Pure partial 7p trisomy including the TWIST, HOXA, and GLI3 genes.
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Adult↗
Biomedical subjects
M Vekemans
Publications and source records attributed to M Vekemans.
beta(1)-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome.
Smith-Magenis syndrome (SMS) is a clinically recognisable contiguous gene syndrome ascribed to interstitial deletions of chromosome 17p11.2. Patients have a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Serum melatonin levels and day-night behaviour were studied in nine SMS children (aged 4 to 17 years) given acebutolol, a selective beta(1)-adrenergic antagonist (10 mg/kg early in the morning). Cardiac examination, serum melatonin, motor activity recordings, and sleep diaries were monitored before and after drug administration. The present study shows that a single morning dose of acebutolol suppressed the inappropriate secretion of melatonin in SMS. A significant improvement of inappropriate behaviour with increased concentration, delayed sleep onset, increased hours of sleep, and delayed waking were also noted. These results suggest that beta(1)-adrenergic antagonists help to manage hyperactivity, enhance cognitive performance, and reduce sleep disorders in SMS.
Acebutolol↗
[Value of molecular cytogenetics in pre- and postnatal diagnostic of chromosome abnormalities].
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Chromosome Aberrations↗
Chromosome 7q22-q31 duplication: report of a new case and review.
We report on a girl with psychomotor retardation, growth retardation, microcephaly, frontal bossing, large ears, small nose, high arched and narrow palate, short neck, and generalized hirsutism. Cytogenetic analysis in addition to fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) showed the presence of a chromosome 7q22-->q31.3 duplication. Comparison with other reported cases shows some resemblance but insufficient to enable us to establish a definite syndrome with specific clinical manifestations. The importance in better analyzing further cases by new molecular cytogenetics techniques is raised.
Child↗
Expression of the PAX2 gene in human embryos and exclusion in the CHARGE syndrome.
The CHARGE syndrome comprises ocular coloboma, heart malformation, choanal atresia, retarded growth and development, central nervous system malformations, genital hypoplasia, ear abnormalities, or deafness. The cause of the CHARGE syndrome remains unknown. In the present study, we analyzed the distribution pattern of the PAX2 gene in human embryos and found that PAX2 gene expression occurs in the primordia affected in the CHARGE syndrome. These data prompted us to consider the PAX2 gene a candidate gene in the CHARGE "association." We analyzed the PAX2 gene in 34 patients fulfilling the diagnostic criteria of the CHARGE syndrome for deletion and nucleotidic variations of the coding sequence and identified only polymorphisms. Our data suggest that mutation of the PAX2 gene is not a cause of the CHARGE association. However, the pattern of expression of PAX2 suggests that genes encoding downstream targets effectors could be candidate genes for the CHARGE syndrome.
Abnormalities, Multiple↗
Expression of the PTEN tumour suppressor protein during human development.
The tumour suppressor gene PTEN, localized to 10q23.3, is the susceptibility gene for Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba (BRR) syndrome, two hamartoma syndromes with an increased risk of breast and thyroid tumours. Somatic mutations have been found in a variety of human tumours. Functional studies have revealed that PTEN plays a fundamental role in cellular growth, death, adhesion and migration. RNA in situ hybridization using the pten coding region in mouse embryos showed ubiquitous transcription, providing evidence that pten could play a versatile role throughout murine development. Nothing is known regarding the pattern of PTEN expression during human development. Here, we present the pattern of PTEN expression during human development using a specific monoclonal antibody and examine the relationship of the temporal and spatial expression pattern to the clinical manifestations of CS and BRR, the somatic genetic data in sporadic cancers, the murine knockout models and the RNA expression data in mouse embryos. We observed mainly high-level PTEN expression in tissues (e.g. skin, thyroid and central nervous system) known to be involved in CS and BRR. In addition, we identified tissues (e.g. peripheral nervous system, autonomomic nervous system and upper gastrointestinal tract) with high PTEN expression not commonly known to play a role in these syndromes nor in sporadic tumorigenesis in those organs. This knowledge may help in identifying roles for PTEN which, as of today, are unknown or even unsuspected.
