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ALK2 mutation in a patient with Down's syndrome and a congenital heart defect.

ABSTRACT: Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with DS and a primum-type atrial septal defect. Structural modeling of the cytoplasmic domain of the ALK2 receptor suggests that H286 is in close proximity to the nucleotide-binding site of the kinase domain. We investigated whether this p.His286Asp substitution altered ALK2 function by using both in vitro as well as in vivo assays. The p.His286Asp variant demonstrated impaired functional activity as measured by BMP-specific transcriptional response assays. Furthermore, mild dominant-interfering activity was observed in vivo compared with wild-type ALK2 as determined by RNA injection into zebrafish embryos. These data indicate that in the context of a DS background, ALK2-mediated reduction of BMP signaling may contribute to CHDs.

SUBMITTER: Joziasse IC

PROVIDER: S-EPMC3060330 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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ALK2 mutation in a patient with Down's syndrome and a congenital heart defect.

Joziasse Irene C IC Smith Kelly A KA Chocron Sonja S van Dinther Maarten M Guryev Victor V van de Smagt Jasper J JJ Cuppen Edwin E Ten Dijke Peter P Mulder Barbara Jm BJ Maslen Cheryl L CL Reshey Benjamin B Doevendans Pieter A PA Bakkers Jeroen J

European journal of human genetics : EJHG 20110119 4

Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morph ...[more]

PMID: 21248739

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Project description:BACKGROUND:The relationship between healthcare system inputs (e.g., human resources and infrastructure) and mortality has been extensively studied. However, the association between healthcare system inputs and patient-reported outcomes remains unclear. Hence, we explored the predictive value of human resources and infrastructures of the countries' healthcare system on patient-reported outcomes in adults with congenital heart disease. METHODS:This cross-sectional study included 3588 patients with congenital heart disease (median age?=?31y; IQR?=?16.0; 52% women; 26% simple, 49% moderate, and 25% complex defects) from 15 countries. The following patient-reported outcomes were measured: perceived physical and mental health, psychological distress, health behaviors, and quality of life. The assessed inputs of the healthcare system were: (i) human resources (i.e., density of physicians and nurses, both per 1000 people) and (ii) infrastructure (i.e., density of hospital beds per 10,000 people). Univariable, multivariable, and sensitivity analyses using general linear mixed models were conducted, adjusting for patient-specific variables and unmeasured country differences. RESULTS:Sensitivity analyses showed that higher density of physicians was significantly associated with better self-reported physical and mental health, less psychological distress, and better quality of life. A greater number of nurses was significantly associated with better self-reported physical health, less psychological distress, and less risky health behavior. No associations between a higher density of hospital beds and patient-reported outcomes were observed. CONCLUSIONS:This explorative study suggests that density of human resources for health, measured on country level, are associated with patient-reported outcomes in adults with congenital heart disease. More research needs to be conducted before firm conclusions about the relationships observed can be drawn. TRIAL REGISTRATION:ClinicalTrials.gov: NCT02150603. Registered 30 May 2014.

Dataset Information

ALK2 mutation in a patient with Down's syndrome and a congenital heart defect.

Publications

ALK2 mutation in a patient with Down's syndrome and a congenital heart defect.

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