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Eén van de te onderzoeken no-regret maatregelen uit de Verkenning Bereikbaarheid Ameland 2030 om op korte termijn de baggervolumes voor de vaargeul Holwerd-Ameland te beperken is het aanpassen van het kwelderonderhoud. Het idee is dat het kombergingsvolume vergroot wordt door een gedeelte van de kwelder(s) bij Holwerd af te graven, waardoor het baggerbezwaar mogelijk kan worden gereduceerd. Het doel van dit rapport is om het te verwachten effect van deze kwelderafgraving op het baggervolume in de vaargeul HolwerdAmeland te bepalen en advies te geven over de omvang van een mogelijke afgraving.

We identified, by homozygosity mapping, a novel locus on 10q21.3-q22.1 for Goldberg-Shprintzen syndrome (GOSHS) in a consanguineous Moroccan family. Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects, as well as Hirschsprung disease, an enteric nervous system defect. Furthermore, since bilateral generalized polymicogyria was diagnosed in all patients in this family, this feature might also be considered a key feature of the syndrome. We demonstrate that homozygous nonsense mutations in KIAA1279 at 10q22.1, encoding a protein with two tetratrico peptide repeats, underlie this syndromic form of Hirschsprung disease and generalized polymicrogyria, establishing the importance of KIAA1279 in both enteric and central nervous system development.

We recently reported that a sequence variant in the cell-cycle-checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 coding sequence in BRCA1/2-negative breast cancer cases from 89 pedigrees with three or more cases of breast cancer. We identified one novel germline variant, R117G, in two separate families. To evaluate the possible association of R117G and two germline variants repor

Recent loss-of-function studies in mice show that the transcription factor GATA6 is important for visceral endoderm differentiation. It is also expressed in early bronchial epithelium and the observation that this tissue does not receive any contribution from Gata6 double mutant embryonic stem (ES) cells in chimeric mice suggests that GATA6 may play a crucial role in lung development. The aim of this study was to determine the role of GATA6 in fetal pulmonary development. We show that Gata6 mRNA is expressed predominantly in the developing pulmonary endoderm and epithelium, but at E15.5 also in the pulmonary mesenchyme. Blocking or depleting GATA6 function results in diminished branching morphogenesis both in vitro and in vivo. TTF1 expression is unaltered in chimeric lungs whereas SPC and CC10 expression are attenuated in abnormally branched areas of chimeric lungs. Chimeras generated in a ROSA26 background show that endodermal cells in these abnormally branched areas are derived from Gata6 mutant ES cells, implicating that the defect is intrinsic to the endoderm. Taken together, these data demonstrate that GATA6 is not essential for endoderm specification, but is required for normal branching morphogenesis and late epithelial cell differentiation.

Hirschsprung disease, mental retardation, microcephaly, and specific craniofacial dysmorphism were observed in three children from a large, consanguineous, Moroccan family. A fourth child showed similar clinical features, with the exception of Hirschsprung disease. The association of these abnormalities in these children represents the Goldberg-Shprintzen syndrome (OMIM 235730). Mutation scanning of genes potentially involved

A wide spectrum of birth defects is caused by deletions of the DiGeorge syndrome chromosomal region at 22q11. Characteristic features include cranio-facial, cardiac and thymic malformations, which are thought to arise form disturbances in the interactions between hindbrain neural crest cells and the endoderm of the pharyngeal po

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The majority of patients with DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS) and a minority of patients with non-syndromic conotruncal heart defects are hemizygous for a region of chromosome 22q11. The chromosomal region that is commonly deleted is larger than 2 Mb. It has not been possible to narrow the smallest region of overlap (SRO) of the deletions to less than ca 500 kb, which suggests that DGS/VCFS might be a contiguous gene syndrome. The saturation cloning of the SRO is being carried out, and one gene (TUPLE1) has been identified. By using a cosmid probe (M51) and fluorescence in situ hybridization, we show here that the anonymous DNA marker locus D22S183 is within the SRO, between TUPLE1 and D22S75 (probe N25). A second locus with weak homology to D22S183, recognized by cosmid M56, lies immediately outside the common SRO of the DGS and VCFS deletions, but inside the SRO of the DGS deletions. D22S183 sequences are strongly conserved in primates and weaker hybridizing signals are found in DNA of other mammalian species; no transcripts are however detected in polyA+ RNA from various adult human organs. Probe M51 allows fast reliable screening for 22q11 deletions using fluorescence in situ hybridization. A deletion was found in 11 out of 12 DGS patients and in 3 out of 7 VCFS patients. Two patients inherited the deletion from a parent with mild (atypical) symptoms.

