A mutation update for the FLNC gene in myopathies and cardiomyopathies

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrim

The etiology of orofacial clefts. An emphasis on lifestyle and nutrition other than folate.

Item does not contain fulltextRU Radboud Universiteit Nijmegen, 10 november 2005Promotores : Kuijpers-Jagtman, A.M., Zielhuis, G.A. Co-promotor : Steegers-Theunissen, R.P.M.141 p

Maternal dietary B vitamin intake, other than folate, and the association with orofacial cleft in the offspring.

Contains fulltext : 57243.pdf (publisher's version ) (Closed access)BACKGROUND: Periconceptional folic acid supplementation is suggested to prevent orofacial clefts (OFCs). Other B vitamins however may be beneficial as well. AIM OF THE STUDY: To investigate the maternal periconceptional dietary intake of thiamine, riboflavin, niacin, pyridoxine and cobalamin in association with the occurrence of OFC. METHODS: Two hundred and six mothers of a child with nonsyndromic OFC and 203 control mothers filled out a general questionnaire and a food frequency questionnaire around 14 months postpartum as a proxy for periconceptional intake. After exclusion of known pregnant and lactating mothers, those who reported to have altered their diet compared to the periconceptional period, and mothers with incidental folic acid supplement use periconceptionally, data of 182 OFC mothers and 173 controls were analysed. After logarithmic transformation, geometric means (P5-P95) were calculated and compared between the groups. After subsequent adjustment for energy, quintiles of dietary B vitamin intake were created. RESULTS: The periconceptional intake of thiamine, niacin and pyridoxine was significantly lower in mothers of an OFC child. A trend towards risk reduction for OFC with increasing dietary intake was demonstrated for thiamine (p = 0.04) and pyridoxine (p = 0.03). Risk reductions were only demonstrated in women using folic acid supplements periconceptionally. Supplement users tended to consume a diet richer in B vitamins. CONCLUSIONS: Periconceptional intake of thiamine, niacin and pyridoxine seems to contribute to the prevention of OFC

Nutrition and genes in the development of orofacial clefting

Clefts of the lip, alveolus, and/or palate, which are called orofacial clefts (OFC), occur in 0.5 to 3 per 1000 live and stillbirths. The pathogenesis of these congenital malformations remains largely unknown, but evidence is increasing that both nutritional and genetic factors are involved. Unlike genetic factors, nutritional causes can be corrected and may therefore contribute to the prevention of OFC. The goal of this review is to summarize the embryogenesis and genes involved in OFC, and to give an overview of the nutrients and related genes in humans. Improving our knowledge of the role of nutrition, genes, and their interactions in the pathogenesis of OFC may stimulate the development of nutritional interventions for OFC prevention in the future

Cytokeratin expression in palatal and marginal mucosa of cleft palate patients.

Contains fulltext : 50053.pdf (publisher's version ) (Closed access)OBJECTIVE: The margin of a palatal cleft is a unique anatomical site since the palatal mucosa is continuous with the nasal or nasopharyngeal mucosa. The aim of this study was to compare the expression patterns of cytokeratins and basal membrane components of the mucosa in the area of the cleft. DESIGN: Biopsies from the mucosa of the hard palate and from the cleft margin in the soft palate were obtained from five patients during the primary surgical closure of the cleft. The tissues were processed for haematoxylin-eosin staining and for immunohistochemistry. Antibodies against the cytokeratins (CK) 4, 7, 8, 10, 13, 16 and 18, and the basal membrane components heparan sulphate (HS) and collagen type IV (CIV) were used for immunostaining. RESULTS: The nasopharyngeal epithelium was thinner than the epithelium of the soft palatal mucosa, and showed less interpapillary ridges. The nasopharyngeal epithelium was stratified but expressed the keratins of a simple epithelium (CK 7, 8 and 18). The expression pattern abruptly changed into that of a typical non-keratinized stratified epithelium (CK 4, 13) at the transition to the soft palatal epithelium. The epithelium of the hard palate was a fully differentiated, keratinized and stratified epithelium (CK 10, 16). The basal membrane was thinner in the nasopharyngeal epithelium, which might be related to the presence of abundant inflammatory cells. CONCLUSION: The area around the palatal cleft showed three different types of epithelium. There was an abrupt transition in phenotype of the epithelium from the oral side to the nasopharyngeal side

Cleft palate cells can regenerate a palatal mucosa in vitro.

Contains fulltext : 69579.pdf (publisher's version ) (Closed access)Cleft palate repair leaves full-thickness mucosal defects on the palate. Healing might be improved by implantation of a mucosal substitute. However, the genetic and phenotypic deviations of cleft palate cells may hamper tissue engineering. The aim of this study was to construct mucosal substitutes from cleft palate cells, and to compare these with substitutes from normal palatal cells, and with native palatal mucosa. Biopsies from the palatal mucosa of eight children with cleft palate and eight age-matched control individuals were taken. Three biopsies of both groups were processed for (immuno)histochemistry; 5 were used to culture mucosal substitutes. Histology showed that the substitutes from cleft-palate and non-cleft-palate cells were comparable, but the number of cell layers was less than in native palatal mucosa. All epithelial layers in native palatal mucosa and mucosal substitutes expressed the cytokeratins 5, 10, and 16, and the proliferation marker Ki67. Heparan sulphate and decorin were present in the basal membrane and the underlying connective tissue, respectively. We conclude that mucosal cells from children with cleft palate can regenerate an oral mucosa in vitro

Cleft palate cells can regenerate a palatal mucosa in vitro.

Contains fulltext : 69579.pdf (publisher's version ) (Closed access)Cleft palate repair leaves full-thickness mucosal defects on the palate. Healing might be improved by implantation of a mucosal substitute. However, the genetic and phenotypic deviations of cleft palate cells may hamper tissue engineering. The aim of this study was to construct mucosal substitutes from cleft palate cells, and to compare these with substitutes from normal palatal cells, and with native palatal mucosa. Biopsies from the palatal mucosa of eight children with cleft palate and eight age-matched control individuals were taken. Three biopsies of both groups were processed for (immuno)histochemistry; 5 were used to culture mucosal substitutes. Histology showed that the substitutes from cleft-palate and non-cleft-palate cells were comparable, but the number of cell layers was less than in native palatal mucosa. All epithelial layers in native palatal mucosa and mucosal substitutes expressed the cytokeratins 5, 10, and 16, and the proliferation marker Ki67. Heparan sulphate and decorin were present in the basal membrane and the underlying connective tissue, respectively. We conclude that mucosal cells from children with cleft palate can regenerate an oral mucosa in vitro

Distinct Cardiac Transcriptomic Clustering in Titin and Lamin A/C-Associated Dilated Cardiomyopathy Patients

Contains fulltext : 225426.pdf (Publisher’s version ) (Closed access

Dynamic Ejection Fraction Trajectory in Patients With Dilated Cardiomyopathy With a Truncating Titin Variant

Contains fulltext : 284809.pdf (Publisher’s version ) (Closed access

A Mutation Update for the FLNC Gene in Myopathies and Cardiomyopathies

Contains fulltext : 220374.pdf (Publisher’s version ) (Open Access