: Little is known about genotype–phenotype correlations of RP1-associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of RP1 variants and provide a detailed description of the clinical findings in Japanese patients. Methods: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an Alu element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous RP1 variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic RP1 variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD. Results: We identified 18 pathogenic RP1 variants, including seven novel variants. Interestingly, the Alu element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients. Conclusions: Our results suggest a genotype–phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the Alu element insertion was the most major variant in Japanese patients with RP1-associated retinal dystrophies.

A complete Alu element within the coding sequence of a central gene

Cell ◽  
1994 ◽  
Vol 78 (2) ◽  
pp. 173-174 ◽  
Author(s):  
Hanah Margalit ◽  
Eyal Nadir ◽  
Shmuel A. Ben-Sasson
Keyword(s):  
Coding Sequence ◽  
Alu Element

scholarly journals An Alu Element Insertion in Intron 1 Results in Aberrant Alternative Splicing of APOBEC3G Pre-mRNA in Northern Pig-Tailed Macaques (Macaca leonina) That May Reduce APOBEC3G-Mediated Hypermutation Pressure on HIV-1

2019 ◽  
Vol 94 (4) ◽  
Author(s):  
Xiao-Liang Zhang ◽  
Meng-Ting Luo ◽  
Jia-Hao Song ◽  
Wei Pang ◽  
Yong-Tang Zheng
Keyword(s):  
Alternative Splicing ◽  
Animal Models ◽  
Family Members ◽  
Element Insertion ◽  
Intron 1 ◽  
Splicing Pattern ◽  
Alu Element ◽  
Aids Therapy ◽  
Apobec3 Family ◽  
Hiv 1

ABSTRACT APOBEC3 family members, particularly APOBEC3F and APOBEC3G, inhibit the replication and spread of various retroviruses by inducing hypermutation in newly synthesized viral DNA. Viral hypermutation by APOBEC3 is associated with viral evolution, viral transmission, and disease progression. In recent years, increasing attention has been paid to targeting APOBEC3G for AIDS therapy. Thus, a controllable model system using species such as macaques, which provide a relatively ideal in vivo system, is needed for the study of APOBEC3-related issues. To appropriately utilize this animal model for biomedical research, important differences between human and macaque APOBEC3s must be considered. In this study, we found that the ratio of APOBEC3G-mediated/APOBEC3-mediated HIV-1 hypermutation footprints was much lower in peripheral blood mononuclear cells (PBMCs) from northern pig-tailed macaques than in PBMCs from humans. Next, we identified a novel and conserved APOBEC3G pre-mRNA alternative splicing pattern in macaques, which differed from that in humans and resulted from an Alu element insertion into macaque APOBEC3G gene intron 1. This alternative splicing pattern generating an aberrant APOBEC3G mRNA isoform may significantly dilute full-length APOBEC3G and reduce APOBEC3G-mediated hypermutation pressure on HIV-1 in northern pig-tailed macaques, which was supported by the elimination of other possibilities accounting for this hypermutation difference between the two hosts. IMPORTANCE APOBEC3 family members, particularly APOBEC3F and APOBEC3G, are important cellular antiviral factors. Recently, more attention has been paid to targeting APOBEC3G for AIDS therapy. To appropriately utilize macaque animal models for the study of APOBEC3-related issues, it is important that the differences between human and macaque APOBEC3s are clarified. In this study, we identified a novel and conserved APOBEC3G pre-mRNA alternative splicing pattern in macaques, which differed from that in humans and which may reduce the APOBEC3G-mediated hypermutation pressure on HIV-1 in northern pig-tailed macaques (NPMs). Our work provides important information for the proper application of macaque animal models for APOBEC3-related issues in AIDS research and a better understanding of the biological functions of APOBEC3 proteins.

Alu-element insertion in the homeodomain ofHESX1and aplasia of the anterior pituitary

2005 ◽  
Vol 25 (5) ◽  
pp. 503-503 ◽  
Author(s):  
Marie-Laure Sobrier ◽  
Irène Netchine ◽  
Claudine Heinrichs ◽  
Nathalie Thibaud ◽  
Marie-Pierre Vié-Luton ◽  
...  
Keyword(s):  
Anterior Pituitary ◽  
Element Insertion ◽  
Alu Element

scholarly journals Alu element insertion inPKLRgene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients

2018 ◽  
Vol 39 (3) ◽  
pp. 389-393 ◽  
Author(s):  
Harry Lesmana ◽  
Lisa Dyer ◽  
Xia Li ◽  
James Denton ◽  
Jenna Griffiths ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Middle Eastern ◽  
Pyruvate Kinase Deficiency ◽  
Element Insertion ◽  
Alu Element

scholarly journals Alu-Element Insertion in Pklr Gene As a Novel Cause of Severe Hereditary Nonspherocytic Hemolytic Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3349-3349 ◽  
Author(s):  
Harry Lesmana ◽  
Lisa Dyer ◽  
Ping Zhou ◽  
Xia Li ◽  
James Denton ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Hemolytic Anemia ◽  
Splice Site ◽  
Family Members ◽  
Next Generation ◽  
Coding Region ◽  
Laboratory Findings ◽  
Element Insertion ◽  
Alu Element ◽  
Generation Sequencing

Abstract Red blood cell pyruvate kinase deficiency (PKD) is the most frequent enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Its incidence has been estimated to be 1 in 20,000, especially in regions where consanguinity is common. It is inherited in autosomal recessive manner occurring as result of homozygous or compound heterozygous mutations affecting both alleles in PKLR gene. Over 200 mutations have been described in patients with PKD causing various severity of hemolysis. Most cases are due to missense mutations, but small deletions, insertions, splice site alterations, frame shifts, disruption of erythroid specific promoters, and nonsense mutations have been reported. Alu elements are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass. These mobile elements have contributed significantly to evolution and human diversity by causing gene rearrangements. Alu insertions particularly have been associated with a number of human diseases either by disrupting a coding region or a splice signal. In this abstract, we report an Alu-element insertion in the coding region of PKLR gene as a novel cause of PKD causing severe hereditary nonspherocytic hemolytic anemia. The proband was a 16-month-old middle eastern male born to consanguineous parents. He was diagnosed with severe chronic hemolytic anemia and neonatal jaundice requiring regular blood transfusion since birth. There were no known family members with anemia requiring transfusions. The patient's RBC phenotypic analysis was challenging since most of the circulating RBCs were donor cells. Using a Next-Generation sequencing panel for 27 hemolytic anemia associated genes, we identified and characterized a novel homozygous insertional mutation in exon 6 of PKLR gene along with heterozygosity for ANK1 c.1404+15C>T variant. The mutation in exon 6 was identified as Alu element insertion. The inserted Alu element (~370 bp in size), belonging to the youngest Yb8 subfamily, disrupts the reading frame at isoleucine 314 in exon 6 of PKLR gene, leading to a premature stop codon within the inserted sequence. Quantitative reverse transcription-PCR (qRT-PCR) in the patient's reticulocyte RNA using primers for the sequence before the Alu insertion revealed a transcript present but decreased by 80% compared to the average of controls' reticulocyte RNA. This truncated transcript even if translated is expected to cause severe enzyme deficiency. Both parents had a normal hemoglobin level with mild reticulocytosis. The mother had a PK enzyme activity of 4.5 units/g Hb (normal range 6.7-14.3 units/g Hb) indicating that she is heterozygous for PKD. Paternal PK activity level was not determined due to insufficient sample. Carrier testing for mutation in PKLR gene in both parents is currently in process at the time of this submission. The variant in ANK1 gene was predicted to be damaging by affecting the splice site in ankyrin gene. However the father was also heterozygous for this variant and his ektacytometry was normal suggesting a benign nature of ANK1 c.1404+15C>T. This case represents, to our knowledge, the first report of a pathogenic PKLR mutation due to an Alu element insertion and demonstrates a novel mechanism causing severe hereditary nonspherocytic hemolytic anemia. This report also illustrates the challenge of diagnosing congenital hemolytic anemias in chronically transfused patients. The patients often present with a complex clinical picture and ambiguous laboratory findings and may have several potentially damaging genetics variants identified by next generation sequencing. A critical evaluation of the clinical symptoms, laboratory findings and genetic data from other family members and bioinformatics analysis are required to clarify the contribution of these variants and to arrive at an accurate diagnosis, which will guide the institution of targeted interventions and appropriate genetic counseling. Disclosures No relevant conflicts of interest to declare.

Predicting Lynch Syndrome Propensity to Cancer

2006 ◽  
Vol 39 (21) ◽  
pp. 52
Author(s):  
MARY ANN MOON
Keyword(s):  
Lynch Syndrome

DIAGNOSE AND DISREGARD POLICY CAN BE IMPLEMENTED IN PATIENTS WITH LYNCH SYNDROME WHEN DONE BY EXPERT COLONOSCOPISTS

2019 ◽  
Author(s):  
A Gavrić ◽  
L Rivero Sanchez ◽  
C Arnau ◽  
J Herrero ◽  
D Remedios ◽  
...  
Keyword(s):  
Lynch Syndrome
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