James Lespinasse
Necker-Enfants Malades Hospital
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Publication
Featured researches published by James Lespinasse.
American Journal of Human Genetics | 2002
Frédéric Laumonnier; Nathalie Ronce; B.C.J. Hamel; Paul Q. Thomas; James Lespinasse; Martine Raynaud; Christine Paringaux; Hans van Bokhoven; Vera M. Kalscheuer; Jean-Pierre Fryns; Jamel Chelly; Claude Moraine; Sylvain Briault
Physical mapping of the breakpoints of a pericentric inversion of the X chromosome (46,X,inv[X][p21q27]) in a female patient with mild mental retardation revealed localization of the Xp breakpoint in the IL1RAPL gene at Xp21.3 and the Xq breakpoint near the SOX3 gene (SRY [sex determining region Y]-box 3) (GenBank accession number NM_005634) at Xq26.3. Because carrier females with microdeletion in the IL1RAPL gene do not present any abnormal phenotype, we focused on the Xq breakpoint. However, we were unable to confirm the involvement of SOX3 in the mental retardation in this female patient. To validate SOX3 as an X-linked mental retardation (XLMR) gene, we performed mutation analyses in families with XLMR whose causative gene mapped to Xq26-q27. We show here that the SOX3 gene is involved in a large family in which affected individuals have mental retardation and growth hormone deficiency. The mutation results in an in-frame duplication of 33 bp encoding for 11 alanines in a polyalanine tract of the SOX3 gene. The expression pattern during neural and pituitary development suggests that dysfunction of the SOX3 protein caused by the polyalanine expansion might disturb transcription pathways and the regulation of genes involved in cellular processes and functions required for cognitive and pituitary development.
European Journal of Human Genetics | 2009
Robert Lyle; Frédérique Béna; Sarantis Gagos; Corinne Gehrig; Gipsy Lopez; Albert Schinzel; James Lespinasse; Armand Bottani; Sophie Dahoun; Laurence Taine; Martine Doco-Fenzy; Pascale Cornillet-Lefebvre; Anna Pelet; Stanislas Lyonnet; Annick Toutain; Laurence Colleaux; Jürgen Horst; Ingo Kennerknecht; Nobuaki Wakamatsu; Maria Descartes; Judy Franklin; Lina Florentin-Arar; Sophia Kitsiou; Emilie Aı̈t Yahya-Graison; Maher Costantine; Pierre-Marie Sinet; Jean Maurice Delabar
Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype–phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within ∼85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.
The Cleft Palate-Craniofacial Journal | 2005
Linda P. Jakobsen; Mary A. Knudsen; James Lespinasse; Carmen Ayuso; Carmen Ramos; Jean-Pierre Fryns; Merete Bugge; Niels Tommerup
Objective The Pierre Robin Sequence (PRS) is subgroup of the cleft palate population. As with the etiology of cleft lip or palate, the etiology of PRS is generally unknown. Some factors are suggestive of a genetic basis for PRS. The purpose of this study was to compare genetic information on PRS available in the literature and in a cytogenetic database to facilitate focused genetic studies of PRS. Design After searching Medline for “pierre robin and genetics,” the Mendelian Cytogenetics Network database for “robin” and “pierre robin,” and two reviews from the Human Cytogenetics Database for “cleft palate” and “micrognathia,” a comparison of the data and a search in Online Mendelian Inheritance in Man (OMIM) Gene Map was performed to identify relevant candidate genes. Results The findings revealed consistency to a certain degree to loci 2q24.1-33.3, 4q32-qter, 11q21-23.1, and 17q21-24.3. A search in the OMIM Gene Map provided many candidate genes for PRS in these regions. The GAD67 on 2q31, the PVRL1 on 11q23-q24, and the SOX9 gene on 17q24.3-q25.1 are suggested to be of particular importance. Conclusion Candidate loci and a few potential candidate genes for PRS are proposed from the present study. This may enable researchers to focus their effort in the studies of PRS.
European Journal of Human Genetics | 2004
Iben Bache; Elvire Van Assche; Sultan Cingöz; Merete Bugge; Zeynep Tümer; Mads F. Hjorth; Claes Lundsteen; James Lespinasse; Kirsten Winther; Anita Niebuhr; Vera M. Kalscheuer; Inge Liebaers; Maryse Bonduelle; Herman Tournaye; Carmen Ayuso; Gotthold Barbi; Elisabeth Blennow; Georges Bourrouillou; Karen Brøndum-Nielsen; Gert Bruun-Petersen; Marie-Françoise Croquette; Sophie Dahoun; Bruno Dallapiccola; Val Davison; Bruno Delobel; Hans-Christoph Duba; Laurence Duprez; Malcolm A. Ferguson-Smith; David Fitzpatrick; Elizabeth Grace
In a search for potential infertility loci, which might be revealed by clustering of chromosomal breakpoints, we compiled 464 infertile males with a balanced rearrangement from Mendelian Cytogenetics Network database (MCNdb) and compared their karyotypes with those of a Danish nation-wide cohort. We excluded Robertsonian translocations, rearrangements involving sex chromosomes and common variants. We identified 10 autosomal bands, five of which were on chromosome 1, with a large excess of breakpoints in the infertility group. Some of these could potentially harbour a male-specific infertility locus. However, a general excess of breakpoints almost everywhere on chromosome 1 was observed among the infertile males: 26.5 versus 14.5% in the cohort. This excess was observed both for translocation and inversion carriers, especially pericentric inversions, both for published and unpublished cases, and was significantly associated with azoospermia. The largest number of breakpoints was reported in 1q21; FISH mapping of four of these breakpoints revealed that they did not involve the same region at the molecular level. We suggest that chromosome 1 harbours a critical domain whose integrity is essential for male fertility.
