Functional study of DAND5 variant in patients with Congenital Heart Disease and laterality defects

F. Cristo, J.M. Inácio, S. de Almeida, P. Mendes, D.S. Martins, J. Maio, R. Anjos, J.A. Belo

Research output: Contribution to journalArticle

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Abstract

Background: Perturbations on the Left-Right axis establishment lead to laterality defects, with frequently associated Congenital Heart Diseases (CHDs). Indeed, in the last decade, it has been reported that the etiology of isolated cases of CHDs or cases of laterality defects with associated CHDs is linked with variants of genes involved in the Nodal signaling pathway. Methods: With this in mind, we analyzed a cohort of 38 unrelated patients with Congenital Heart Defects that can arise from initial perturbations in the formation of the Left-Right axis and 40 unrelated ethnically matched healthy individuals as a control population. Genomic DNA was extracted from buccal epithelial cells, and variants screening was performed by PCR and direct sequencing. A Nodal-dependent luciferase assay was conducted in order to determine the functional effect of the variant found. Results: In this work, we report two patients with a DAND5 heterozygous non-synonymous variant (c.455G>A) in the functional domain of the DAND5 protein (p.R152H), a master regulator of Nodal signaling. Patient 1 presents left isomerism, ventricular septal defect with overriding aorta and pulmonary atresia, while patient 2 presents ventricular septal defect with overriding aorta, right ventricular hypertrophy and pulmonary atresia (a case of extreme tetralogy of Fallot phenotype). The functional analysis assay showed a significant decrease in the activity of this variant protein when compared to its wild-type counterpart. Conclusion: Altogether, our results provide new insight into the molecular mechanism of the laterality defects and related CHDs, priming for the first time DAND5 as one of multiple candidate determinants for CHDs in humans. © 2017 The Author(s).
Original languageEnglish
Pages (from-to)Online
Number of pages9
JournalBMC Medical Genetics
Volume18
Issue number1
DOIs
Publication statusPublished - 24 Jul 2017

Fingerprint

Heart Diseases
Pulmonary Atresia
Ventricular Heart Septal Defects
Aorta
Isomerism
Right Ventricular Hypertrophy
Tetralogy of Fallot
Congenital Heart Defects
Cheek
Luciferases
Epithelial Cells
Phenotype
Polymerase Chain Reaction
DNA
Population
Genes
Proteins

Keywords

  • Allelic variation
  • Congenital Heart Diseases
  • DAND5
  • Laterality defects
  • Nodal signaling
  • DAND5 protein, human
  • NODAL protein, human
  • protein Nodal
  • signal peptide
  • congenital heart malformation
  • female
  • genetic association study
  • genetic predisposition
  • genetics
  • genotype
  • heart septum defect
  • human
  • male
  • mutation
  • pathophysiology
  • phenotype
  • signal transduction
  • single nucleotide polymorphism
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Heart Defects, Congenital
  • Heart Septal Defects, Ventricular
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Mutation
  • Nodal Protein
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Signal Transduction

Cite this

Cristo, F. ; Inácio, J.M. ; de Almeida, S. ; Mendes, P. ; Martins, D.S. ; Maio, J. ; Anjos, R. ; Belo, J.A. / Functional study of DAND5 variant in patients with Congenital Heart Disease and laterality defects. In: BMC Medical Genetics. 2017 ; Vol. 18, No. 1. pp. Online.
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Functional study of DAND5 variant in patients with Congenital Heart Disease and laterality defects. / Cristo, F.; Inácio, J.M.; de Almeida, S.; Mendes, P.; Martins, D.S.; Maio, J.; Anjos, R.; Belo, J.A.

In: BMC Medical Genetics, Vol. 18, No. 1, 24.07.2017, p. Online.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Functional study of DAND5 variant in patients with Congenital Heart Disease and laterality defects

AU - Cristo, F.

AU - Inácio, J.M.

AU - de Almeida, S.

AU - Mendes, P.

AU - Martins, D.S.

AU - Maio, J.

AU - Anjos, R.

AU - Belo, J.A.

