Finding genetic contributions to sporadic disease: A recessive locus at 12q24 commonly contributes to patent ductus arteriosus

Mani, Arya; Meraji, Seyed-Mahmoud; Houshyar, Roozbeh; Radhakrishnan, Jayaram; Mani, Alaleh; Ahangar, Mehrabeh; Rezaie, Tayebeh; Taghavinejad, Mohammad-Ali; Broumand, B.; Zhao, Hongyu; Nelson‐Williams, Carol; Lifton, Richard P.

doi:10.1073/pnas.192582999

Cited by 80 publications

(51 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increasing evidence suggests that multiple genes may predispose to PDA, possibly exacerbated by environmental triggers (7,8,11,42,43). The demonstration that selective ablation of Myocd in cardiac neural crest-derived SMCs populating the DA gives rise to PDA suggests myocardin and/or myocardin-regulated genes may be involved in the pathogenesis of PDA.…”

Section: Discussionmentioning

confidence: 99%

“…In full-term infants, environmental exposures and maternal infection predispose to PDA (3)(4)(5). However, there is emerging evidence that PDA in full-term infants may frequently have a genetic basis (6,7). Familial PDA has been observed in Char syndrome, which is caused by a mutation in TFAP2B, encoding a helix-span-helix transcription factor expressed in the cardiac neural crest (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice

Huang¹,

Cheng²,

Li³

et al. 2008

J. Clin. Invest.

114

133

View full text Add to dashboard Cite

Myocardin (Myocd) is a potent transcriptional coactivator that has been implicated in cardiovascular development and adaptation of the cardiovascular system to hemodynamic stress. To determine the function of myocardin in the developing cardiovascular system, Myocd F/F /Wnt1-Cre + and Myocd F/F /Pax3-Cre + mice were generated in which the myocardin gene was selectively ablated in neural crest-derived SMCs populating the cardiac outflow tract and great arteries. Both Myocd F/F /Wnt1-Cre + and Myocd F/F /Pax3-Cre + mutant mice survived to birth, but died prior to postnatal day 3 from patent ductus arteriosus (PDA). Neural crest-derived SMCs populating the ductus arteriosus (DA) and great arteries exhibited a cell autonomous block in expression of myocardin-regulated genes encoding SMC-restricted contractile proteins. Moreover, Myocd-deficient vascular SMCs populating the DA exhibited ultrastructural features generally associated with the SMC synthetic, rather than contractile, phenotype. Consistent with these findings, ablation of the Myocd gene in primary aortic SMCs harvested from Myocd conditional mutant mice caused a dramatic decrease in SMC contractile protein expression. Taken together, these data demonstrate that myocardin regulates expression of genes required for the contractile phenotype in neural crest-derived SMCs and provide new insights into the molecular and genetic programs that may underlie PDA.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice

Huang¹,

Cheng²,

Li³

et al. 2008

J. Clin. Invest.

114

133

View full text Add to dashboard Cite

show abstract

“…Low penetrance recessive alleles imparting large effects have been implicated in several other complex traits such as patent ductus arteriosus, Hirschsprung disease, or autism. 23,24,36 For these traits, gene localization was achieved by homozygosity mapping in consanguineous populations that were enriched for recessive disorders. 23,24,36,37 Although we did not set out to study consanguineous populations, our cohort included six Hasidic Jewish kindreds, which contributed a significant proportion (but not all) of the linkage signal on chromosome 12 ( Figure 2B).…”

Section: Discussionmentioning

confidence: 99%

“…9 -12,16,17,20 -22 However, recent studies have identified an unexpected recessive contribution to several complex traits such as ductus arteriosus or autism. 23,24 Thus, in addition to genetic heterogeneity, genes with alternative modes of transmission may segregate among pVUR families, and misspecification of the inheritance model may complicate mapping studies of this trait.…”

mentioning

confidence: 99%

A Recessive Gene for Primary Vesicoureteral Reflux Maps to Chromosome 12p11-q13

Weng

Sanna‐Cherchi

Hensle

et al. 2009

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Primary vesicoureteral reflux (pVUR) is one of the most common causes of pediatric kidney failure. Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance. Absence of pVUR in parents of affected individuals raises the possibility of a recessive contribution to pVUR. We performed a genome-wide linkage scan in 12 large families segregating pVUR, comprising 72 affected individuals. To avoid potential misspecification of the trait locus, we performed a parametric linkage analysis using both dominant and recessive models. Analysis under the dominant model yielded no signals across the entire genome. In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping. This interval achieved a peak heterogeneity LOD score of 3.6 with 60% of families linked. This heterogeneity LOD score improved to 4.5 with exclusion of two high-density pedigrees that failed to link across the entire genome. The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations. In conclusion, this study identifies a major new locus for pVUR and suggests that in addition to genetic heterogeneity, recessive contributions should be considered in all pVUR genome scans.

show abstract

“…(The length of shared homozygosity among children of n first cousin marriages is expected to be approximately 30 cM/n.) If the region is unique, one expects the disease causing gene to lie within this region (Mani et al, 2002). Even if the disease is heterogeneous, meaning that any of several genes may be responsible for the disease, the same approach can be used after limiting the analysis to families of a limited population.…”

Section: Homozygosity Mappingmentioning

confidence: 99%

Global Genetic Analysis

Elahi¹,

Kumm²,

Ronaghi³

2004

BMB Reports

View full text Add to dashboard Cite

The introduction of molecular markers in genetic analysis has revolutionized medicine. These molecular markers are genetic variations associated with a predisposition to common diseases and individual variations in drug responses. Identification and genotyping a vast number of genetic polymorphisms in large populations are increasingly important for disease gene identification, pharmacogenetics and population-based studies. Among variations being analyzed, single nucleotide polymorphisms seem to be most useful in large-scale genetic analysis. This review discusses approaches for genetic analysis, use of different markers, and emerging technologies for large-scale genetic analysis where millions of genotyping need to be performed.

show abstract

Finding genetic contributions to sporadic disease: A recessive locus at 12q24 commonly contributes to patent ductus arteriosus

Cited by 80 publications

References 28 publications

Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice

Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice

A Recessive Gene for Primary Vesicoureteral Reflux Maps to Chromosome 12p11-q13

Global Genetic Analysis

Contact Info

Product

Resources

About