Véronique David - Profile on Academia.edu (original) (raw)
Papers by Véronique David
Human Mutation, 2009
Mutations of the ZIC2 transcription factor gene are among the most common heterozygous variations... more Mutations of the ZIC2 transcription factor gene are among the most common heterozygous variations detected in holoprosencephaly (HPE) patients, a patient group who lack critical midline forebrain specification due to defective embryonic signaling during development. Recent studies indicate that complete deficiency of the related murine Zic2 transcription factor can also be a contributing factor to variable midline deficiencies, presenting during mid-gastrulation, that could explain similar forebrain anomalies in this model system. Here we collect and summarize all available mutations in the human ZIC2 gene detected in HPE patients (21 published and 62 novel). Our analysis corroborates this mechanism proposed in mice by predicting loss-of-function as the likely pathogenetic mechanism common to most, if not all, of these mutations in HPE.
Archives of General Psychiatry, 2009
Results of comparative genomic hybridization studies have suggested that rare copy number variati... more Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia.
Human Molecular Genetics
We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a... more We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes. Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations. Thus, ZIC2 mutation was the apparent cause of HPE in 3-4% of cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE. One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in seven patients from six different families. In three of those families, the father was found to be apparently mosaic for the mutation. We hypothesize that this mutation can arise through errors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one mutation was an in-frame d...
Array-CGH enables the detection of submicroscopic chromosomal deletions and duplications and lead... more Array-CGH enables the detection of submicroscopic chromosomal deletions and duplications and leads to an accurate delineation of the imbalances, raising the possibility of correlating genotype to phenotype and mapping minimal critical regions associated with particular patterns of clinical features. We report here on four patients sharing common clinical features (psychomotor retardation, coarse facies and ocular anomalies), with proximal 5q deletions identified by oligo array-CGH. The deletions range from 5.75 to 17.26-Mb in size and occurred de novo. A common 2.63-Mb region between the deletions described here can be defined in 5q12.1 (59,390,122-62,021,754 bp bp from 5pter, hg18) and includes 12 genes. Among them, KIF2A, which encodes a kinesin superfamily protein, is a particularly interesting candidate for the phenotype, as it suppresses the growth of axonal collateral branches and is involved in normal brain development. Ocular defects, albeit unspecific, seem to be common in the 5q12.1 deletion. Identification of additional cases of deletions involving the 5q12.1 region will allow more accurate genotype-phenotype correlations.
Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results. The European Haemochromatosis Consortium
Nature genetics, 1999
1. Nat Genet. 1999 Nov;23(3):272. Polymorphism in intron 4 of HFE does not compromise haemochroma... more 1. Nat Genet. 1999 Nov;23(3):272. Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results. Gomez PS, Parks S, Ries R, Tran TC, Gomez PF, Press RD. Comment on: Nat Genet. 1999 Aug;22(4):325-6. Nat Genet. 1996 Aug;13(4):399-408. ...
La Presse Médicale, 2007
Disponible sur internet : le 22 mai 2007 1. Inserm U-522, IFR140, Université de Rennes 1, Rennes ... more Disponible sur internet : le 22 mai 2007 1. Inserm U-522, IFR140, Université de Rennes 1, Rennes (35) 2. Département de biochimie et génétique moléculaire, Rennes (35) 3. Centre d'investigation clinique 0203, Rennes (35) 4. Service des maladies du foie, CHRU Pontchaillou, Rennes (35) SAS Tous droits réservés. en ligne sur / on line on www.masson.fr/revues/pm h é m o c h r o m ato s e tome 36 > n°9 > septembre 2007 > cahier 2
PLOS ONE, 2015
Holoprosencephaly (HPE) is a frequent congenital malformation of the brain characterized by impai... more Holoprosencephaly (HPE) is a frequent congenital malformation of the brain characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been identified in HPE patients that account for only 30% of HPE cases, suggesting the existence of other HPE genes. Data from homozygosity mapping and whole-exome sequencing in a consanguineous Turkish family were combined to identify a homozygous missense mutation (c.2150G>A; p.Gly717Glu) in STIL, common to the two affected children. STIL has a role in centriole formation and has previously been described in rare cases of microcephaly. Rescue experiments in U2OS cells showed that the STIL p.Gly717Glu mutation was not able to fully restore the centriole duplication failure following depletion of endogenous STIL protein indicating the deleterious role of the mutation. In situ hybridization experiments using chick embryos demonstrated that expression of Stil was in accordance with a function during early patterning of the forebrain. It is only the second time that a STIL homozygous mutation causing a recessive form of HPE was reported. This result also supports the genetic heterogeneity of HPE and increases the panel of genes to be tested for HPE diagnosis.
Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations
Human genetics, 2003
Holoprosencephaly (HPE) is the most common severe brain anomaly in humans, which results from inc... more Holoprosencephaly (HPE) is the most common severe brain anomaly in humans, which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, TGIF ( TG-interacting factor), which codes for a transcription factor modulating the signalling pathway of TGF-beta, was previously implicated. We investigated 127 HPE probands by sequencing their TGIF gene and identified the first nonsense mutation reported so far and also a novel missense mutation, in two families that presented a large range of disease severity. The low number of mutations in TGIF suggests that this gene has no major contribution to the aetiology of HPE and our study confirms the wide clinical heterogeneity of the disease.
[Argininosuccinic aciduria. A new case revealed by psychiatric disorders]
Journal de génétique humaine, 1989
The case of a 4 years old boy, hospitalized for an unexplained coma, is reported. He is the first... more The case of a 4 years old boy, hospitalized for an unexplained coma, is reported. He is the first child of a non-consanguin couple. The psychomotor development of this child was considered as normal up to the age of 18 months; then, a delay in language development, behaviour disorders with an important instability interrupted by episodes of somnolence, were observed. This child was treated for psychotic disorders. At the age of 3 and half, he had two episodes of seizures associated with fever. He was hospitalized for a 24 hours coma (4 years old). An hepatomegaly and a dry, brittle hair were then observed. Hyperammonemia was made obvious by a protein tolerance test. The diagnosis of argininosuccinate lyase (ASAL) deficiency was based on the increased levels of ASA in plasma and urine. The deficiency was proved by a fibroblast culture. With protein restriction, hepatomegaly disappeared, hair became normal, the behaviour disorders and the delay in language development was improved. Ho...
Orphanet journal of rare diseases, 2007
Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the... more Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like...
[Pathophysiology and genetics of classic HFE (type 1) hemochromatosis]
Presse médicale (Paris, France : 1983), 2007
Hereditary type 1 HFE hemochromatosis is associated with homozygosity for the p.Cys282Tyr mutatio... more Hereditary type 1 HFE hemochromatosis is associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene (C282Y mutation). The p.Cys282Tyr mutation of the HFE gene leads to an abnormal reduction in hepatic expression of hepcidin, a protein that appears to control the release of iron from enterocytes and macrophages towards plasma. Abnormally low hepcidin levels promote an increase in the bioavailability of plasma iron, characterized by elevated transferrin saturation and the appearance of non transferrin bound iron. This nontransferrin-bound iron is avidly taken up by the liver, heart, and pancreas, the principal target organs for systemic iron overload. The variable penetrance of this disease is related to environmental and genetic factors. Among the genetic factors, mutations of some newly identified genes may aggravate the phenotype of iron overload associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene; these new genes include those of hemojuvelin (H...
Comparing the clinical evolution of cystic fibrosis screened neonatally to that of cystic fibrosis diagnosed from clinical symptoms: A 10-year retrospective study in a French region (Brittany)
Pediatric Pulmonology, 2003
Until the year 2000, systematic cystic fibrosis (CF) neonatal screening was only performed in a f... more Until the year 2000, systematic cystic fibrosis (CF) neonatal screening was only performed in a few regions of France. The Brittany region began in 1989, but not the neighboring region of Loire-Atlantique. The present study compares the clinical evolution of both affected populations 10 years after screening was started. Although the 77 screened and 36 nonscreened children were followed in different CF centers, they were included in similar care protocols. The clinical characteristics at diagnosis and their evolution over a 10-year period of all the children affected with CF and born between January 1, 1989 and December 31, 1998, excluding those with meconium ileus, were compared. There were no significant differences in sex ratio, gestational age, anthropometric data at birth, frequency of deltaF508 homozygotes, proportion of pancreatic-insufficient patients, and mean age between the two populations. Age at diagnosis was lower in the screened group (38 days vs. 472 days, P < 10(-7)), as was the delay in supplementation with pancreatic enzymes (1.7 months vs.15.9 months, P < 10(-7)). The proportion of children who were hospitalized at least once was higher among the nonscreened than the screened patients (86% vs. 49%, P < 10(-4)). Z-scores for weight and height were significantly better in the screened population, not only in the first years of life, but also at 5 years old for height and 8 years old for weight. The Shwachman and Brasfield scores were higher among the screened children during the whole period of follow-up. No significant differences in colonization by Pseudomonas aeruginosa nor in lung function were found. Given the homogeneity in the characteristics and the follow-up of both populations, the benefits in terms of nutrition and clinical well-being of neonatal screening appear to be clear, thus confirming the advantages of its general implementation.
