Publications by authors named "Francois Cartault"

27 Publications

  • Page 1 of 1

How history and geography may explain the distribution in the Comorian archipelago of a novel mutation in DNA repair-deficient xeroderma pigmentosum patients.

Genet Mol Biol 2019 13;43(1 suppl 1):e20190046. Epub 2019 Dec 13.

Department of Medical Genetics, INSERM U781 CHU Félix Guyon, La Réunion, France.

Xeroderma pigmentosum (XP) is a rare, genetic, autosomal nucleotide excision repair-deficient disease characterized by sun-sensitivity and early appearance of skin and ocular tumors. Thirty-two black-skinned XP from Comoros, located in the Indian Ocean, were counted, rendering this area the highest world prevalence of XP. These patients exhibited a new homozygous XPC mutation at the 3'-end of the intron12 (IVS 12-1G>C) leading to the absence of XPC protein. This mutation, characteristic of the consanguineous Comorian families, is associated with a founder effect with an estimated age of about 800 years. Analysis of mt-DNA and Y-chromosome identified the haplogroups of patients, who are derived from the Bantu people. Although the four Comorian islands were populated by the same individuals during the 7-10th centuries, XP was found now only in the Comorian island of Anjouan. To avoid the slavery process caused by the arrival of the Arabs around the 11-13th centuries, inhabitants of Anjouan, including XP-heterozygotes, hid inland of the island protected by volcanoes. This population lived with an endogamic style, without connection with the other islands. XP patients still live in the same isolated villages as their ancestries. Local history and geography may, thus, explain the high incidence of XP located exclusively in one island.
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http://dx.doi.org/10.1590/1678-4685-GMB-2019-0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198018PMC
December 2019

High prevalence of congenital deafness on Reunion Island is due to a founder variant of LHFPL5.

Clin Genet 2019 01 4;95(1):177-181. Epub 2018 Nov 4.

INSERM UMR_S1163 IHU Imagine - Institut des Maladies Génétiques - Université Paris Descartes, Paris, France.

Reunion Island is a French oversea department in the Indian Ocean with 1.6/1000, an estimated prevalence of deafness that is almost double as compared to the mainland France. Twelve children having isolated bilateral prelingual profound deafness along with motor delay attributed to vestibular areflexia were enrolled. Their mean walking age was 19 months. Electroretinography and temporal bone CT-scans were normal in all cases. A novel homozygous frameshift lipoma HMGIC fusion partner-like 5 (LHFPL5) variant c.185delT p.(Phe62Serfs*23) was identified using whole-exome sequencing. It was found in seven families. Four patients from two different families from both Reunion Island and mainland France, were compound heterozygous: c.185delT p.(Phe62Serfs*23) and c.472C > T p.(Arg158Trp). The phenotype observed in our patients completely mimics the hurry-scurry (hscy) murine Tmhs knock-out model. The recurrent occurrence of same LHFPL5 variant in Reunion Island is attributed to common ancestor couple born in 1693.
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http://dx.doi.org/10.1111/cge.13460DOI Listing
January 2019

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype.

Eur J Hum Genet 2016 07 2;24(7):992-1000. Epub 2015 Dec 2.

Département de Génétique et INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker-Enfants malades, AP-HP, Paris, France.

Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.
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http://dx.doi.org/10.1038/ejhg.2015.250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070901PMC
July 2016

A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH.

Eur J Hum Genet 2016 06 28;24(6):844-51. Epub 2015 Oct 28.

Service de Génétique, CHU de Poitiers, Poitiers, France.

Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ∼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.
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http://dx.doi.org/10.1038/ejhg.2015.219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867458PMC
June 2016

Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Réunion Island.

Am J Hum Genet 2015 May 23;96(5):826-31. Epub 2015 Apr 23.

Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany. Electronic address:

Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to tRNA and is critical for protein biosynthesis. We identified biallelic missense mutations in MARS in a specific form of pediatric pulmonary alveolar proteinosis (PAP), a severe lung disorder that is prevalent on the island of Réunion and the molecular basis of which is unresolved. Mutations were found in 26 individuals from Réunion and nearby islands and in two families from other countries. Functional consequences of the mutated alleles were assessed by growth of wild-type and mutant strains and methionine-incorporation assays in yeast. Enzyme activity was attenuated in a liquid medium without methionine but could be restored by methionine supplementation. In summary, identification of a founder mutation in MARS led to the molecular definition of a specific type of PAP and will enable carrier screening in the affected community and possibly open new treatment opportunities.
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http://dx.doi.org/10.1016/j.ajhg.2015.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570277PMC
May 2015

Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium.