Digestive System↗
Apparent Sotos syndrome (cerebral gigantism) in a child with trisomy 20p11.2-p12.1 mosaicism.
We report on a child with apparent Sotos syndrome (cerebral gigantism) and partial duplication of the short arm of chromosome 20 mosaicism. Trisomy 20p11.2-p12.1 was diagnosed using cytogenetic and FISH studies. The somatostatin receptor 4 (SSTR4) gene is included in the duplicated segment. This suggests that a dosage effect of this gene might be related to some of the clinical findings observed in our patient. The present observation emphasizes the importance of chromosome analysis in patients with well-delineated but sporadic conditions.
Adult↗
Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.
Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S251X [corrected] in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest-derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest-derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system.
Autonomic Nervous System↗
Expression of the sonic hedgehog gene in human embryos with neural tube defects.
BACKGROUND: To estimate the rate of malformations observed during early human development, a series of 38,913 first-trimester abortions were studied. Neural tube defects (NTD) were found in 57 cases. METHODS: A histological study of serial sections performed in 25 embryos revealed a spectrum of axial structure abnormalities. Expression of the SHH gene was studied by in situ hybridization in one case of CRS and in two cases of SB. RESULTS: A cervical notochord duplication was always found in craniorachischisis (CRS, n = 8), but not in spina bifida (SB, n = 10) or diplomyelia (split cord malformation, n = 3). In the embryo with CRS, expression of SHH was found in both domains, corresponding to the duplicated part of the notochord, whereas a single signal was observed in the nonduplicated part. This expression was associated at the cervical level of the open neural tube with a broad SHH expression domain and with two or even three domains in its lumbar region, suggesting multiple functional floor plates. Similarly, in two embryos with SB, two domains of SHH expression were found in the ventral neural tube. CONCLUSIONS: Our findings suggest that notochord splitting in the cervical region might be involved in the pathogenesis of CRS. Interestingly, similar notochord abnormality and altered expression of the shh gene are observed in Lp mice with NTD. This suggests that the Lp gene could be a candidate gene for human CRS. Further studies are needed to establish the primary event responsible for the notochord splitting and for the abnormal expression of the SHH gene in the floor plate in embryos with CRS and SB.
Abortion, Induced↗
Subtle familial unbalanced translocation t(8;11)(p23.2;p15.5) in two fetuses with Beckwith-Wiedemann features.
We describe a subtle translocation t(8;11)(p23.2;p15.5) ascertained after two induced abortions in the same sibship because of the discovery of fetal hydrops on ultrasound examination. Initial cytogenetic studies performed on cultured amniotic fluid cells were considered as normal in both fetuses. High resolution banding analysis and FISH studies performed on the parents' chromosomes revealed a paternal translocation t(8;11)(p23.2;p15.5). Retrospective FISH analysis of both fetuses showed that they carried the same chromosomal imbalance including a distal monosomy 8pter and a distal trisomy 11pter. The phenotypes of the fetuses were re-examined and found to be compatible with Beckwith-Wiedemann syndromes (BWS). FISH analysis using an IGF2 probe demonstrated the presence of three copies of the IGF2 gene. This study highlights the value of searching for subtle chromosome rearrangements in families with recurrent unexplained multiple malformation syndromes discovered prenatally. Also, it contributes to a better delineation of the prenatal phenotype of BWS. Finally, it sheds new light on the aetiology of non-immune hydrops fetalis.
Adult↗
First specific preimplantation genetic diagnosis for ornithine transcarbamylase deficiency.