Orphanet Journal of Rare Diseases, 2011
Background: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia... more Background: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. The uterovaginal aplasia is either isolated (type I) or more frequently associated with other malformations (type II or Müllerian Renal Cervico-thoracic Somite (MURCS) association), some of which belong to the malformation spectrum of DiGeorge phenotype (DGS). Its etiology remains poorly understood. Thus the phenotypic manifestations of MRKH and DGS overlap suggesting a possible genetic link. This would potentially have clinical consequences. Methods: We searched DiGeorge critical chromosomal regions for chromosomal anomalies in a cohort of 57 subjects with uterovaginal aplasia (55 women and 2 aborted fetuses). For this candidate locus approach, we used a multiplex ligation-dependent probe amplification (MLPA) assay based on a kit designed for investigation of the chromosomal regions known to be involved in DGS. The deletions detected were validated by Duplex PCR/liquid chromatography (DP/LC) and/or array-CGH analysis. Results: We found deletions in four probands within the four chromosomal loci 4q34-qter, 8p23.1, 10p14 and 22q11.2 implicated in almost all cases of DGS syndrome. Conclusion: Uterovaginal aplasia appears to be an additional feature of the broad spectrum of the DGS phenotype. The DiGeorge critical chromosomal regions may be candidate loci for a subset of MRKH syndrome (MURCS association) individuals. However, the genes mapping at the sites of these deletions involved in uterovaginal anomalies remain to be determined. These findings have consequences for clinical investigations, the care of patients and their relatives, and genetic counseling.
Two polymorphisms at the locus D698 defined by a YAC
Nucleic Acids Research, 1990
Haemochromatosis and HLA–H
Nature Genetics, 1996
1. Nat Genet. 1996 Nov;14(3):251-2. Haemochromatosis and HLA-H. Jouanolle AM, Gandon G, Jézéquel ... more 1. Nat Genet. 1996 Nov;14(3):251-2. Haemochromatosis and HLA-H. Jouanolle AM, Gandon G, Jézéquel P, Blayau M, Campion ML, Yaouanq J, Mosser J, Fergelot P, Chauvel B, Bouric P, Carn G, Andrieux N, Gicquel I, Le Gall JY, David V. Comment on: Nat Genet. ...
Molecular Human Reproduction, 2000
Many studies have shown that congenital absence of the vas deferens (CAVD) is a genital cystic fi... more Many studies have shown that congenital absence of the vas deferens (CAVD) is a genital cystic fibrosis transmembrane conductance regulator (CFTR)-mediated phenotype, with a broad spectrum of abnormalities causing male infertility. The genotype of these patients includes mutations in the CFTR gene, e.g. ∆ ∆F508, R117H and the T5 allele; all of which are commonly found in CAVD. In this study we have screened the entirety of CFTR gene in 47 males with anomalies of the vas deferens: 37 cases of congenital bilateral absence of the vas deferens, three cases of congenital unilateral absence of the vas deferens and seven cases of obstructive azoospermia with hypoplastic vas deferens. Among the 94 chromosomes studied, 65 mutations, of which three are novel (2789⍣2insA, L1227S, 4428insGA), were identified. The majority of patients (63.8%) had two detectable CFTR gene mutations. Furthermore, high frequencies of the ∆ ∆F508 mutation (44.7%), the T5 allele (36.2%) and R117H mutation (19.1%) were observed.
Mechanisms of Development, 2009
Holoprosencephaly (HPE), the most common developmental defect of the forebrain, is caused by a fa... more Holoprosencephaly (HPE), the most common developmental defect of the forebrain, is caused by a failure to delineate the midline. HPE occurs in sporadic and inherited forms, and even HPE in pedigrees is characterized by variable expressivity. Point mutations and deletions were found in SHH, ZIC2, SIX3 and TGIF genes in about 30% of the genetic cases. HPE is now believed to be a multihit pathology requiring two or more events involving several genes from one or several signalling pathways. However, the major event leading to HPE is the disruption of Sonic Hedgehog signalling in the rostroventral region of the embryo. Now, novel regulators of mammalian hedgehog pathway have been identified, such as proteins involved in primary cilia formation, increasing the complexity of this signalling network.
MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations
Journal of Medical Genetics, 2010
Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved ... more Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.
Human Mutation, 2009
Mutations of the ZIC2 transcription factor gene are among the most common heterozygous variations... more Mutations of the ZIC2 transcription factor gene are among the most common heterozygous variations detected in holoprosencephaly (HPE) patients, a patient group who lack critical midline forebrain specification due to defective embryonic signaling during development. Recent studies indicate that complete deficiency of the related murine Zic2 transcription factor can also be a contributing factor to variable midline deficiencies, presenting during mid-gastrulation, that could explain similar forebrain anomalies in this model system. Here we collect and summarize all available mutations in the human ZIC2 gene detected in HPE patients (21 published and 62 novel). Our analysis corroborates this mechanism proposed in mice by predicting loss-of-function as the likely pathogenetic mechanism common to most, if not all, of these mutations in HPE.
Archives of General Psychiatry, 2009
Results of comparative genomic hybridization studies have suggested that rare copy number variati... more Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia.
Human Molecular Genetics
We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a... more We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes. Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations. Thus, ZIC2 mutation was the apparent cause of HPE in 3-4% of cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE. One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in seven patients from six different families. In three of those families, the father was found to be apparently mosaic for the mutation. We hypothesize that this mutation can arise through errors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one mutation was an in-frame d...
Array-CGH enables the detection of submicroscopic chromosomal deletions and duplications and lead... more Array-CGH enables the detection of submicroscopic chromosomal deletions and duplications and leads to an accurate delineation of the imbalances, raising the possibility of correlating genotype to phenotype and mapping minimal critical regions associated with particular patterns of clinical features. We report here on four patients sharing common clinical features (psychomotor retardation, coarse facies and ocular anomalies), with proximal 5q deletions identified by oligo array-CGH. The deletions range from 5.75 to 17.26-Mb in size and occurred de novo. A common 2.63-Mb region between the deletions described here can be defined in 5q12.1 (59,390,122-62,021,754 bp bp from 5pter, hg18) and includes 12 genes. Among them, KIF2A, which encodes a kinesin superfamily protein, is a particularly interesting candidate for the phenotype, as it suppresses the growth of axonal collateral branches and is involved in normal brain development. Ocular defects, albeit unspecific, seem to be common in the 5q12.1 deletion. Identification of additional cases of deletions involving the 5q12.1 region will allow more accurate genotype-phenotype correlations.
Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results. The European Haemochromatosis Consortium
Nature genetics, 1999
1. Nat Genet. 1999 Nov;23(3):272. Polymorphism in intron 4 of HFE does not compromise haemochroma... more 1. Nat Genet. 1999 Nov;23(3):272. Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results. Gomez PS, Parks S, Ries R, Tran TC, Gomez PF, Press RD. Comment on: Nat Genet. 1999 Aug;22(4):325-6. Nat Genet. 1996 Aug;13(4):399-408. ...
La Presse Médicale, 2007
Disponible sur internet : le 22 mai 2007 1. Inserm U-522, IFR140, Université de Rennes 1, Rennes ... more Disponible sur internet : le 22 mai 2007 1. Inserm U-522, IFR140, Université de Rennes 1, Rennes (35) 2. Département de biochimie et génétique moléculaire, Rennes (35) 3. Centre d'investigation clinique 0203, Rennes (35) 4. Service des maladies du foie, CHRU Pontchaillou, Rennes (35) SAS Tous droits réservés. en ligne sur / on line on www.masson.fr/revues/pm h é m o c h r o m ato s e tome 36 > n°9 > septembre 2007 > cahier 2
PLOS ONE, 2015
Holoprosencephaly (HPE) is a frequent congenital malformation of the brain characterized by impai... more Holoprosencephaly (HPE) is a frequent congenital malformation of the brain characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been identified in HPE patients that account for only 30% of HPE cases, suggesting the existence of other HPE genes. Data from homozygosity mapping and whole-exome sequencing in a consanguineous Turkish family were combined to identify a homozygous missense mutation (c.2150G>A; p.Gly717Glu) in STIL, common to the two affected children. STIL has a role in centriole formation and has previously been described in rare cases of microcephaly. Rescue experiments in U2OS cells showed that the STIL p.Gly717Glu mutation was not able to fully restore the centriole duplication failure following depletion of endogenous STIL protein indicating the deleterious role of the mutation. In situ hybridization experiments using chick embryos demonstrated that expression of Stil was in accordance with a function during early patterning of the forebrain. It is only the second time that a STIL homozygous mutation causing a recessive form of HPE was reported. This result also supports the genetic heterogeneity of HPE and increases the panel of genes to be tested for HPE diagnosis.
Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations
Human genetics, 2003
Holoprosencephaly (HPE) is the most common severe brain anomaly in humans, which results from inc... more Holoprosencephaly (HPE) is the most common severe brain anomaly in humans, which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, TGIF ( TG-interacting factor), which codes for a transcription factor modulating the signalling pathway of TGF-beta, was previously implicated. We investigated 127 HPE probands by sequencing their TGIF gene and identified the first nonsense mutation reported so far and also a novel missense mutation, in two families that presented a large range of disease severity. The low number of mutations in TGIF suggests that this gene has no major contribution to the aetiology of HPE and our study confirms the wide clinical heterogeneity of the disease.
[Argininosuccinic aciduria. A new case revealed by psychiatric disorders]
Journal de génétique humaine, 1989
The case of a 4 years old boy, hospitalized for an unexplained coma, is reported. He is the first... more The case of a 4 years old boy, hospitalized for an unexplained coma, is reported. He is the first child of a non-consanguin couple. The psychomotor development of this child was considered as normal up to the age of 18 months; then, a delay in language development, behaviour disorders with an important instability interrupted by episodes of somnolence, were observed. This child was treated for psychotic disorders. At the age of 3 and half, he had two episodes of seizures associated with fever. He was hospitalized for a 24 hours coma (4 years old). An hepatomegaly and a dry, brittle hair were then observed. Hyperammonemia was made obvious by a protein tolerance test. The diagnosis of argininosuccinate lyase (ASAL) deficiency was based on the increased levels of ASA in plasma and urine. The deficiency was proved by a fibroblast culture. With protein restriction, hepatomegaly disappeared, hair became normal, the behaviour disorders and the delay in language development was improved. Ho...
Orphanet journal of rare diseases, 2007
Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the... more Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like...
[Pathophysiology and genetics of classic HFE (type 1) hemochromatosis]
Presse médicale (Paris, France : 1983), 2007
Hereditary type 1 HFE hemochromatosis is associated with homozygosity for the p.Cys282Tyr mutatio... more Hereditary type 1 HFE hemochromatosis is associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene (C282Y mutation). The p.Cys282Tyr mutation of the HFE gene leads to an abnormal reduction in hepatic expression of hepcidin, a protein that appears to control the release of iron from enterocytes and macrophages towards plasma. Abnormally low hepcidin levels promote an increase in the bioavailability of plasma iron, characterized by elevated transferrin saturation and the appearance of non transferrin bound iron. This nontransferrin-bound iron is avidly taken up by the liver, heart, and pancreas, the principal target organs for systemic iron overload. The variable penetrance of this disease is related to environmental and genetic factors. Among the genetic factors, mutations of some newly identified genes may aggravate the phenotype of iron overload associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene; these new genes include those of hemojuvelin (H...
Comparing the clinical evolution of cystic fibrosis screened neonatally to that of cystic fibrosis diagnosed from clinical symptoms: A 10-year retrospective study in a French region (Brittany)
Pediatric Pulmonology, 2003
Until the year 2000, systematic cystic fibrosis (CF) neonatal screening was only performed in a f... more Until the year 2000, systematic cystic fibrosis (CF) neonatal screening was only performed in a few regions of France. The Brittany region began in 1989, but not the neighboring region of Loire-Atlantique. The present study compares the clinical evolution of both affected populations 10 years after screening was started. Although the 77 screened and 36 nonscreened children were followed in different CF centers, they were included in similar care protocols. The clinical characteristics at diagnosis and their evolution over a 10-year period of all the children affected with CF and born between January 1, 1989 and December 31, 1998, excluding those with meconium ileus, were compared. There were no significant differences in sex ratio, gestational age, anthropometric data at birth, frequency of deltaF508 homozygotes, proportion of pancreatic-insufficient patients, and mean age between the two populations. Age at diagnosis was lower in the screened group (38 days vs. 472 days, P < 10(-7)), as was the delay in supplementation with pancreatic enzymes (1.7 months vs.15.9 months, P < 10(-7)). The proportion of children who were hospitalized at least once was higher among the nonscreened than the screened patients (86% vs. 49%, P < 10(-4)). Z-scores for weight and height were significantly better in the screened population, not only in the first years of life, but also at 5 years old for height and 8 years old for weight. The Shwachman and Brasfield scores were higher among the screened children during the whole period of follow-up. No significant differences in colonization by Pseudomonas aeruginosa nor in lung function were found. Given the homogeneity in the characteristics and the follow-up of both populations, the benefits in terms of nutrition and clinical well-being of neonatal screening appear to be clear, thus confirming the advantages of its general implementation.
