CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down Syndrome

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland, United States
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 11/2006; 140(22):2501-5. DOI: 10.1002/ajmg.a.31494
Source: PubMed


Available from: Darcie Babcock
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    • "However, even small genomic variations can play a pivotal role in phenotype penetrance in DS (Antonarakis et al. 2004) and thus interlaboratory variation might affect the OM phenotype. For example, allelic variation in CRELD1 on HSA3 modifies the risk of cardiac malformation in children (Maslen et al. 2006). In the mouse, breeding the Ts1RhR mouse model onto a mixed B6;C3H/129 background, as opposed to pure B6, leads to loss of the craniofacial phenotype (Keane et al. 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Chronic otitis media (OM) is common in Down syndrome (DS), but underlying aetiology is unclear. We analysed the entire available mouse resource of partial trisomy models of DS looking for histological evidence of chronic middle-ear inflammation. We found a highly penetrant OM in the Dp(16)1Yey mouse, which carries a complete trisomy of MMU16. No OM was found in the Dp(17)1Yey mouse or the Dp(10)1Yey mouse, suggesting disease loci are located only on MMU16. The Ts1Cje, Ts1RhR, Ts2Yah, and Ts65Dn trisomies and the transchomosomic Tc1 mouse did not develop OM. On the basis of these findings, we propose a two-locus model for chronic middle-ear inflammation in DS, based upon epistasis of the regions of HSA21 not in trisomy in the Tc1 mouse. We also conclude that environmental factors likely play an important role in disease onset.
    Full-text · Article · Sep 2013 · Mammalian Genome
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    • ") + 200 control chromosomes with DS (Maslen et al, 2006) † "
    [Show abstract] [Hide abstract] ABSTRACT: About half of people with Down syndrome (DS) exhibit some form of congenital heart disease (CHD); however, trisomy for human chromosome 21 (Hsa21) alone is insufficient to cause CHD, as half of all people with DS have a normal heart, suggesting that genetic modifiers interact with dosage-sensitive gene(s) on Hsa21 to result in CHD. We hypothesize that a threshold exists in both DS and euploid populations for the number of genetic perturbations that can be tolerated before CHD results. We ascertained a group of individuals with DS and complete atrioventricular septal defect and sequenced 2 candidate genes for CHD: CRELD1, which is associated with atrioventricular septal defect in people with or without DS, and HEY2, whose mouse ortholog (Hey2) produces septal defects when mutated. Several deleterious variants were identified, but the frequency of these potential modifiers was low. We crossed mice with mutant forms of these potential modifiers to the Ts65Dn mouse model of DS. Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD, demonstrating an interaction between the modifiers and trisomic genes. We showed further that, although each of these mutant modifiers is benign by itself, they interact to affect heart development when inherited together. Using mouse models of Down syndrome and of genes associated with congenital heart disease, we demonstrate a biological basis for an interaction that supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population.
    Full-text · Article · Apr 2012 · Circulation Cardiovascular Genetics
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    • "Studies investigating the penetrance and variability in DS phenotypes have previously singled out nontrisomic genes as important factors in DS phenotypes (Epstein 2001; Kerstann et al. 2004). For example, nontrisomic CRELD1 mutations have been linked to an increased penetrance of atrioventricular septal defects in individuals with DS, and the occurrence of DS-like heart defects in the Tc1 DS mouse model were dependent upon genetic background (Maslen et al. 2006; Dunlevy et al. 2010). Certain alleles of GATA1, also not found on Hsa21, may predispose individuals with Ts21 to DS-related acute megakaryoblastic leukemia (Wechsler et al. 2002). "
    [Show abstract] [Hide abstract] ABSTRACT: Individuals with full or partial Trisomy 21 (Ts21) present with clinical features collectively referred to as Down syndrome (DS), although DS phenotypes vary in incidence and severity between individuals. Differing genetic and phenotypic content in individuals with DS as well as mouse models of DS facilitate the understanding of the correlation between specific genes and phenotypes associated with Ts21. The Ts1Rhr mouse model is trisomic for 33 genes (the "Down syndrome critical region" or DSCR) hypothesized to be responsible for many clinical DS features, including craniofacial dysmorphology with a small mandible. Experiments with Ts1Rhr mice showed that the DSCR was not sufficient to cause all DS phenotypes by identifying uncharacteristic craniofacial abnormalities not found in individuals with DS or other DS mouse models. We hypothesized that the origins of the larger, dysmorphic mandible observed in adult Ts1Rhr mice develop from larger embryonic craniofacial precursors. Because of phenotypic variability seen in subsequent studies with Ts1Rhr mice, we also hypothesized that genetic background differences would alter Ts1Rhr developmental phenotypes. Using Ts1Rhr offspring from two genetic backgrounds, we found differences in mandibular precursor volume as well as total embryonic volume and postnatal body size of Ts1Rhr and nontrisomic littermates. Additionally, we observed increased relative expression of Dyrk1a and differential expression of Ets2 on the basis of the genetic background in the Ts1Rhr mandibular precursor. Our results suggest that trisomic gene content and allelic differences in trisomic or nontrisomic genes influence variability in gene expression and developmental phenotypes associated with DS.
    Full-text · Article · Sep 2011 · Genetics
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