Publications by authors named "Karen Rouault"

7 Publications

  • Page 1 of 1

Analysis of the R1b-DF27 haplogroup shows that a large fraction of Iberian Y-chromosome lineages originated recently in situ.

Sci Rep 2017 08 4;7(1):7341. Epub 2017 Aug 4.

Institut de Biologia Evolutiva (CSIC-UPF), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.

Haplogroup R1b-M269 comprises most Western European Y chromosomes; of its main branches, R1b-DF27 is by far the least known, and it appears to be highly prevalent only in Iberia. We have genotyped 1072 R1b-DF27 chromosomes for six additional SNPs and 17 Y-STRs in population samples from Spain, Portugal and France in order to further characterize this lineage and, in particular, to ascertain the time and place where it originated, as well as its subsequent dynamics. We found that R1b-DF27 is present in frequencies ~40% in Iberian populations and up to 70% in Basques, but it drops quickly to 6-20% in France. Overall, the age of R1b-DF27 is estimated at ~4,200 years ago, at the transition between the Neolithic and the Bronze Age, when the Y chromosome landscape of W Europe was thoroughly remodeled. In spite of its high frequency in Basques, Y-STR internal diversity of R1b-DF27 is lower there, and results in more recent age estimates; NE Iberia is the most likely place of origin of DF27. Subhaplogroup frequencies within R1b-DF27 are geographically structured, and show domains that are reminiscent of the pre-Roman Celtic/Iberian division, or of the medieval Christian kingdoms.
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http://dx.doi.org/10.1038/s41598-017-07710-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544771PMC
August 2017

A founder mutation underlies a severe form of phosphoglutamase 3 (PGM3) deficiency in Tunisian patients.

Mol Immunol 2017 10 10;90:57-63. Epub 2017 Jul 10.

Laboratory of Transmission, Control and Immunobiology of Infections (LR11IPT02), Tunis, Tunisia; Université Tunis El Manar, 1068 Tunis, Tunisia.

Phosphoglucomutase 3 (PGM3) protein catalyzes the conversion of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6-P) to N-acetyl-d-glucosamine-1-phosphate (GlcNAc-1-P), which is required for the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) an important precursor for protein glycosylation. Mutations in PGM3 gene have been recently shown to underlie a new congenital disorder of glycosylation often associated to elevated IgE. Herein, we report twelve PGM3 deficient patients. They belong to three highly consanguineous families, originating from a rural district in the west central Tunisia. The patient's clinical phenotype is characterized by severe respiratory and cutaneous infections as well as developmental delay and severe mental retardation. Fourteen patients died in early infancy before diagnosis supporting the severity of the clinical phenotype. Laboratory findings revealed elevated IgE, CD4 lymphopenia and impaired T cell proliferation in most patients. Genetic analysis showed the presence, of a unique homozygous mutation (p.Glu340del) in PGM3 gene leading to reduced PGM3 abundance. Segregating analysis using fifteen polymorphic markers overlapping PGM3 gene showed that all patients inherited a common homozygous haplotype encompassing 10-Mb on chromosome 6. The founder mutational event was estimated to have occurred approximately 100 years ago. To date, (p.Glu340del) mutation represents the first founder mutation identified in PGM3 gene. These findings will facilitate the development of preventive approaches through genetic counselling and prenatal diagnosis in the affected families.
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http://dx.doi.org/10.1016/j.molimm.2017.06.248DOI Listing
October 2017

A genetic overview of Atlantic coastal populations from Europe and North-West Africa based on a 17 X-STR panel.

Forensic Sci Int Genet 2017 03 30;27:167-171. Epub 2016 Nov 30.

BIOMICs Research Group, Lascaray Research Center, University of the Basque Country UPV/EHU. Avda. Miguel de Unamuno, 3, 01006 Vitoria-Gasteiz, Spain. Electronic address:

The forensic use of X-STRs requires the creation of allele and haplotype frequency databases in the populations where they are going to be used. Recently, an updated Spanish allele and haplotype frequency database for the new 17 X-STR panel has been created, being the only database available up to now for this new multiplex. In order to broaden the forensic applicability of the 17 X-STR panel, 513 individuals from four different populations located on the Atlantic Coast of Europe and North-West Africa have been studied, i.e. Brittany (France), Ireland, northern Portugal, and Casablanca (Morocco). Allele and haplotype frequency databases, as well as parameters of forensic interest for these populations are presented. The obtained results showed that the 17 X-STR panel constitutes a highly discriminative tool for forensic identification and kinship testing in the studied populations. Furthermore, we aimed to study if these populations located on the Atlantic coast actually share alike allele and haplotype frequency distributions since they have experienced genetic exchanges throughout history. This would allow creating larger forensic databases that include several genetically similar populations for its use in forensic casework. For this purpose, pairwise F genetic distances between the analyzed populations and others from the Atlantic Coast previously studied with the 17 X-STR panel or the ten coincident markers included in the decaplex of the GHEP-ISFG were estimated. Our results suggest that certain nearby populations located on the European Atlantic coast could have underwent episodes of genetic interchange as they have not shown statistically significant differentiation between them. However, the population of Casablanca showed significant differentiation with the majority of the European populations. Likewise, the autochthonous Basque Country and Brittany populations have shown distinctive allele frequency distributions between them. Therefore, these findings seem to support that the use of independent allele and haplotype frequency databases for each population instead of a global database would be more appropriate for forensic purposes.
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http://dx.doi.org/10.1016/j.fsigen.2016.11.011DOI Listing
March 2017

A Founder Effect of c.257 + 2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients.