Ornithine transcarbamylase (OTC) deficiency is an X-linked dominant metabolic disorder with partial penetrance in heterozygous females. Affected boys usually die from hyperammonemia in the first few days of life, while clinical expression in carrier females ranges from no symptoms to neonatal death. A young couple whose boy had died of OTC deficiency in the neonatal period was referred to our genetic department for their subsequent pregnancy. The fetus was found to be affected, and after genetic counseling the pregnancy was terminated. Prenatal diagnosis of the third pregnancy identified a heterozygous female, who died after a normal birth at age 11 days from hyperammonemia. After this, the couple asked for preimplantation genetic diagnosis (PGD). We have developed a duplex nested PCR assay allowing the amplification of both the mutation and an informative restriction fragment length polymorphism (RFLP) located in the 3' end of the OTC gene. After nested amplification, allele identification was carried out for both loci by double restriction digestion and electrophoresis gel analysis. The co-amplification of both loci provided a means of detecting potential allele dropout or incomplete digestion. Two PGD cycles were carried out, a total of 14 embryos were analysed and a diagnosis could be obtained in 13/14 embryos. There were four unaffected male embryos, four heterozygous females and four unaffected females; the final embryo was an affected one of undetermined gender. In both cycles, three unaffected embryos could be transferred early on Day 4 post-insemination. The second cycle resulted in the birth of a baby boy devoid of the OTC mutation. This constitutes the first birth following PGD carried out by a French team.
Base Sequence↗
Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulatingtumor cells.
We have developed a new assay, ISET (isolation by size of epithelial tumor cells), which allows the counting and the immunomorphological and molecular characterization of circulating tumor cells in patients with carcinoma, using peripheral blood sample volumes as small as 1 ml. Using this assay, epithelial tumor cells can be isolated individually by filtration because of their larger size when compared to peripheral blood leukocytes. ISET parameters were defined using peripheral blood spiked with tumor cell lines (HepG2, Hep3B, MCF-7, HeLa, and LNCaP). ISET can detect a single, micropipetted tumor cell, added to 1 ml of blood. We also demonstrate that fluorescence in situ hybridization can be used to perform chromosomal analyses on tumor cells collected using ISET. Polymerase chain reaction-based genetic analyses can be applied to ISET-isolated cells, and, as an example, we demonstrate homozygous p53 deletion in single Hep3B cells after filtration and laser microdissection. Finally, we provide evidence for the in vivo feasibility of ISET in patients with hepatocellular carcinoma undergoing tumor resection. ISET, but not reverse transcriptase-polymerase chain reaction, allowed analysis of cell morphology, counting of tumor cells, and demonstration of tumor microemboli spread into peripheral blood during surgery. Overall, ISET constitutes a novel approach that should open new perpectives in molecular medicine.
Carcinoma, Hepatocellular↗
Regional and cellular specificity of the expression of TPRD, the tetratricopeptide Down syndrome gene, during human embryonic development.
The TPRD gene (tetratricopeptide (TPR) containing Down syndrome gene) is one of the candidate genes in the Down syndrome chromosomal region-1. Duplication of this gene may be the cause of major phenotypic features of Down syndrome. Here we show that the TPRD expression is developmentally regulated during human embryogenesis. At the earliest stages of development (Carnegie 8-12) TPRD expression is ubiquitous. At later developmental stages (Carnegie stages 14, 16 and 18), it becomes restricted to the nervous system, as is the case for the mtprd gene during mouse development. We extended our analysis of TPRD expression during fetal development of the human nervous system (13, 22 and 24 weeks). A new oblique illumination technique was used to compare signal intensity and cell density. Some regions of the nervous system such as the external cortical layers of the brain, and the inner neuroblastic layer of the eye, strongly express the TPRD gene.
Cerebral Cortex↗
PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism.
The renal-coloboma syndrome (RCS, MIM 120330) is an autosomal dominant disorder caused by PAX2 gene mutations. We screened the entire coding sequence of the PAX2 gene for mutations in nine patients with RCS. We found five heterozygous PAX2 gene mutations: a dinucleotide insertion (2G) at position 619 in one sporadic RCS case, a single nucleotide insertion (619 + G) in three unrelated cases, and a single nucleotide deletion in a familial case. In this familial case, three affected sibs showed a striking ocular phenotypic variability. Each of the sibs carried a 619insG mutation, whilst unaffected parents did not, suggesting the presence of germline mosaicism. Interestingly, the 619insG mutation has been previously reported in several patients and is also responsible for the Pax21Neu mouse mutant, an animal model of human RCS. This study confirms the critical role of the PAX2 gene in human renal and ocular development. In addition, it emphasises the high variability of ocular defects associated with PAX2 mutations ranging from subtle optic disc anomalies to microphthalmia. Finally, the presence of PAX2 germline mosaicism highlights the difficulties associated with genetic counselling for PAX2 mutations.