European Journal of Human Genetics | 2000
Maria Kirchhoff; Hanne Rose; Jan Maahr; Tommy Gerdes; Merete Bugge; Niels Tommerup; Zeynep Tümer; James Lespinasse; Peter Ka Jensen; Jutta Wirth; Claes Lundsteen
A sensitive technique is needed for screening whole genome imbalances in dyschromosomal patients when G-banding shows normal karyotypes or apparently balanced translocations. In this study we performed highly sensitive comparative genomic hybridisation analysis on a number of such cases and revealed chromosomal imbalances in all.
European Journal of Human Genetics | 2008
Chrystel Leroy; Corinne Fouveaut; Sandrine Leclercq; Sébastien Jacquemont; Hélène Du Boullay; James Lespinasse; Marc Delpech; Jean-Michel Dupont; Jean-Pierre Hardelin; Catherine Dodé
Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann syndrome genes.
Human Mutation | 2012
Thomas Besnard; Christel Vaché; David Baux; Lise Larrieu; Caroline Abadie; Catherine Blanchet; Sylvie Odent; Patricia Blanchet; Patrick Calvas; Christian P. Hamel; Hélène Dollfus; Geneviève Lina-Granade; James Lespinasse; Albert David; Bertrand Isidor; Gilles Morin; Sue Malcolm; Sylvie Tuffery-Giraud; Mireille Claustres; Anne-Françoise Roux
We have systematically analyzed the two known minor genes involved in Usher syndrome type 2, DFNB31 and GPR98, for mutations in a cohort of 31 patients not linked to USH2A. PDZD7, an Usher syndrome type 2 (USH2) related gene, was analyzed when indicated. We found that mutations in GPR98 contribute significantly to USH2. We report 17 mutations in 10 individuals, doubling the number of GPR98 mutations reported to date. In contrast to mutations in usherin, the mutational spectrum of GPR98 predominantly results in a truncated protein product. This is true even when the mutation affects splicing, and we have incorporated a splicing reporter minigene assay to show this, where appropriate. Only two mutations were found which we believe to be genuine missense changes. Discrepancy in the mutational spectrum between GPR98 and USH2A is discussed. Only two patients were found with mutations in DFNB31, showing that mutations of this gene contribute to only a very small extent to USH2. Close examination of the clinical details, where available, for patients in whom no mutation was found in USH2A, GPR98, or DFNB31, showed that most of them had atypical features. In effect, these three genes account for the vast majority of USH2 patients and their analysis provide a robust pathway for routine molecular diagnosis. Hum Mutat 33:504–510, 2012.
Prenatal Diagnosis | 2010
Radu Harbuz; James Lespinasse; Stéphanie Boulet; Christine Francannet; Isabelle Creveaux; Mariem Benkhelifa; Pierre-Simon Jouk; Joël Lunardi; Pierre F. Ray
Molecular diagnosis and prenatal care of two pregnant women at risk of transmitting immunodysregulation, polyendocrinopathy, enteropathy X‐linked (IPEX) syndrome.
Human Mutation | 2015
Frédéric Brioude; Irène Netchine; Françoise Praz; Marilyne Le Jule; Claire Calmel; Didier Lacombe; Martin Catala; Sylvie Odent; Bertrand Isidor; Stanislas Lyonnet; Sabine Sigaudy; Bruno Leheup; Séverine Audebert-Bellanger; Lydie Burglen; Fabienne Giuliano; Jean-Luc Alessandri; Valérie Cormier-Daire; Fanny Laffargue; Sophie Blesson; Isabelle Coupier; James Lespinasse; Patricia Blanchet; Odile Boute; Clarisse Baumann; Michel Polak; Bérénice Doray; Alain Verloes; Géraldine Viot; Yves Le Bouc; Sylvie Rossignol
Beckwith–Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron–exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.
Human Mutation | 2009
Christel Thauvin-Robinet; Brunella Franco; Pascale Saugier-Veber; Bernard Aral; Nadège Gigot; Anne Donzel; Lionel Van Maldergem; Eric Bieth; Valérie Layet; Michèle Mathieu; Ahmad S. Teebi; James Lespinasse; Patrick Callier; Francine Mugneret; Alice Masurel-Paulet; Elodie Gautier; Frédéric Huet; Jean-Raymond Teyssier; Mario Tosi; Thierry Frebourg; Laurence Faivre
Oral‐facial‐digital type I syndrome (OFDI) is characterised by an X‐linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, dental and distal abnormalities, polycystic kidney disease and central nervous system malformations. Considerable allelic heterogeneity has been reported within the OFD1 gene, but DNA bi‐directional sequencing of the exons and intron‐exon boundaries of the OFD1 gene remains negative in more than 20% of cases. We hypothesized that genomic rearrangements could account for the majority of the remaining undiagnosed cases. Thus, we took advantage of two independent available series of patients with OFDI syndrome and negative DNA bi‐directional sequencing of the exons and intron‐exon boundaries of the OFD1 gene from two different European labs: 13/36 cases from the French lab; 13/95 from the Italian lab. All patients were screened by a semiquantitative fluorescent multiplex method (QFMPSF) and relative quantification by real‐time PCR (qPCR). Six OFD1 genomic deletions (exon 5, exons 1–8, exons 1–14, exons 10–11, exons 13–23 and exon 17) were identified, accounting for 5% of OFDI patients and for 23% of patients with negative mutation screening by DNA sequencing. The association of DNA direct sequencing, QFMPSF and qPCR detects OFD1 alteration in up to 85% of patients with a phenotype suggestive of OFDI syndrome. Given the average percentage of large genomic rearrangements (5%), we suggest that dosage methods should be performed in addition to DNA direct sequencing analysis to exclude the involvement of the OFD1 transcript when there are genetic counselling issues.