J Clin Immunol 2016 08 25;36(6):547-54. Epub 2016 May 25.

Laboratory of Transmission, Control and Immunobiology of Infections (LTCII), LR11IPT02, Institut Pasteur de Tunis, Pasteur, 1002, Tunis-Belvedere, Tunisia.

Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families.
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http://dx.doi.org/10.1007/s10875-016-0299-9DOI Listing
August 2016

New clues to the evolutionary history of the main European paternal lineage M269: dissection of the Y-SNP S116 in Atlantic Europe and Iberia.

Eur J Hum Genet 2016 Mar 17;24(3):437-41. Epub 2015 Jun 17.

BIOMICs Research Group, Lascaray Research Center, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.

The dissection of S116 in more than 1500 individuals from Atlantic Europe and the Iberian Peninsula has provided important clues about the controversial evolutionary history of M269. First, the results do not point to an origin of M269 in the Franco-Cantabrian refuge, owing to the lack of sublineage diversity within M269, which supports the new theories proposing its origin in Eastern Europe. Second, S116 shows frequency peaks and spatial distribution that differ from those previously proposed, indicating an origin farther west, and it also shows a high frequency in the Atlantic coastline. Third, an outstanding frequency of the DF27 sublineage has been found in Iberia, with a restricted distribution pattern inside this peninsula and a frequency maximum in the area of the Franco-Cantabrian refuge. This entire panorama indicates an old arrival of M269 into Western Europe, because it has generated at least two episodes of expansion in the Franco-Cantabrian area. This study demonstrates the importance of continuing the dissection of the M269 lineage in different European populations because the discovery and study of new sublineages can adjust or even completely revise the theories about European peopling, as has been the case for the place of origin of M269.
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http://dx.doi.org/10.1038/ejhg.2015.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755366PMC
March 2016

Evidence for the high importance of co-morbid factors in HFE C282Y/H63D patients cared by phlebotomies: results from an observational prospective study.

PLoS One 2013 5;8(12):e81128. Epub 2013 Dec 5.

Inserm, UMR 1078, Brest, France ; Université de Bretagne Occidentale, Brest, France ; Etablissement Français du Sang - Bretagne, Brest, France ; CHRU Brest, Hôpital Morvan, Laboratoire d'hygiène et de santé publique, Brest, France.

Despite type I haemochromatosis (HC) is mainly associated with the HFE C282Y/C282Y genotype, a second genotype -C282Y/H63D- has mostly been described in other patients. Its association with HC, apart from any associated co-morbid factors, remains unclear and complex to interpret for physicians. This study assesses the weight of this genotype and the role of co-morbid factors in the occurrence of iron overload. This prospective study included the C282Y/C282Y (n = 172) and C282Y/H63D (n = 58) patients enrolled in a phlebotomy program between 2004 and 2007 in a blood centre of western Brittany (Brest, France), where HC is frequent. We compared prevalence of these two genotypes, as well as patients' profile regarding degree of iron overload and prevalence of co-morbid factors. First, we confirmed the obvious deficit of C282Y/H63D compound heterozygotes among patients cared by phlebotomies. This genotype was 3.0 times less frequent than the C282Y/C282Y genotype among those patients (18.9% vs. 56.0%) whereas it was 4.9 times more frequent in the general population (4.3% vs. 0.9%; p<0.0001). Despite a similar level of hyperferritinaemia, the C282Y/H63D patients who came to medical attention had a milder plasma iron overload, reflected by a lower transferrin saturation median (52.0% vs. 84.0%; p<0.0001). They also exhibited more frequently co-morbid factors, as heavy drinking (26.0% vs. 13.9%; p = 0.0454), overweight (66.7% vs. 39.4%; p = 0.0005) or both (21.3% vs. 2.6%; p<0.0001). Ultimately, they required a lower amount of iron removed to reach depletion (2.1 vs. 3.4 g; p<0.0001), clearly reflecting their lower tissue iron. This study confirms that H63D is a discrete genetic susceptibility factor whose expression is most visible in association with other co-factors. It highlights the importance of searching for co-morbidities in these diagnostic situations and of providing lifestyle and dietary advice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081128PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855242PMC
March 2015

A missense mutation in the alpha-actinin 1 gene (ACTN1) is the cause of autosomal dominant macrothrombocytopenia in a large French family.

PLoS One 2013 17;8(9):e74728. Epub 2013 Sep 17.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France ; Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France ; Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France.

Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22) with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln) in the alpha-actinin 1 gene (ACTN1) that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074728PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775762PMC
June 2014