The vagal neural crest adjacent to the first seven somites gives rise to both ganglionic and ectomesenchymal derivatives. Ganglionic derivatives are the neurons and supportive cells of the enteric nervous system (ENS), cardiac, and dorsal root ganglia. Ectomesenchymal derivatives are cells in the cardiac outflow tract and the mesenchymal components of thymus and parathyroids. Ectomesenchymal derivatives are formed by a segment of the vagal neural crest, from the level of the otic vesicle down to the caudal boundary of the third somite, called the cardiac neural crest. We performed neural crest ablations to study regional differences within the avian vagal neural crest with regard to the formation of the ENS. Ablation of the entire vagal neural crest from the mid‐otic vesicle down to the seventh somite plus the nodose placode resulted in the absence of ganglia in the midgut (jejunum and ileum) and hindgut (colon). The foregut (esophagus, proventriculus, gizzard, and duodenum) was normally innervated. After ablation of the vagal neural crest adjacent to somites 3–5, ganglia were absent in the hindgut. Ablations of vagal neural crest not including this segment had no effect on the formation of the ENS. We surmise that the innervation of the hindgut in vivo depends specifically on the neural crest adjacent to somites 3–5, whereas innervation of the midgut can be accomplished by all segments within the vagal neural crest. The foregut can also be innervated by a source outside the vagal neural crest. To study intrinsic differences between various vagal neural crest segments regarding ENS formation, we performed chorioallantoic membrane cocultures of segments of quail vagal neural anlage and E4 chicken hindgut. We found that all vagal neural crest segments were able to give rise to enteric ganglia in the hindgut. When the neural crest of somites 6 and 7 was included in the segment, we also found melanocytes in the hindgut, suggesting that this segment is more related to tr

The heart originates from splanchnic mesoderm and to a lesser extent from neural crest cells. The HNK-1 monoclonal antibody is a marker for early migrating neural crest cells, but reacts also with structures which are not derived from the neural crest. We investigated whether heart structures are HNK-1 positive before neural crest cells colonize these target tissues. To that end, we determined the HNK-1 antigen expression in the developing avian heart on immunohistochemical sections and on Western blots. The HNK-1 immunoreactivity in the developing chick heart is compared with data from literature cm the localization of neural crest cells in chick/quail chimeras. Structures with neural crest contribution, including parts of the early outflow tract and the related endocardial cushions, the primordia of the semilunar valve leaflets and the aorticopulmonary septum were HNK-1 positive. Furthermore, other structures were HNK-1 positive, such as the atrioventricular cushions, the wall of the sinus venosus at stage HH 15 through 21, parts of the endocardium at E3, parts of the myocardium at E6, and the extracellular matrix in the myocardial base of the semilunar valves at E14. HNK-1 expression was particularly observed in morphologically dynamic regions such as the developing valves, the outflow tract cushion, the developing conduction system and the autonomie nervous system of the heart. We observed that atrioventricular endocardial cushions are HNK-1 positive. We conclude that: a HNK-1 immunoreactivity does not always coincide with the presence of neural crest cells or their derivatives; (2) the outflow tract cushions and atrioventricular endocardial cushions are HNK-1 positive before neural crest cells are expected (stage HH 19) to enter the endocardial cushions of the outflow tract; (3) the observed spatio-temporal HNK-1 patterns observed in the developing heart correspond with various HNK-1 antigens. Apart from a constant pattern of HNK-1 antigens during development