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Biomedical subjects

P Edery

Publications and source records attributed to P Edery.

At least 37 records · Page 2Linked to original sources
PubMed1998

Prenatal diagnosis of an 8p23.1 deletion in a fetus with a diaphragmatic hernia and review of the literature.

The prenatal diagnosis of an 8p23.1 deletion is reported. The diagnosis was ascertained at 22 weeks of gestation because of the discovery of a diaphragmatic hernia at ultrasound. Following cytogenetic studies and counselling, the pregnancy was terminated. An autopsy confirmed the presence of a diaphragmatic hernia and revealed also the existence of an atrio-ventricular canal (AVC) and an atrial septal defect (ASD). The clinical features of this antenatally diagnosed case are compared with those observed in 16 previously reported cases with an identical deletion of the short arm of chromosome 8. This suggests that a deletion 8p23.1 should be considered whenever a diaphragmatic hernia and/or an AVC is detected on ultrasound.

Adult↗
PubMed1997

RET in human development and oncogenesis.

Hirschsprung disease and the multiple endocrine neoplasia type 2 syndromes are hereditary disorders related to the abnormal migration, proliferation or survival of neural crest cells and their derivatives. Hirschsprung disease is a frequent disorder of the enteric nervous system, resulting in intestinal obstruction. The multiple endocrine neoplasia type 2 syndromes predispose to cancers of neural crest derivatives. Both diseases are associated with heterozygous mutations in the RET proto-oncogene. RET encodes a transmembrane receptor tyrosine kinase expressed in neural crest lineages and whose ligand, glial-cell-line-derived neurotrophic factor, has been very recently identified. In vitro expression studies demonstrate that while Hirschsprung disease mutations result in loss of function of the mutant RET tyrosine kinase, multiple endocrine neoplasia type 2 mutations lead to its constitutive activation. Thus, the two 'faces' of RET, gain of function and loss of function, each lead to a different syndrome, respectively: multiple endocrine neoplasia type 2, a cancer syndrome, or Hirschsprung disease, a developmental defect.

Animals↗
PubMed1997

[Mutations of the endothelin-3 gene in isolated and syndromic forms of Hirschsprung disease].

AIMS AND METHODS: Hirschsprung's disease is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been identified in Hirschsprung's disease, namely the RET proto-oncogene, the Glial cell line-Derived Neurotrophic Factor and the endothelin B receptor. A total of 174 probands with isolated Hirschsprung's disease (59 familial, 117 sporadic cases), and 4 patients with associated Waardenburg's syndrome and Hirschsprung's disease (1 familial, 3 sporadic cases) were screened for mutations in the coding sequence of the endothelin 3 gene. The coding sequence of the endothelin 3 gene was analyzed for point mutations, using a combination of SSCP analysis and direct DNA sequencing. RESULTS: Two heterozygous mutations (A17T and A224T) were identified in two patients with isolated Hirschsprung's disease. Two homozygous truncations mutations (E55X and GC262->T) were identified in patients with the Waardenburg's syndrome/Hirschsprung's disease association. CONCLUSION: The present data give further support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also suggest that either recessive and weakly penetrant dominant alleles could occur at the EDN3 locus, depending on the nature of the mutation.

Endothelin-3↗
PubMed1996

Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome).

Hirschsprung disease (HSCR) and Waardenburg sundrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells. The WS-HSCR association (Shah-Waardenburg syndrome) is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype, the EDN3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDN3 gene in a WS-HSCR patient. EDN3 thus becomes the third known gene (after RET and EDNRB) predisposing to HSCR, supporting the view that the endothelin-signaling pathways play a major role in the development of neural crests.

Amino Acid Sequence↗
PubMed1996

Waardenburg-Hirschsprung disease in two sisters: a possible clue to the genetics of this association?

A Tunisian infant of consanguineous parents had pigmentary disorders, congenital deafness and long-segment Hirschsprung disease. Her elder sister had the same disorders but with short-segment aganglionosis. Their father, mother and two brothers are healthy without history of deafness, constipation or pigmentary disorder. We confirm that this Waardenburg-Hirschsprung association seems to be a distinct clinical entity with a possible autosomal recessive mode of inheritance. Linkage analyses performed in this family support the view that neither the RET locus (candidate for familial dominant Hirschsprung disease) nor the HuP2 locus (candidate for Waardenburg syndrome type I) are involved in the disease phenotype. We suggest that Waardenburg-Hirschsprung complex is a distinct genetic entity and at least one additional locus altering cranial neural crest cell development is responsible for pleiotropic features observed in this association.

Hirschsprung Disease↗
PubMed1996

Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease.

Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Two susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association. Here, we report heterozygous EDNRB missense mutations (G57S, R319W and P383L) in isolated HSCR. These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features. In addition, the present data give further support to the role of the endothelin-signalling pathway in the development of neural crest-derived enteric neurons.