PY - 2017/7/24

Y1 - 2017/7/24

N2 - Background: Perturbations on the Left-Right axis establishment lead to laterality defects, with frequently associated Congenital Heart Diseases (CHDs). Indeed, in the last decade, it has been reported that the etiology of isolated cases of CHDs or cases of laterality defects with associated CHDs is linked with variants of genes involved in the Nodal signaling pathway. Methods: With this in mind, we analyzed a cohort of 38 unrelated patients with Congenital Heart Defects that can arise from initial perturbations in the formation of the Left-Right axis and 40 unrelated ethnically matched healthy individuals as a control population. Genomic DNA was extracted from buccal epithelial cells, and variants screening was performed by PCR and direct sequencing. A Nodal-dependent luciferase assay was conducted in order to determine the functional effect of the variant found. Results: In this work, we report two patients with a DAND5 heterozygous non-synonymous variant (c.455G>A) in the functional domain of the DAND5 protein (p.R152H), a master regulator of Nodal signaling. Patient 1 presents left isomerism, ventricular septal defect with overriding aorta and pulmonary atresia, while patient 2 presents ventricular septal defect with overriding aorta, right ventricular hypertrophy and pulmonary atresia (a case of extreme tetralogy of Fallot phenotype). The functional analysis assay showed a significant decrease in the activity of this variant protein when compared to its wild-type counterpart. Conclusion: Altogether, our results provide new insight into the molecular mechanism of the laterality defects and related CHDs, priming for the first time DAND5 as one of multiple candidate determinants for CHDs in humans. © 2017 The Author(s).

AB - Background: Perturbations on the Left-Right axis establishment lead to laterality defects, with frequently associated Congenital Heart Diseases (CHDs). Indeed, in the last decade, it has been reported that the etiology of isolated cases of CHDs or cases of laterality defects with associated CHDs is linked with variants of genes involved in the Nodal signaling pathway. Methods: With this in mind, we analyzed a cohort of 38 unrelated patients with Congenital Heart Defects that can arise from initial perturbations in the formation of the Left-Right axis and 40 unrelated ethnically matched healthy individuals as a control population. Genomic DNA was extracted from buccal epithelial cells, and variants screening was performed by PCR and direct sequencing. A Nodal-dependent luciferase assay was conducted in order to determine the functional effect of the variant found. Results: In this work, we report two patients with a DAND5 heterozygous non-synonymous variant (c.455G>A) in the functional domain of the DAND5 protein (p.R152H), a master regulator of Nodal signaling. Patient 1 presents left isomerism, ventricular septal defect with overriding aorta and pulmonary atresia, while patient 2 presents ventricular septal defect with overriding aorta, right ventricular hypertrophy and pulmonary atresia (a case of extreme tetralogy of Fallot phenotype). The functional analysis assay showed a significant decrease in the activity of this variant protein when compared to its wild-type counterpart. Conclusion: Altogether, our results provide new insight into the molecular mechanism of the laterality defects and related CHDs, priming for the first time DAND5 as one of multiple candidate determinants for CHDs in humans. © 2017 The Author(s).

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KW - Congenital Heart Diseases

KW - DAND5

KW - Laterality defects

KW - Nodal signaling

KW - DAND5 protein, human

KW - NODAL protein, human

KW - protein Nodal

KW - signal peptide

KW - congenital heart malformation

KW - female

KW - genetic association study

KW - genetic predisposition

KW - genetics

KW - genotype

KW - heart septum defect

KW - human

KW - male

KW - mutation

KW - pathophysiology

KW - phenotype

KW - signal transduction

KW - single nucleotide polymorphism

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Heart Defects, Congenital

KW - Heart Septal Defects, Ventricular

KW - Humans

KW - Intercellular Signaling Peptides and Proteins

KW - Male

KW - Mutation

KW - Nodal Protein

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Signal Transduction

U2 - 10.1186/s12881-017-0444-1

DO - 10.1186/s12881-017-0444-1

M3 - Article

VL - 18

SP - Online

JO - BMC Medical Genetics

JF - BMC Medical Genetics

SN - 1471-2350

IS - 1

ER -