Hum Mol Genet 2015 Jul 23;24(14):4126-37. Epub 2015 Apr 23.

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain, CIBER de Enfermedades Raras (CIBERER), Madrid, Spain,

Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35(-/-) cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1(-/-), indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35(-/-) fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc(-/-) and Evc2(-/-) mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia.
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http://dx.doi.org/10.1093/hmg/ddv152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560068PMC
July 2015

Antenatal presentation of hereditary lymphedema type I.

Eur J Med Genet 2015 Jun-Jul;58(6-7):329-31. Epub 2015 Apr 18.

Service Réanimation Néonatale, Service Gynécologie-Obstétrique, Pole Femme Mère Enfant, CH Felix Guyon, CHU La Réunion, France. Electronic address:

Fetal edema can present as limited subcutaneous edema, fluid accumulation in body cavities or hydrops fetalis. Hydrops fetalis is the end stage of a variety of fetal/maternal disorders and nonimmune etiology represents more than 3/4 of cases. Lymphatic dysplasia may account for a subset of patients with nonimmune and "idiopathic" hydrops fetalis, fetal chylous ascites or chylothorax. We present two unrelated patients with antenatal features of hereditary lymphedema syndrome, in whom Milroy disease was diagnosed after birth. At least, 20 genes have been identified to cause primary lymphedema, with sometimes antenatal features. Hereditary lymphedema syndrome should be considered in cases of nonimmune hydrops fetalis/fetal edema after ruling out the more common etiologies.
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http://dx.doi.org/10.1016/j.ejmg.2015.03.006DOI Listing
March 2016

The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes.

J Cyst Fibros 2015 May 28;14(3):305-9. Epub 2014 Nov 28.

AP-HP, Laboratoire de Biochimie et Génétique Moléculaire, GH Cochin-Broca-Hôtel Dieu, Paris, France; Université Paris Descartes Paris, Institut Cochin, INSERM U1016, Paris, France. Electronic address:

Examination of genotype-phenotype correlations along with functional evaluation of CFTR mutations may not be straightforward. The c.1865G>A, p.Gly622Asp (G622D), located at the NBD1 C terminus of the CFTR protein, was initially reported in patients with male infertility. However, the substitution of Gly622 by an aspartic acid in vitro would perturb the local structure or even affect the CFTR folding itself. In order to determine whether p.Gly622Asp affects the risk of developing a CFTR-Related disorder (CFTR-RD) or cystic fibrosis (CF), we analyzed the phenotype of subjects bearing the p.Gly622Asp mutation. We report molecular and clinical analyses in eleven unrelated patients with CF or CFTR-RD with compound heterozygosity for the p.Gly622Asp mutation. On the basis of the clinical features presented by the eleven patients, we postulate that the p.Gly622Asp might be associated with a wide spectrum of phenotypes including classical cystic fibrosis.
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http://dx.doi.org/10.1016/j.jcf.2014.11.001DOI Listing
May 2015

Toward male individualization with rapidly mutating y-chromosomal short tandem repeats.

Hum Mutat 2014 Aug 14;35(8):1021-32. Epub 2014 Jul 14.

Department of Forensic Molecular Biology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands; Office of the Chief Forensic Scientist, Victoria Police Forensic Services Department, Macleod, Victoria, Australia.

Relevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, >99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836-0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father-son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RM Y-STRs in identifying and separating unrelated and related males and provides a reference database.
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http://dx.doi.org/10.1002/humu.22599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145662PMC
August 2014

Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome.

Eur J Hum Genet 2015 Jan 23;23(1):49-53. Epub 2014 Apr 23.

Département de génétique, INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France.

First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C>T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers-Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations.
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http://dx.doi.org/10.1038/ejhg.2014.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266744PMC
January 2015

Comprehensive functional annotation of 18 missense mutations found in suspected hemochromatosis type 4 patients.

Hum Mol Genet 2014 Sep 8;23(17):4479-90. Epub 2014 Apr 8.

Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Inserm U1078, Université de Brest, SFR SnInBioS, CHRU de Brest, Etablissement Français du Sang - Bretagne, Brest, France CHRU de Brest, Inserm CIC0502, Brest, France

Hemochromatosis type 4 is a rare form of primary iron overload transmitted as an autosomal dominant trait caused by mutations in the gene encoding the iron transport protein ferroportin 1 (SLC40A1). SLC40A1 mutations fall into two functional categories (loss- versus gain-of-function) underlying two distinct clinical entities (hemochromatosis type 4A versus type 4B). However, the vast majority of SLC40A1 mutations are rare missense variations, with only a few showing strong evidence of causality. The present study reports the results of an integrated approach collecting genetic and phenotypic data from 44 suspected hemochromatosis type 4 patients, with comprehensive structural and functional annotations. Causality was demonstrated for 10 missense variants, showing a clear dichotomy between the two hemochromatosis type 4 subtypes. Two subgroups of loss-of-function mutations were distinguished: one impairing cell-surface expression and one altering only iron egress. Additionally, a new gain-of-function mutation was identified, and the degradation of ferroportin on hepcidin binding was shown to probably depend on the integrity of a large extracellular loop outside of the hepcidin-binding domain. Eight further missense variations, on the other hand, were shown to have no discernible effects at either protein or RNA level; these were found in apparently isolated patients and were associated with a less severe phenotype. The present findings illustrate the importance of combining in silico and biochemical approaches to fully distinguish pathogenic SLC40A1 mutations from benign variants. This has profound implications for patient management.
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http://dx.doi.org/10.1093/hmg/ddu160DOI Listing
September 2014

Creatine and guanidinoacetate reference values in a French population.

Mol Genet Metab 2013 Nov 16;110(3):263-7. Epub 2013 Sep 16.

Département de Biochimie et Biologie Moléculaire, Laboratoire d'Hormonologie, Metabolisme-Nutrition & Oncologie (HMNO) - Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand, CHRU Lille, 59037 Lille, France.

Creatine and guanidinoacetate are biomarkers of creatine metabolism. Their assays in body fluids may be used for detecting patients with primary creatine deficiency disorders (PCDD), a class of inherited diseases. Their laboratory values in blood and urine may vary with age, requiring that reference normal values are given within the age range. Despite the long known role of creatine for muscle physiology, muscle signs are not necessarily the major complaint expressed by PCDD patients. These disorders drastically affect brain function inducing, in patients, intellectual disability, autistic behavior and other neurological signs (delays in speech and language, epilepsy, ataxia, dystonia and choreoathetosis), being a common feature the drop in brain creatine content. For this reason, screening of PCDD patients has been repeatedly carried out in populations with neurological signs. This report is aimed at providing reference laboratory values and related age ranges found for a large scale population of patients with neurological signs (more than 6 thousand patients) previously serving as a background population for screening French patients with PCDD. These reference laboratory values and age ranges compare rather favorably with literature values for healthy populations. Some differences are also observed, and female participants are discriminated from male participants as regards to urine but not blood values including creatine on creatinine ratio and guanidinoacetate on creatinine ratio values. Such gender differences were previously observed in healthy populations; they might be explained by literature differential effects of testosterone and estrogen in adolescents and adults, and by estrogen effects in prepubertal age on SLC6A8 function. Finally, though they were acquired on a population with neurological signs, the present data might reasonably serve as reference laboratory values in any future medical study exploring abnormalities of creatine metabolism and transport.
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http://dx.doi.org/10.1016/j.ymgme.2013.09.005DOI Listing
November 2013

Genetic variations creating microRNA target sites in the FXN 3'-UTR affect frataxin expression in Friedreich ataxia.

PLoS One 2013 30;8(1):e54791. Epub 2013 Jan 30.

INSERM U781 Hôpital Necker-Enfants Malades, Université Paris Descartes-Sorbonne Cité, Institut Imagine, Paris, France.