Female↗
PubMed1996

[Genetics of Hirschsprung disease].

Hirschsprung's disease (HD) is one of the commonest gastrointestinal malformations, as it affects one child out of 5,000 births. It classically induces severe neonatal intestinal obstruction requiring surgical treatment which currently ensures a favourable prognosis for most of the affected children. Although the great majority of cases are sporadic, the existence of familial forms (10% of cases) has allowed localization and then identification of an autosomal dominant gene on chromosome 10, the RET proto-oncogene, responsible for 50% of familial forms and 15% of sporadic cases. A second gene has been recently localized on chromosome 13, the endothelium beta receptor (EDNRB) gene. Two homozygous mutations of the EDNRB gene have been identified in two consanguineous families, in which HD is associated with Waardenburg's syndrome (WS). Other heterozygous mutations have been identified in patients presenting with isolated HD and an 5% of cases of HD can be considered to present mutations of this gene. Finally, the authors have recently identified a mutation of the endothelium gene 3 (EDN3), one of the EDNRB ligands in a patient presenting with a combination of HD and WS. This mutation, present at the homozygous state in this patient, is predictive of complete absence of EDN3 protein: this is therefore the third known gene responsible for HD.

Drosophila Proteins↗
PubMed1996

[Genetics of Hirschsprung disease].

Hirschsprung disease (HD) is one of the commonest gastro-intestinal malformations, as it affects one child out of 5,000 births. It classically induces severe neonatal intestinal obstruction requiring surgical treatment which currently ensures a favourable prognosis for most of the affected children. Although the great majority of cases are sporadic, the existence of familial forms (10% of cases) has allowed the localization and then the identification of an autosomal dominant gene on chromosome 10, the RET proto-oncogene, responsible for 50% of familial forms and 15% of sporadic cases. A second gene has been recently localized on chromosome 13, the endothelin beta receptor (EDNRB) gene. Two homozygous mutations have been identified in two consanguineous families, in which HD is associated with Waardenburg syndrome (WS). Other heterozygous mutations have been identified in patients presenting with isolated HD and 5% of cases can be considered to present mutations of this gene. Finally the authors have recently identified a mutation of the endothelin 3 gene (EDN3), one of EDNRB ligands in a patient presenting a combination of HD and WS. This mutation, present at the homozygous state in this patient, is predictive of complete absence of EDN3 protein: this is therefore the third known gene responsible for HD.

Endothelin-3↗
PubMed1995

Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease.

Hirschsprung disease (HSCR) is a common congenital malformation (1 in 5,000 live births) due to the absence of autonomic ganglia in the terminal hindgut, and resulting in intestinal obstruction in neonates. Recently, a dominant gene for familial HSCR has been mapped to chromosome sub-band 10q11.2 and the disease has been ascribed to mutations in a tyrosine kinase receptor gene mapping to this region, the RET proto-oncogene. Studying the 20 exons of the RET gene by a combination of denaturating gradient gel electrophoresis and single strand conformation polymorphism in a large series of HSCR patients (45 sporadic cases and 35 familial forms), we found mutations of the RET gene in 50% of familial HSCR, regardless of the length of the aganglionic segment. The mean penetrance of the mutant allele in familial HSCR was significantly higher in males (72%) than in females (51%). Most interestingly, mutations at the RET locus accounted for at least 1/3 of sporadic HSCR in our series. These mutations were scattered along the length of the gene. Finally, among the mutations identified in sporadic cases (16/45), seven proved to be de novo mutations suggesting that new mutations at the RET locus significantly contribute to sporadic HSCR. Taken together, the low penetrance of the mutant gene, the lack of genotype-phenotype correlation, the sex-dependent effect of RET mutations and the variable clinical expression of the disease support the existence of one or more modifier genes in familial HSCR.

Base Sequence↗
PubMed1995

Exclusion of RET and Pax 3 loci in Waardenburg-Hirschsprung disease.

The RET and the Pax 3 genes have recently been shown to account for autosomal dominant Hirschsprung's disease (HSCR) and Waardenburg syndrome type 1 (WS1) respectively, which led us to consider them as candidate genes in the WS/HSCR association. Linkage analyses performed in a consanguineous WS/HSCR family support the view that neither the RET locus nor the Pax 3 locus are involved in the disease phenotype. Hence, at least one further locus altering neural crest cell development is responsible for the pleiotropic features observed in the WS/HSCR association.

Consanguinity↗
PubMed1994

Apparent genetic homogeneity of the Treacher Collins-Franceschetti syndrome.

