Abstract
BackgroundPerturbations 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.MethodsWith 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.ResultsIn 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.ConclusionAltogether, 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.
Highlights
Perturbations on the Left-Right axis establishment lead to laterality defects, with frequently associated Congenital Heart Diseases (CHDs)
The impairment of the Nodal signaling in the lateral plate mesoderm, by variants in the genes involved in the pathway such as ActRIIB (MIM #602730) [11, 12], LEFTY 1 (MIM #603037) [13, 14], LEFTY 2 (MIM #601877) [13, 14], CRYPTIC/CFC1 (MIM #605194) [15, 16], CRIPTO/ TDGF1 (MIM #187395) [17, 18], FOXH1 (MIM #603621) [19, 20], NODAL (MIM #601265) [21, 22] and PITX2C (MIM # 601542) [23, 24] had already been associated to laterality disorders and/or CHDs in humans
Using the up-to-date PolyPhen-2 algorithm, we observed that the DAND5 p.R152H variant had no effect on the DAND5 protein
Summary
Perturbations on the Left-Right axis establishment lead to laterality defects, with frequently associated Congenital Heart Diseases (CHDs). Nodal itself induces its intracellular signaling by binding to type I (ALK4 and ALK7) and type II (ActRIIa and ActRIIb) serine-threonine kinase receptors in the presence of one EGF-CFC (epidermal growth factor-Cripto-FRL1-Cryptic) family co-receptor, Cripto or Cryptic. This leads to the phosphorylation of regulatory Smads (Smad and Smad3), their association with Smad, translocation into the nucleus, and to the interaction with the transcription factor FoxH1, which at the end activates the expression of Nodal target genes, in particular, Pitx2 [9]. Several variations in Nodal co-receptor CFC1 were linked to TOF, TGA, DORV and/or laterality defects [15, 17, 25]
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