Friedreich's ataxia (FRDA) is a severe neurodegenerative disease caused by GAA repeat expansion within the first intron of the frataxin gene. It has been suggested that the repeat is responsible for the disease severity due to impaired transcription thereby reducing expression of the protein. However, genotype-phenotype correlation is imperfect, and the influence of other gene regions of the frataxin gene is unknown. We hypothesized that FRDA patients may harbor specific regulatory variants in the 3'-UTR. We sequenced the 3'-UTR region of the frataxin gene in a cohort of 57 FRDA individuals and 58 controls. Seven single nucleotide polymorphisms (SNPs) out of 19 were polymorphic in our case-control sample. These SNPs defined several haplotypes with one reaching 89% of homozygosity in patients versus 24% in controls. In another cohort of 47 FRDA Reunionese patients, 94% patients were found to be homozygous for this haplotype. We found that this FRDA 3'-UTR conferred a 1.2-fold decrease in the expression of a reporter gene versus the alternative haplotype configuration. We established that differential targeting by miRNA could account for this functional variability. We specifically demonstrated the involvement of miR-124 (i.e hsa-mir-124-3p) in the down-regulation of FRDA-3'-UTR. Our results suggest for the first time that post-transcriptional regulation of frataxin occurs through the 3'-UTR and involves miRNA targeting. We propose that the involvement of miRNAs in a FRDA-specific regulation of frataxin may provide a rationale to increase residual levels of frataxin through miRNA-inhibitory molecules.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3559822PMC
August 2013

Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.

Orphanet J Rare Dis 2012 Dec 13;7:96. Epub 2012 Dec 13.

Hospices Civils de Lyon, Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Groupement Hospitalier, Bron, France.

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.
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http://dx.doi.org/10.1186/1750-1172-7-96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552865PMC
December 2012

Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy.

Proc Natl Acad Sci U S A 2012 Mar 12;109(13):4980-5. Epub 2012 Mar 12.

Département de Génétique and Groupe de Recherche Immunopathologies et Maladies Infectieuses, Université de La Réunion, Centre Hospitalier Régional de La Réunion, 97405 Saint-Denis, La Réunion, France.

The human genome is densely populated with transposons and transposon-like repetitive elements. Although the impact of these transposons and elements on human genome evolution is recognized, the significance of subtle variations in their sequence remains mostly unexplored. Here we report homozygosity mapping of an infantile neurodegenerative disease locus in a genetic isolate. Complete DNA sequencing of the 400-kb linkage locus revealed a point mutation in a primate-specific retrotransposon that was transcribed as part of a unique noncoding RNA, which was expressed in the brain. In vitro knockdown of this RNA increased neuronal apoptosis, consistent with the inappropriate dosage of this RNA in vivo and with the phenotype. Moreover, structural analysis of the sequence revealed a small RNA-like hairpin that was consistent with the putative gain of a functional site when mutated. We show here that a mutation in a unique transposable element-containing RNA is associated with lethal encephalopathy, and we suggest that RNAs that harbor evolutionarily recent repetitive elements may play important roles in human brain development.
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http://dx.doi.org/10.1073/pnas.1111596109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323976PMC
March 2012

Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis.

Hum Mutat 2012 Feb 22;33(2):316-26. Epub 2011 Dec 22.

Inserm U983, Faculté de Médecine Paris Descartes, Université Paris Descartes, Paris, France.

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.
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http://dx.doi.org/10.1002/humu.21661DOI Listing
February 2012

A new XPC gene splicing mutation has lead to the highest worldwide prevalence of xeroderma pigmentosum in black Mahori patients.

DNA Repair (Amst) 2011 Jun 8;10(6):577-85. Epub 2011 Apr 8.

Department of Medical Genetics, INSERM U781 CHR Félix Guyon, La Réunion, and CHU Necker, Paris, France.

Xeroderma pigmentosum (XP) is a rare, recessive disease characterized by sunlight hypersensitivity and early appearance of cutaneous and ocular malignancies. We report the first description of a very high incidence (around 1/5000) of black XP patients in the Mayotte population in the Indian Ocean. Among a cohort of 32 XP, we describe the clinical and genetic features of 18 living Comorian black XP patients. We discuss the remarkable clinical differences between white and black XPs. Skin and ocular abnormalities are remarkably precocious and severe XP phenotypes are recognized by the early ocular injuries. In our cohort, the first skin cancer appeared at a median age of 4.5 years with no neurological symptoms. Post-UV DNA repair, cell survival and genetic complementation assigned these patients to the XP group C. All patients exhibited a new G→C homozygous substitution at 3'-end of XPC intron 12 (IVS 12-1G>C) leading to the abolition of an acceptor splicing site and the absence of the XPC protein. We found 3 different mRNA isoforms: one with retention of intron 12, one showing exon 13 skipping, and a third with a 44bp deletion in exon 13. These 3 isoforms were differently expressed in XP-C cells compared to normal cells. This new mutation found in the Comorian islands, where consanguinity is frequent, represents a founder effect, with an estimated age of about 770 years. Due to the African origin of the black XPs from Mayotte, it would be valuable to search for this mutation in African XPs whenever possible.
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http://dx.doi.org/10.1016/j.dnarep.2011.03.005DOI Listing
June 2011