Orphanet Journal of Rare Diseases, 2011
Background: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia... more Background: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. The uterovaginal aplasia is either isolated (type I) or more frequently associated with other malformations (type II or Müllerian Renal Cervico-thoracic Somite (MURCS) association), some of which belong to the malformation spectrum of DiGeorge phenotype (DGS). Its etiology remains poorly understood. Thus the phenotypic manifestations of MRKH and DGS overlap suggesting a possible genetic link. This would potentially have clinical consequences. Methods: We searched DiGeorge critical chromosomal regions for chromosomal anomalies in a cohort of 57 subjects with uterovaginal aplasia (55 women and 2 aborted fetuses). For this candidate locus approach, we used a multiplex ligation-dependent probe amplification (MLPA) assay based on a kit designed for investigation of the chromosomal regions known to be involved in DGS. The deletions detected were validated by Duplex PCR/liquid chromatography (DP/LC) and/or array-CGH analysis. Results: We found deletions in four probands within the four chromosomal loci 4q34-qter, 8p23.1, 10p14 and 22q11.2 implicated in almost all cases of DGS syndrome. Conclusion: Uterovaginal aplasia appears to be an additional feature of the broad spectrum of the DGS phenotype. The DiGeorge critical chromosomal regions may be candidate loci for a subset of MRKH syndrome (MURCS association) individuals. However, the genes mapping at the sites of these deletions involved in uterovaginal anomalies remain to be determined. These findings have consequences for clinical investigations, the care of patients and their relatives, and genetic counseling.
Two polymorphisms at the locus D698 defined by a YAC
Nucleic Acids Research, 1990
Haemochromatosis and HLA–H
Nature Genetics, 1996
1. Nat Genet. 1996 Nov;14(3):251-2. Haemochromatosis and HLA-H. Jouanolle AM, Gandon G, Jézéquel ... more 1. Nat Genet. 1996 Nov;14(3):251-2. Haemochromatosis and HLA-H. Jouanolle AM, Gandon G, Jézéquel P, Blayau M, Campion ML, Yaouanq J, Mosser J, Fergelot P, Chauvel B, Bouric P, Carn G, Andrieux N, Gicquel I, Le Gall JY, David V. Comment on: Nat Genet. ...
Molecular Human Reproduction, 2000
Many studies have shown that congenital absence of the vas deferens (CAVD) is a genital cystic fi... more Many studies have shown that congenital absence of the vas deferens (CAVD) is a genital cystic fibrosis transmembrane conductance regulator (CFTR)-mediated phenotype, with a broad spectrum of abnormalities causing male infertility. The genotype of these patients includes mutations in the CFTR gene, e.g. ∆ ∆F508, R117H and the T5 allele; all of which are commonly found in CAVD. In this study we have screened the entirety of CFTR gene in 47 males with anomalies of the vas deferens: 37 cases of congenital bilateral absence of the vas deferens, three cases of congenital unilateral absence of the vas deferens and seven cases of obstructive azoospermia with hypoplastic vas deferens. Among the 94 chromosomes studied, 65 mutations, of which three are novel (2789⍣2insA, L1227S, 4428insGA), were identified. The majority of patients (63.8%) had two detectable CFTR gene mutations. Furthermore, high frequencies of the ∆ ∆F508 mutation (44.7%), the T5 allele (36.2%) and R117H mutation (19.1%) were observed.
Mechanisms of Development, 2009
Holoprosencephaly (HPE), the most common developmental defect of the forebrain, is caused by a fa... more Holoprosencephaly (HPE), the most common developmental defect of the forebrain, is caused by a failure to delineate the midline. HPE occurs in sporadic and inherited forms, and even HPE in pedigrees is characterized by variable expressivity. Point mutations and deletions were found in SHH, ZIC2, SIX3 and TGIF genes in about 30% of the genetic cases. HPE is now believed to be a multihit pathology requiring two or more events involving several genes from one or several signalling pathways. However, the major event leading to HPE is the disruption of Sonic Hedgehog signalling in the rostroventral region of the embryo. Now, novel regulators of mammalian hedgehog pathway have been identified, such as proteins involved in primary cilia formation, increasing the complexity of this signalling network.
MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations
Journal of Medical Genetics, 2010
Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved ... more Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.