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

Rupp, Paul A.; Fouad, Gameil T.; Egelston, Carley A.; Reifsteck, Carol A.; Olson, Susan B.; Knosp, Wendy M.; Glanville, Robert W.; Thornburg, Kent L.; Robinson, Susan W.; Maslen, Cheryl L.

doi:10.1016/s0378-1119(02)00696-0

Cited by 69 publications

(85 citation statements)

References 24 publications

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“…Aside from Ccn1 and AVSD1, another genetic locus known to be associated with nonsyndromic AVSD is CRELD1, which encodes a predicted matricellular cell adhesion molecule based on its sequence. 6,32 Although the activities of CRELD1 have not yet been examined, these findings are consistent with the notion that matrix signaling is crucial for AV septation and valvular formation.…”

Section: Discussionsupporting

confidence: 80%

The Matricellular Protein CCN1 Is Essential for Cardiac Development

Lau

2006

Circulation Research

104

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Abstract-The matricellular protein CCN1 (formerly named CYR61) regulates cell adhesion, migration, proliferation, survival, and differentiation through binding to integrin receptors and heparan sulfate proteoglycans. Here we show that Ccn1-null mice are impaired in cardiac valvuloseptal morphogenesis, resulting in severe atrioventricular septal defects (AVSD). Remarkably, haploinsufficiency for Ccn1 also results in delayed formation of the ventricular septum in the embryo and persistent ostium primum atrial septal defects (ASD) in Ϸ20% of adults. Mechanistically, Ccn1 is not required for epithelial-to-mesenchymal transformation or cell proliferation and differentiation in the endocardial cushion tissue. However, Ccn1 deficiency leads to precocious apoptosis in the atrial junction of the cushion tissue and impaired gelatinase activities in the muscular component of the interventricular septum at embryonic day 12.5, when fusion between the endocardial cushion tissue and the atrial and ventricular septa occurs, indicating that these defects may underlie the observed AVSD. Moreover, human CCN1 maps to 1p21-p31, the chromosomal location of an AVSD susceptibility gene. Together, these results provide evidence that deficiency in matrix signaling can lead to autosomal dominant AVSD, identify Ccn1 ϩ/Ϫ mice as a genetic model for ostium primum ASD, and implicate CCN1 as a candidate gene for AVSD in humans. Key Words: apoptosis Ⅲ cardiac development Ⅲ cardiovascular disease Ⅲ integrin Ⅲ matricellular genes Ⅲ matrix metalloproteinases Ⅲ transgenic mice A trioventricular septal defect (AVSD) is a common family of genetic disorders, accounting for Ϸ7.5% of the recognized congenital heart disease (CHD) in humans. 1 During cardiac development, the endocardial cushion tissue expands through formation of the cardiac jelly, a specialized extracellular matrix (ECM) between the endocardium and myocardium, into which endocardial cells that have undergone epithelial-to-mesenchymal transformation (EMT) invade. Subsequent growth and remodeling of the cushion tissue, coupled with its fusion with the developing atrial septum and muscular interventricular septum, lead to formation of the definitive atrioventricular (AV) septa and valves. 2,3 Defects in this process are manifested in a spectrum of abnormalities with varying severities, ranging from partial forms of AVSD with ostium primum atrial septal defects (ASD) to complete forms with absence of the AV septa and lack of partitioning of the AV valve into separate mitral (left) and tricuspid (right) valves. Although AVSD is frequently associated with Down's syndrome (trisomy 21), nonsyndromic AVSD also occur. Although nonsyndromic AVSD may be a sporadic trait or the result of multifactorial inheritance, strong evidence also support the presence of susceptibility genes for AVSD that are autosomal dominant and incompletely penetrant. 4 -6 CCN1 (formerly named CYR61 [CYsteine-Rich angiogenic inducer 61; NM_001554) is a secreted, cysteine-rich protein associated with the ECM. A dynamically ...

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Section: Discussionsupporting

confidence: 80%

The Matricellular Protein CCN1 Is Essential for Cardiac Development

Lau

2006

Circulation Research

104

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“…The α3 (VI) chain is encoded by the COL6A3 located at chromosome 2, and individuals with Down syndrome who have single nucleotide polymorphisms in COL6A3 are at increased risk of muscle hypotonia and CHD [135]. Loss-of-function mutations in the cell adhesion molecule cysteine-rich epidermal growth factor-like domain (CRELD)1, encoded on chromosome 3, contribute to CHD in Down syndrome [136]. Increased gene dosage of the Hsa21 gene junctional adhesion molecule ( JAM)2 was recently shown to potentiate CHD in mice with CRELD1 mutations [137].…”

Section: Congenital Heart Defects and Cardiovascular Disease In Down mentioning

confidence: 99%

What people with Down Syndrome can teach us about cardiopulmonary disease

Colvin

Yeager

2017

Eur Respir Rev

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Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with cognitive impairment, congenital malformations ( particularly cardiovascular) and dysmorphic features. Immune disturbances in Down syndrome account for an enormous disease burden ranging from quality-of-life issues (autoimmune alopecia) to more serious health issues (autoimmune thyroiditis) and life-threatening issues (leukaemia, respiratory tract infections and pulmonary hypertension). Cardiovascular and pulmonary diseases account for ∼75% of the mortality seen in persons with Down syndrome. This review summarises the cardiovascular, respiratory and immune challenges faced by individuals with Down syndrome, and the genetic underpinnings of their pathobiology. We strongly advocate increased comparative studies of cardiopulmonary disease in persons with and without Down syndrome, as we believe these will lead to new strategies to prevent and treat diseases affecting millions of people worldwide.

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“…Protein microarray and data analysis FLAG-tagged human CRELD1 cDNA with the two transmembrane domains removed (DCRELD1) (Rupp et al, 2002) was expressed in GripTite 293 cells. The secreted DCRELD1 was purified by anti-FLAG M2 affinity gel (Sigma Chemical).…”

Section: Co-immunoprecipitationmentioning

confidence: 99%

Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

Edie

Klinedinst

et al. 2016

Genetics

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Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of .100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1. No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models.

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

Cited by 69 publications

References 24 publications

The Matricellular Protein CCN1 Is Essential for Cardiac Development

The Matricellular Protein CCN1 Is Essential for Cardiac Development

What people with Down Syndrome can teach us about cardiopulmonary disease

Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

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