Complete mitochondrial sequences for haplogroups M23 and M46: insights into the Asian ancestry of the Malagasy population.

Hum Biol 2009 Aug;81(4):495-500

Aix-Marseille Université, CNRS, IRD, UMR 6116-IMEP, Equipe Evolution Génome Environnement, Centre Saint-Charles, Case 36, 3 place Victor Hugo, 13331 Marseille Cedex 3, France.

Through the sequencing of the complete mitochondrial genome of three individuals of Malagasy ancestry, we completed the characterization of the island southeastern Asian specific M46 haplogroup. We assumed that the association of the np 3588 and np 16278 polymorphisms were M46 specific. In addition, we characterized a novel basal M subhaplogroup: M23. This clade can be defined by one coding region transition at np 10295 and one control region transition at np 16263. Our data suggest the arrival of South Asian migrants before the start of the 15th century and highlights the fact that future studies dealing with the settlement of Madagascar should consider at least three potential source populations (Africa, Indonesia, and India).
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http://dx.doi.org/10.3378/027.081.0407DOI Listing
August 2009

Inter- and extra-Indian admixture and genetic diversity in reunion island revealed by analysis of mitochondrial DNA.

Ann Hum Genet 2009 May 15;73(Pt 3):314-34. Epub 2009 Apr 15.

Université Bordeaux 1, CNRS, UMR 5199 - PACEA, Laboratoire d'Anthropologie des Populations du Passé, Talence, France.

Reunion Island is a French territory located in the western Indian Ocean. The genetic pattern of the Reunionese population has been shaped by contributions from highly contrasting regions of the world. Over the last 350 years, several migration waves and cultural and socio-economic factors have led to the emergence of six main ethnic groups in Reunion. India is one of the principal regions that contributed to the setting up of the Reunionese population. Diversity, demographic and admixture analyses were performed on mtDNA variation of the Reunionese of Indian ancestry, including the Malbar and Zarab ethnic groups, in order to question their history. Using a phylogeographical approach, we generated and analysed quantitative data on the contribution of the Indian parental populations. Furthermore, we showed that the settlement of Reunion Island by Indians did not involve a founder effect, except in the very beginning of the Reunionese settlement (at the end of the 17(th) century). The accuracy of our results was optimised by a re-evaluation of the classification of the Southern Asian mtDNA haplogroups. Finally, by comparing our results to a previous study dealing with the Reunionese population, we highlighted how ethno-historical data are critical for reconstructing the complex history of multiethnic populations.
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http://dx.doi.org/10.1111/j.1469-1809.2009.00519.xDOI Listing
May 2009

Genetic data analysis of 10 Y-STR loci in two ethnic groups of Asian ancestry (Gujarat and Guangdong-Fujian provinces) from Reunion Island (Indian Ocean).

Leg Med (Tokyo) 2009 Mar 2;11(2):104-6. Epub 2008 Dec 2.

Université Bordeaux 1, CNRS, UMR 5199 - PACEA, Laboratoire d'Anthropologie des Populations du Passé, Avenue des Facultés, Talence Cedex, France.

One hundred and twenty-three unrelated individuals belonging to two ethnic groups (Shinwa and Zarab) of Asian ancestry from Reunion Island (Indian Ocean) were analyzed for 10 Y-STR loci. Haplotype diversity and frequencies were determined for loci DYS19, DYS385a/b, DYS388, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393 and YCAIIa/b. The two ethnic groups do not share haplotypes, and a total of 98 distinct haplotypes were identified. Unique haplotypes were obtained for 49 Shinwa and 33 Zarab. Moreover, 52 of the identified distinct haplotypes revealed to have not been described to date.
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http://dx.doi.org/10.1016/j.legalmed.2008.09.005DOI Listing
March 2009

A frequent large rearrangement in the CFTR gene in cystic fibrosis patients from Reunion Island.