The Treacher Collins-Franceschetti syndrome (TCOF) or mandibulofacial dysostosis (MFD) is an autosomal dominant disorder characterized by craniofacial abnormalities and hearing loss. A refined genetic linkage map of the TCOF locus was established in 8 independent families, using 12 microsatellite DNA markers of the distal 5q. Positive lod score values were obtained for all markers with a maximum at the D5S413 locus (Zmax = 3.79 at theta = 0%). Multipoint linkage analysis and haplotype analysis supported the location of the gene between loci D5S434 and D5S412. These results are consistent with previous linkage analyses [Dixon et al.: Am J Hum Genet 49:17-22, 1991, Am J Hum Genet 52:907-914, 1993; Jabs et al.: Genomics 11:193-198, 1991, Genomics 18:7-13, 1993] and provide further evidence of genetic homogeneity in this syndrome.

Chromosomes, Human, Pair 5↗
PubMed1994

Mutations of the RET proto-oncogene in Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates and megacolon in infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR. Recently, a gene for HSCR has been mapped to chromosome 10q11.2 (refs 6, 7). No recombination was observed between the disease locus and the locus for the RET proto-oncogene, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. Here we report nonsense and missense mutations in the extracellular domain of RET protein (exons 2, 3, 5 and 6) in six unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A). Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.

Base Sequence↗
PubMed1994

Liver cytochrome c oxidase deficiency in a case of neonatal-onset hepatic failure.

In the last few years, inborn errors of oxidative phosphorylation have been recognized as possible causes of hepatic failure in infancy and respiratory enzyme deficiencies have been described in several tissues of affected individuals. Here, we report on cytochrome c oxidase deficiency in the liver but not in the skeletal muscle of a 5-month-old girl who presented hepatic failure in early infancy. Persistent hyperlactatemia (> 4 mM, normal < 2.4) with high lactate/pyruvate (L/P) molar ratios in plasma, and their further elevation in the post-absorptive period were suggestive of an inborn error of oxidative phosphorylation. However, no mutation in the coding sequences of the liver-specific subunits of cytochrome c oxidase (VIa and VIIa) has been detected and no major rearrangement or depletion of the mitochondrial DNA has been observed. Based on this observation we suggest that inborn errors of oxidative phosphorylation be considered in the diagnosis of severe hepatocellular dysfunction of unknown origin, especially when an abnormal oxidation-reduction status is found in the plasma and even if normal respiratory enzyme activities are found in peripheral tissues. The findings of normal respiratory enzyme activities in skeletal muscle, circulating lymphocytes or cultured skin fibroblasts does not rule out this diagnosis. Instead, the negativity of these tests should prompt one to carry out the specific enzyme assays in the tissue which expresses the disease, namely the liver.

Cytochrome-c Oxidase Deficiency↗
PubMed1994

Long segment and short segment familial Hirschsprung's disease: variable clinical expression at the RET locus.

Hirschsprung's disease (aganglionic megacolon, HSCR) is a frequent condition of unknown origin (1/5000 live births) resulting in intestinal obstruction in neonates and severe constipation in infants and adults. In the majority of cases (80%), the aganglionic tract involves the rectum and the sigmoid colon only (short segment HSCR), while in 20% of cases it extends toward the proximal end of the colon (long segment HSCR). In a previous study, we mapped a gene for long segment familial HSCR to the proximal long arm of chromosome 10 (10q11.2). Further linkage analyses in familial HSCR have suggested tight linkage of the disease gene to the RET protoncogene mapped to chromosome 10q11.2. Recently, nonsense and missense mutations of RET have been identified in HSCR patients. However, the question of whether mutations of the RET gene account for both long segment and short segment familial HSCR remained unanswered. We have performed genetic linkage analyses in 11 long segment HSCR families and eight short segment HSCR families using microsatellite DNA markers of chromosome 10q. In both anatomical forms, tight pairwise linkage with no recombinant events was observed between the RET proto-oncogene locus and the disease locus (Zmax = 2.16 and Zmax = 5.38 for short segment and long segment HSCR respectively at 0 = 0%) Multipoint linkage analyses performed in the two groups showed that the maximum likelihood estimate was at the RET locus. Moreover, we show that point mutations of the RET proto-oncogene occur either in long segment or in short segment HSCR families and we provide evidence for incomplete penetrance of the disease causing mutation. These data suggest that the two anatomical forms of familial HSCR, which have been separated on the basis of clinical and genetic criteria, may be regarded as the variable clinical expression of mutations at the RET locus.

Chromosome Mapping↗
PubMed1994

[Identification of mutation of RET proto-oncogene in Hirschsprung disease].

Hirschsprung's disease is a frequent congenital malformation of the hindgut. The existence of Hirschsprung's families favors the role of an autosomal dominant gene with a reduced penetrance. We have successively localized and identified the RET proto-oncogene as the gene responsible for familial Hirschsprung's disease. Interestingly, other mutations of the RET proto-oncogene have been described in inherited predisposition to endocrine cancers. This observation shows that, depending on their nature, mutations of the RET proto-oncogene could lead either to early developmental defects or to tumor predisposition.

Endocrine Gland Neoplasms↗