The Determination Factors of Left-Right Asymmetry Disorders - a Short Review

Abstract

Laterality defects in humans, situs inversus and heterotaxy, are rare disorders, with an incidence of 1:8000 to 1:10 000 in the general population, and a multifactorial etiology. It has been proved that 1.44/10 000 of all cardiac problems are associated with malformations of left-right asymmetry and heterotaxy accounts for 3% of all congenital heart defects. It is considered that defects of situs appear due to genetic and environmental factors. Also, there is evidence that the ciliopathies (defects of structure or function) are involved in development abnormalities. Over 100 genes have been reported to be involved in left-right patterning in model organisms, but only a few are likely to candidate for left-right asymmetry defects in humans. Left-right asymmetry disorders are genetically heterogeneous and have variable manifestations (from asymptomatic to serious clinical problems). The discovery of the right mechanism of left-right development will help explain the clinical complexity and may contribute to a therapy of these disorders.

Imaging evaluation of the heterotaxy syndrome

“…5,6 Cells in the node have a single motile cilium and these cilia generate with a rotational motion a leftward flow of the perinodal fluid that transports morphogenic proteins. 3,4,5,7 This motion would explain the asymmetric transfer of certain genes. The combination of situs abnormalities and primary ciliary dysfunction in human syndromes would strongly support this model.…”

“…5 An alternative theory suggests that increased calcium levels in endodermal cells to the left of the node play an important role in the asymmetric development of organs. 7,8…”

“…More than one hundred genes have been identified that play an important role in left-right pattering in animals, but only a few seem to be implicated in heterotaxy syndrome in humans. 7 Most cases of heterotaxy are sporadic 3 but familial cases have also been identified, with the autosomal recessive pattern of inheritance being the most common, like in primary ciliary dyskinesia. The autosomal dominant and X-linked patterns of inheritance are less common.…”

Situs Inversus Totalis

“…The cause of laterality disorders has been explored for over two decades, with a consensus that their etiology is multifactorial with genetic and environmental contributions (6,7). The development of laterality disor-…”

Dioxin and AHR impairs mesoderm gene expression and cardiac differentiation in human embryonic stem cells

“…Congenital heart defects (CHDs) are the most common type of birth defect, affecting close to 1% of live births worldwide 1 . They are thought to be caused by a combination of genetic and environmental factors 2 . However, only a small fraction of CHDs can be attributed to heritable gene mutations and the same CHD mutations can cause a variety of disease phenotypes, suggesting the involvement of modifier genes as well as non-genetic factors 3-5 . In human populations, epidemiology studies showed that occupational or accidental exposure to environmental chemicals such as dioxins can lead to increased congenital defects in newborns and ischemic heart diseases in adults [6][7][8][9] .…”