Genet Test 2006 ;10(3):208-14

Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, Paris, France.

Reunion Island is a French province, 800 km east of Madagascar and 200 km west of Mauritius. On Reunion Island, the birth prevalence of cystic fibrosis (CF) is particularly high in the population of European origin, approximately 1:1000. In a previous study, we demonstrated that the screening of the 27 exons of the CF transmembrane conductance regulator (CFTR) gene by denaturing high-pressure liquid chromatography (DHPLC) in 114 CF families allowed the detection of about 93% of the molecular defects present on Reunion Island. Unidentified CF mutations may lie in introns or in regulatory regions that are not routinely investigated, or may correspond to gene rearrangements such as large, heterozygous deletions that escape detection using current PCR-based techniques. Using a combination of different methods (such as multiplex ligation-dependent probe amplification), 6 of the 13 unidentified CF alleles (46%) were found to harbor a deletion of 5288 bp, spanning from exon 17a to 18. Identification and examination of the breakpoint sequences showed that this deletion is different from the 3120+1kbdel8.6Kb previously found in the Palestinian Arabs. The chromosomes bearing IVS16+3316_IVS18+644del5288 did not have a common extragenic haplotype. Clinical evaluation of homozygotes (2 unrelated patients) and compound heterozygotes indicated that this deletion represents a severe mutation associated with positive sweat chloride test, pancreatic insufficiency, and early age at diagnosis.
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http://dx.doi.org/10.1089/gte.2006.10.208DOI Listing
June 2007

mtDNA polymorphisms in five French groups: importance of regional sampling.

Eur J Hum Genet 2004 Apr;12(4):293-300

Laboratoire d'Anthropologie des Populations du Passé, UMR 5809 CNRS, Avenue des Facultés, Université Bordeaux 1, 33405 Talence cedex, France.

According to classical markers, France has been reported to be regionally heterogeneous. Here, we propose to test the homogeneity of the French mitochondrial gene pool by analysing D-Loop and coding regions polymorphisms in 210 individuals stemming from five regions. The data set obtained was also used to test the ability of mitochondrial DNA to detect well historically established admixtures (admixtures between British/Irish people and native Breton people in our case). For these purposes, the sampling procedure was subject to special care, concerning the individuals' geographical origin and maternal pedigree. The mtDNA analysis revealed some regional specificities in haplogroup distribution, which is discussed in terms of successive settlements of France. Statistical analyses were conducted to investigate mtDNA diversity and structure within and between British, Irish and French groups. They tended to show affinities between Morbihan region and Britain plus Ireland. Furthermore, genetic evidences were in line with the fact that Morbihan region results from an admixture event, agreeing with historical evidences of successive migrations from Britain and Ireland into Brittany. These results also tended to outline the fact that two geographically very adjacent samples (Morbihan and Finistère), sharing a cultural and linguistic area, can present a distinct genetic pattern. Although mtDNA analyses were able to identify a historically reported admixture event, we point out here the high influence of the sampling procedure and representativeness over the migrations hypothesis. We also underline the importance of regional sampling for studies on the spread and/or origin of specific European haplogroups (here U5a1a and U8).
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http://dx.doi.org/10.1038/sj.ejhg.5201145DOI Listing
April 2004

Evolution of the proto-MHC ancestral region: more evidence for the plesiomorphic organisation of human chromosome 9q34 region.

Immunogenetics 2003 Oct 3;55(7):429-36. Epub 2003 Oct 3.

EA Biodiversité 2202, Université de Provence, Place V. Hugo, 13331 Marseille cedex 3, France.

The present day structure of the vertebrate major histocompatibility complex (MHC) and its three paralogous regions has always been a focus of interest. In a recent study, nine human anchor genes located in the MHC region were cloned from a Branchiostoma floridae (amphioxus) cosmid library. The identification and analysis of 31 surrounding genes led to the most probable model of two rounds of en bloc duplication giving rise to these regions. These events were estimated to have occurred after the cephalochordata-craniata divergence [approximately 766 million years ago (Mya)] and before the Gnathostomata radiation (approximately 528 Mya). Furthermore, it was also shown that after this large-scale duplication one of these regions, corresponding to the human 9q33-q34, had retained an ancestral organisation. In the present study, four new cosmids in the amphioxus proto-MHC region were identified by the chromosomal walking technique. These cosmids were sequenced, and their structural annotation was performed, leading to the prediction of eleven genes. Their phylogenetic relationships among species corroborate the results obtained previously and provide more evidence for the plesiomorphic state of the human chromosome 9q33-34 MHC paralogous region.
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http://dx.doi.org/10.1007/s00251-003-0601-xDOI Listing
October 2003

FOunder effect in patients with Unverricht-Lundborg disease on reunion island.