Base Sequence↗
Confined placental mosaicism and genomic imprinting.
The concept of confined placental mosaicism and its relationship to genomic imprinting and uniparental disomy is explained in this chapter. Clinically significant imprinting syndromes, such as Prader-Willi syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome, Silver-Russell syndrome and transient neonatal diabetes mellitus, potentially associated with confined placental mosaicism are described and referenced. Non-Mendelian inheritance of recessive mutations in uniparental disomy is illustrated. Both skewed X chromosome inactivation and isolated gonadal mosaicism are outlined as newly recognized consequences of post-zygotic chromosomal mutation and confined placental mosaicism. Clinical management of pregnancies with confined placental mosaicism is proposed as well as future research directions in the field of confined placental mosaicism and its consequences.
Abnormalities, Multiple↗
JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome.
Mutations of the JAGGED1 gene, encoding a NOTCH receptor ligand, cause Alagille syndrome (AGS), a complex malformative disorder affecting mainly the liver, heart, vertebrae, eye, and face. Minor and occasional features involving kidney, pharynx, systemic arteries, skeleton, and ear are in some cases associated with the syndrome. To describe the expression of JAGGED1 during human embryogenesis and to study its relationship with all the features of AGS, we performed in situ hybridization studies on human embryos and fetal tissue sections. JAGGED1 was mainly expressed in the cardiovascular system. In the liver, JAGGED1 transcripts were only detected in blood vessels. JAGGED1 was also expressed in other structures of mesenchymal origin (distal mesenchyme of limb buds; mesonephric and metanephric tubules of the kidney) and in epithelial structures including the ciliary margin of the retina and the posterior part of the lens, the ventral epithelium of the otic vesicle, the neurosensory epithelium of the ear vestibule, the epithelium of pharyngeal arches, and the developing central nervous system. The strong JAGGED1 expression during human embryo- and feto-genesis both in the vascular system and in other mesenchymal and epithelial tissues implicates abnormal angiogenesis in the pathogenesis of Alagille syndrome and particularly the paucity of interlobular bile ducts. However, it is probably not the only mechanism of the disease. Except for the central nervous system, there is a strong correlation between JAGGED1 expression and all the features of AGS. This implies that the features occasionally associated with the syndrome are not coincidental.
Alagille Syndrome↗
Improvement of cystic fibrosis using antitumoral drugs: a hypothesis.
The improvement of cystic fibrosis using antitumoral drugs has been reported. The hypothesis of a somatic reduction to heterozygosity of the CFTR gene mutations by homologous recombination in lung epithelium is proposed.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Circulating sex hormones and endometrial stromelysin-1 (matrix metalloproteinase-3) at the start of bleeding episodes in levonorgestrel-implant users.
Unpredictable endometrial bleeding is the major side-effect of levonorgestrel-releasing s.c. implants (Norplant), otherwise a method of choice for long-term contraception. The mechanisms responsible for bleeding are still unknown and no reliable treatment is available. Several matrix metalloproteinases (MMP) are expressed and activated in human endometrium only at menstruation and specific synthetic inhibitors of MMP fully prevent the tissue breakdown that occurs in menstrual-like endometrial explants. To investigate whether MMP are inappropriately expressed and activated in Norplant-treated endometria during bleeding episodes, volunteers were recruited to provide blood and endometrial biopsies at the start of bleeding episodes and during non-bleeding intervals. Whereas serum concentrations of levonorgestrel and sex hormones showed no change at bleeding, except for a slight decrease of oestradiol concentration, the expression and activation of stromelysin-1 released by explants cultured for 1 day were consistently increased at the start of bleeding episodes. Furthermore, stromelysin-1 was immunolocalized in stromal cells within breakdown areas of several bleeding endometria, but not in non-bleeding endometria. These observations suggest that the expression and activation of stromelysin-1 participate in the initiation of bleeding episodes upon Norplant contraception. New strategies in the prevention and treatment of abnormal bleeding based on MMP control should be envisaged.
Adult↗