Randomization of Left-Right Asymmetry and Congenital Heart Defects

Abstract

Background: Nearly one in 100 live births presents with congenital heart defects (CHD). CHD is frequently associated with laterality defects, such as situs inversus , a mirrored positioning of internal organs. Body laterality is established by a complex process: monocilia at the embryonic left-right organizer facilitate both the generation and sensing of a leftward fluid flow. This induces the conserved left-sided Nodal signaling cascade to initiate asymmetrical organogenesis. Primary ciliary dyskinesia originates from dysfunction of motile cilia, causing symptoms such as chronic sinusitis, bronchiectasis and frequently situs inversus totalis . The most frequently mutated gene in primary ciliary dyskinesia, DNAH5 is associated with randomization of body asymmetry resulting in situs inversus totalis in half of the patients; however, its relation to CHD occurrence in humans has not been investigated in detail so far. Methods: We performed genotype/phenotype correlations in 132 patients with primary ciliary dyskinesia carrying disease-causing DNAH5 mutations, focusing on situs defects and CHD. Using high-speed video microscopy-, immunofluorescence-, and in situ hybridization analyses, we investigated the initial steps of left-right axis establishment in embryos of a Dnah5 -mutant mouse model. Results: In patients with primary ciliary dyskinesia carrying disease-causing DNAH5 mutations, 65.9% (87/132) had laterality defects: 88.5% (77/87) presented with situs inversus totalis , 11.5% (10/87) presented with situs ambiguus ; and 6.1% (8/132) presented with CHD. In Dnah5 mut/mut mice, embryonic left-right organizer monocilia lack outer dynein arms resulting in immotile cilia, impaired flow at the left-right organizer, and randomization of Nodal signaling with normal, reversed or bilateral expression of key molecules. Conclusions: For the first time, we directly demonstrate the disease-mechanism of laterality defects linked to DNAH5 deficiency at the molecular level during embryogenesis. We highlight that mutations in DNAH5 are not only associated with classical randomization of left-right body asymmetry but also with severe laterality defects including CHD.

Motility of efferent duct cilia aids passage of sperm cells through the male reproductive system

“…As reported for other types of DNAH5 deficient motile cilia ( Ibanez-Tallon, 2002 ; Fliegauf et al , 2005 ; Nöthe-Menchen et al , 2019 ), the DNAH5-deficient efferent duct cilia were—compared to controls—mostly immotile, with some cilia displaying residual flickering motility ( Supplementary Videos S3 and S4 ). At 37°C, the median CBF was significantly reduced from 13 Hz (controls) to 3 Hz ( Mdnah5 mut/mut ) ( P < 0.0001: ***; Fig.…”

“…These findings demonstrate that Mdnah5 mut/mut mice specifically lost ODAs in their efferent duct cilia, similar to respiratory cilia ( Nöthe-Menchen et al , 2019 ), but not in their sperm flagella and provide evidence for a conserved function of DNAH5 in cell types with multiple motile cilia but not sperm flagella.…”

CFAP53 regulates mammalian cilia-type motility patterns through differential localization and recruitment of axonemal dynein components

“…In tracheal cilia, on the other hand, DNAH5 was detected throughout the axoneme, in both control ( Fig 4G–4I ) and in Cfap53 -/- mice ( Fig 4J–4L ). Since DNAH5 is essential for ciliary motility [ 27 , 28 ], the absence or presence of DNAH5 in the two types of cilia correlated with effects of the loss of CFAP53 on their ability to move.…”

Gallbladder Adenosquamous Cancer With Situs Inversus Totalis: A Case Report and Literature Review

“…Meanwhile, the DNAH11 mutations are also associated with esophageal squamous cell carcinoma, ovarian cancer, and breast cancer 16,17 . Another DNAH family member DNAH5, another SIT-related gene, was found to be mutated in several malignancies [18][19][20] . Inversin, whose mutations cause an autosomal recessive cystic disorder characterized by SIT, functions as a molecular switch between Wnt signaling pathways 21 , as the Wnt pathways has close relationship with carcinogenesis including development of gallbladder cancer 22,23 .…”