Epilepsia 2003 Oct;44(10):1357-60

Division de Neuropsychiatrie, Hôpitaux Universitaires de Genève, Switzerland.

Purpose: Unverricht-Lundborg disease (ULD) is the most frequent form of progressive myoclonus epilepsy. ULD is caused mostly by a homozygous expansion of a dodecamer repeat in the cystatin B gene (CSTB) promoter. We present here a clinical and molecular study of 14 ULD patients originating from Reunion Island, a French island in the Indian Ocean.

Methods: These ULD patients were clinically evaluated, and the diagnosis of ULD was confirmed molecularly. We analyzed 12 microsatellites flanking CSTB and estimated the date of introduction of the ULD mutation on Reunion Island.

Results: These cases were clinically very similar, with the typical myoclonus syndrome associated with generalized tonic-clonic seizures, cerebellar involvement and, in some cases, mild mental deterioration. The mean age at onset was 9.6 years (range, 5-14 years), and the mean disease duration was 27 years (range, 5-47 years). The 14 patients harbored the typical ULD mutation, with variable degrees of expansion (mean of 56.3 repeats; range, 49-63). A founder effect was detected, with all but one of the Reunion ULD chromosomes displaying expansions belonging to the same haplotype, 1-1-1-2-6-4-3. We estimated the date of arrival of the most recent common ancestor (MRCA) of these patients on Reunion Island to the middle of the eighteenth century.

Conclusions: These Reunion ULD patients displayed a homogeneous phenotype. Our molecular results are compatible with the instability of the repeat expansion and revealed a founder effect in Reunion ULD patients and the existence of a MRCA about 12 generations ago.
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http://dx.doi.org/10.1046/j.1528-1157.2003.03703.xDOI Listing
October 2003

Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB.

Am J Med Genet A 2003 Jun;119A(3):324-39

Service de Biochimie et Biologie Moléculaire, Hôpital d'Enfants Armand-Trousseau (AP-HP), Paris, France.

We have analyzed surfactant protein B (SP-B) and its encoding gene (SFTPB, MIM 178640) in 40 unrelated pediatric patients with unexplained respiratory distress (URD). There was high consanguinity (eight kindreds) and an underlying autosomal recessive trait could be inferred in most cases, with overall high sex ratio (32/17) suggesting proband's gender to impact on penetrance. The clinical/biological presentations fitted into three major nosologic frameworks. I: SP-B deficiency (nine probands), complete or incomplete, with homozygous/compoundly heterozygous mutations identified (six probands), including one from the population isolate of Réunion Island (496delG). In addition, there was a consanguineous kindred in which incomplete deficiency was unambiguously unlinked to SFTPB. II: pulmonary alveolar proteinosis (PAP, 19 probands), with typical storage of PAS-positive material within the alveoli with foamy macrophages and variable interstitial reaction, which was diagnosed in most patients from Réunion Island. In contrast to previously published findings, mutation and/or segregation analyses excluded SFTPB as a disease locus, although slight metabolic derangement related to SP-B and/or mild SFTPB changes could somehow contribute to disease. III: URD without evidence for SP-B deficiency or PAP (12 probands), equally unlinked to SFTPB, although a single patient had a possibly causal, maternally-derived, heterozygous genetic change (G4521A). The population frequency of five known and four novel SNPs was studied, providing as many potential markers for pulmonary disease related to SFTPB. Overall, URD was found to be heterogeneous, both phenotypically and genetically, even in population isolates where a founder effect might have been expected. When disease loci are identified, patient genotyping will be crucial as a diagnostic aid, for devising proper treatment, and as a basis for genetic counseling.
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http://dx.doi.org/10.1002/ajmg.a.20058DOI Listing
June 2003
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