Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects.

Atrioventricular septal defects (AVSD) are highly heritable, clinically significant congenital heart malformations. Genetic and environmental modifiers of risk are thought to work in unknown combinations to cause AVSD. Approximately 5-10% of simplex AVSD cases carry a missense mutation in CRELD1. However, CRELD1 mutations are not fully penetrant and require interactions with other risk factors to result in AVSD. Vascular endothelial growth factor-A (VEGFA) is a well-characterized modulator of heart valve development. A functional VEGFA polymorphism, VEGFA c.-634C, which causes constitutively increased VEGFA expression, has been associated with cardiac septal defects suggesting it may be a genetic risk factor. To determine if there is an allelic association with AVSD we genotyped the VEGFA c.-634 SNP in a simplex AVSD study cohort. Over-representation of the c.-634C allele in the AVSD group suggested that this genotype may increase risk. Correlation of CRELD1 and VEGFA genotypes revealed that potentially pathogenic missense mutations in CRELD1 were always accompanied by the VEGFA c.-634C allele in individuals with AVSD suggesting a potentially pathogenic allelic interaction. We used a Creld1 knockout mouse model to determine the effect of deficiency of Creld1 combined with increased VEGFA on atrioventricular canal development. Morphogenic response to VEGFA was abnormal in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis. This supports our hypothesis that an additive effect between missense mutations in CRELD1 and a functional SNP in VEGFA contributes to the pathogenesis of AVSD.

A randomized, double-blind clinical study on the safety and tolerability of an iron multi-amino acid chelate preparation in premenopausal women.

ABSTRACT Considerable risk of iron deficiency has been identified in premenopausal women because of the adverse effects associated with commercial iron preparations. This study examined the safety and tolerability of a novel iron multi-amino acid chelate (IMAAC) preparation in premenopausal women. A single-centre, randomized, double-blind, three-arm placebo-controlled (n = 60) study was conducted where subjects received one of three test materials: IMAAC (600 mg) or ferrous sulfate (600 mg) each containing 25 mg of elemental iron, or placebo as a single daily dose for 7 days. After testing, there were no significant differences found in any of the hematological outcomes between the different test groups. The safety analyses showed that a significantly (p = .044) higher number of patients reported adverse events when taking the ferrous sulfate supplement compared to IMAAC. A significantly lower number of adverse effects (p = .008) were reported by subjects on IMAAC. The current study demonstrated the superiority of the IMAAC preparation over ferrous sulfate with regards to tolerability and adverse effects.

Identification, genomic organization and mRNA expression of CRELD1, the founding member of a unique family of matricellular proteins.

We have isolated and characterized a unique gene that encodes a highly conserved membrane bound extracellular protein that defines a new epidermal growth factor-related gene family. The CRELD1 (Cysteine-Rich with EGF-Like Domains 1) gene (previously known as cirrin) was cloned from a human chromosome 3 BAC. Mapping of the gene confirmed its position at chromosome 3p25.3. The gene is ubiquitously expressed in early development and later becomes more markedly expressed in the developing heart, limb buds, mandible and central nervous system. Expression persists in adulthood in most tissues. Sequence analysis suggests that this is a cell adhesion protein. The mouse orthologue was cloned and mapped to the syntenic region of mouse chromosome 6. Orthologues or homologues have also been identified for cow, Chinese hamster, Drosophila and Caenorhabditis elegans. The CRELD1 gene is deleted in the human cytogenetic disorder 3p- syndrome and is in the region of loss of heterozygosity for several types of cancer. A potential role for this protein in these disorders is discussed.