Genetic variation in the <i>COL6A1</i> region is associated with congenital heart defects in trisomy 21 (Down's syndrome)

Davies, Gail E.; Howard, Catherine M.; Farrer, Matthew J.; Coleman, Michelle; Bennett, Lynda; Cullen, Louise; Wyse, Richard K.H.; Burn, John; Williamson, R.; Kessling, Anna M.

doi:10.1111/j.1469-1809.1995.tb00746.x

Cited by 51 publications

(38 citation statements)

References 28 publications

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“…Human molecular genetic analyses demonstrate an association between variations in the type VI collagen locus on human chromosome 21 and AV valve defects in trisomy 21 infants (Davies et al, 1995). Type VI collagenmediated cell migration normally involves ␣1β1 and ␣2β2 integrins and is not inhibited by synthetic Arg-GlyAsp (RGD) peptides.…”

Section: Resultsmentioning

confidence: 99%

Expression of type VI collagen in the developing mouse heart

et al. 1998

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During development, the embryonic atrioventricular (AV) endocardial cushions undergo a morphogenic process to form mature valve leaflets and the membranous septa in the heart. Several extracellular matrix (ECM) proteins are expressed in the developing AV endocardial cushions, but it remains to be established if any specific ECM proteins are necessary for normal cushion morphogenesis. Abnormal development of the cardiac AV valves is a frequent cause of congenital heart defects, particularly in infants with trisomy 21 (Down syndrome). The genes encoding the α1 and α2 chains of type VI collagen are located on human chromosome 21 within the region thought to be critical for congenital heart defects in trisomy 21 infants. This suggests that the type VI collagen α1(VI) and α2(VI) chains may be important in normal AV valve morphogenesis. As a first step in understanding the role of type VI collagen in valve development, the authors examined the normal spatial and temporal expression patterns of mRNA and protein for type VI collagen in the embryonic mouse heart. Ribonuclease protection assay analysis demonstrates cardiac expression of the type VI collagen for α1(VI), α2(VI), and α3(VI) transcripts beginning at embryonic days 11–11.5 of mouse development. In situ hybridization studies demonstrate a coordinated pattern of cardiac expression within the AV valves for each type VI collagen chain from embryonic day 11.5 through the neonatal period. Immunohistochemical studies confirm a concentrated type VI collagen localization pattern in the endocardial cushions from the earliest stages of valve development through the neonatal period. These data indicate that type VI collagen is expressed in the developing AV canal in a pattern consistent with cushion tissue mesenchymal cell migration and proliferation, and suggest that type VI collagen plays a role in the morphogenesis of the developing cardiac AV endocardial cushions into the valve leaflets and membranous septa of the heart. Dev. Dyn. 1998;211:248–255. © 1998 Wiley‐Liss, Inc.

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Section: Resultsmentioning

confidence: 99%

Expression of type VI collagen in the developing mouse heart

et al. 1998

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“…Those that do are mentally retarded and display mod-erate to severe developmental malformations (Larsen, 1993). The presence of congenital heart defects among individuals with Down syndrome has been correlated with three restriction length fragment polymorphisms in the region of COL6A1 on chromosome 21 (Davies et al, 1995). This finding suggests that the severity of a syndrome caused by aneuploidy may be modified in part by the genetic background of the affected individual.…”

Section: Introductionmentioning

confidence: 81%

Tetraploid development in the mouse

Eakin

Behringer

2003

Developmental Dynamics

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Spontaneous duplication of the mammalian genome occurs in approximately 1% of fertilizations. Although one or more whole genome duplications are believed to have influenced vertebrate evolution, polyploidy of contemporary mammals is generally incompatible with normal development and function of all but a few tissues. The production of tetraploid (4n) embryos has become a common experimental manipulation in the mouse. Although development of tetraploid mice has generally not been observed beyond midgestation, tetraploid:diploid (4n:2n) chimeras are widely used as a method for rescuing extraembryonic defects. The tolerance of tissues to polyploidy appears to be dependent on genetic background. Indeed, the recent discovery of a naturally tetraploid rodent species suggests that, in rare genetic backgrounds, mammalian genome duplications may be compatible with the development of viable and fertile adults. Thus, the range of developmental potentials of tetraploid embryos remains in large part unexplored. Here, we review the biological consequences and experimental utility of tetraploid mammals, in particular the mouse. Developmental Dynamics 228:751-766, 2003.

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“…30 Collagen VI is a globular heterotrimer expressed in the basement membranes of endothelia and in the endocardial cushions during development, 31 which suggested it as a potential candidate for DS-CHD. 32 However, DUP21ZSC and two other cases in the literature 33 have complex CHD of the types associated with DS and have duplications which do not include collagen VI. Subject LI has TOF associated with duplication from 21pter through CRYA1, 33 and subject AL has a VSD associated with duplication extending at least to ITGB2 and excluding collagen VI 33 (see Fig.…”

Section: Narrowing the Borders Of The Ds-chd Region The Telomeric Bormentioning

confidence: 99%

Down syndrome congenital heart disease: A narrowed region and a candidate gene

Barlow

Chen

Shi

et al. 2001

Genetics in Medicine

170

122

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Purpose: Down syndrome (DS) is a major cause of congenital heart disease (CHD) and the most frequent known cause of atrioventricular septal defects (AVSDs). Molecular studies of rare individuals with CHD and partial duplications of chromosome 21 established a candidate region that included D21S55 through the telomere. We now report human molecular and cardiac data that narrow the DS-CHD region, excluding two candidate regions, and propose DSCAM (Down syndrome cell adhesion molecule) as a candidate gene. Methods: A panel of 19 individuals with partial trisomy 21 was evaluated using quantitative Southern blot dosage analysis and fluorescence in situ hybridization (FISH) with subsets of 32 BACs spanning the region defined by D21S16 (21q11.2) through the telomere. These BACs span the molecular markers D21S55, ERG, ETS2, MX1/2, collagen XVIII and collagen VI A1/A2. Fourteen individuals are duplicated for the candidate region, of whom eight (57%) have the characteristic spectrum of DS-CHD. Results: Combining the results from these eight individuals suggests the candidate region for DS-CHD is demarcated by D21S3 (defined by ventricular septal defect), through PFKL (defined by tetralogy of Fallot). Conclusions: These data suggest that the presence of three copies of gene(s) from the region is sufficient for the production of subsets of DS-CHD. This region does not include genes located near D21S55, previously proposed as a "DS critical region," or the genes encoding collagens VI and XVIII. Of the potential gene candidates in the narrowed DS-CHD region, DSCAM is notable in that it encodes a cell adhesion molecule, spans more than 840 kb of the candidate region, and is expressed in the heart during cardiac development. Given these properties, we propose DSCAM as a candidate for DS-CHD. Genetics in Medicine, 2001:3(2):91-101.

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Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down's syndrome)

Cited by 51 publications

References 28 publications

Expression of type VI collagen in the developing mouse heart

Expression of type VI collagen in the developing mouse heart

Tetraploid development in the mouse

Down syndrome congenital heart disease: A narrowed region and a candidate gene

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