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Dworniczak Bernd - One of the best experts on this subject based on the ideXlab platform.
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Randomization of Left-right Asymmetry and Congenital Heart Defects: The Role of DNAH5 in Humans and Mice
American Heart Association, 2019Co-Authors: Nöthe-menchen Tabea, Wallmeier Julia, Pennekamp Petra, Höben, Inga M, Olbrich Heike, Loges, Niki T, Raidt Johanna, Dougherty, Gerard W, Hjeij Rim, Dworniczak BerndAbstract:Background - Nearly one in 100 live births presents with congenital heart defects (CHD). CHD are frequently associated with laterality defects, such as Situs inversus totalis (SIT), a mirrored positioning of internal organs. Body laterality is established by a complex process: monocilia at the embryonic left-right organizer (LRO) facilitate both the generation and sensing of a leftward fluid flow. This induces the conserved left-sided Nodal signaling cascade to initiate asymmetric organogenesis. Primary ciliary dyskinesia (PCD) originates from dysfunction of motile cilia, causing symptoms such as chronic sinusitis, bronchiectasis and frequently SIT. The most frequently mutated gene in PCD, DNAH5 is associated with randomization of body asymmetry resulting in SIT 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 PCD patients 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 - 65.9% (87 / 132) of the PCD patients carrying disease-causing DNAH5 mutations had laterality defects: 88.5% (77 / 87) presented with SIT, 11.5% (10 / 87) presented with Situs Ambiguus; and 6.1% (8 / 132) presented with CHD. In Dnah5$^{mut/mut}$ mice, embryonic LRO monocilia lack outer dynein arms resulting in immotile cilia, impaired flow at the LRO, 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
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Randomization of Left-Right Asymmetry and Congenital Heart Defects The Role of DNAH5 in Humans and Mice
'Ovid Technologies (Wolters Kluwer Health)', 2019Co-Authors: Nöthe-menchen Tabea, Wallmeier Julia, Pennekamp Petra, Olbrich Heike, Loges, Niki T, Raidt Johanna, Dougherty, Gerard W, Hjeij Rim, Hoeben, Inga M., Dworniczak BerndAbstract: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
Nöthe-menchen Tabea - One of the best experts on this subject based on the ideXlab platform.
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Randomization of Left-right Asymmetry and Congenital Heart Defects: The Role of DNAH5 in Humans and Mice
American Heart Association, 2019Co-Authors: Nöthe-menchen Tabea, Wallmeier Julia, Pennekamp Petra, Höben, Inga M, Olbrich Heike, Loges, Niki T, Raidt Johanna, Dougherty, Gerard W, Hjeij Rim, Dworniczak BerndAbstract:Background - Nearly one in 100 live births presents with congenital heart defects (CHD). CHD are frequently associated with laterality defects, such as Situs inversus totalis (SIT), a mirrored positioning of internal organs. Body laterality is established by a complex process: monocilia at the embryonic left-right organizer (LRO) facilitate both the generation and sensing of a leftward fluid flow. This induces the conserved left-sided Nodal signaling cascade to initiate asymmetric organogenesis. Primary ciliary dyskinesia (PCD) originates from dysfunction of motile cilia, causing symptoms such as chronic sinusitis, bronchiectasis and frequently SIT. The most frequently mutated gene in PCD, DNAH5 is associated with randomization of body asymmetry resulting in SIT 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 PCD patients 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 - 65.9% (87 / 132) of the PCD patients carrying disease-causing DNAH5 mutations had laterality defects: 88.5% (77 / 87) presented with SIT, 11.5% (10 / 87) presented with Situs Ambiguus; and 6.1% (8 / 132) presented with CHD. In Dnah5$^{mut/mut}$ mice, embryonic LRO monocilia lack outer dynein arms resulting in immotile cilia, impaired flow at the LRO, 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
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Randomization of Left-Right Asymmetry and Congenital Heart Defects The Role of DNAH5 in Humans and Mice
'Ovid Technologies (Wolters Kluwer Health)', 2019Co-Authors: Nöthe-menchen Tabea, Wallmeier Julia, Pennekamp Petra, Olbrich Heike, Loges, Niki T, Raidt Johanna, Dougherty, Gerard W, Hjeij Rim, Hoeben, Inga M., Dworniczak BerndAbstract: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
Sharon D Dell - One of the best experts on this subject based on the ideXlab platform.
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laterality defects other than Situs inversus totalis in primary ciliary dyskinesia insights into Situs Ambiguus and heterotaxy
Chest, 2014Co-Authors: Adam J Shapiro, Stephanie D Davis, Thomas W Ferkol, Sharon D Dell, Margaret Rosenfeld, Kenneth N Olivier, Scott D Sagel, Carlos Milla, Maimoona A Zariwala, Whitney E WolfAbstract:BACKGROUND Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), Situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied. METHODS In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) Situs solitus (SS), (2) SI, or (3) Situs Ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD. RESULTS Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9%), 125 (41.0%), and 37 (12.1%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6% and 2.3% with SA plus complex or simple cardiac defects, respectively; 4.6% with SA but no cardiac defect; and 2.6% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P CONCLUSIONS At least 12.1% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects. TRIAL REGISTRY ClinicalTrials.gov ; No.: NCT00323167; URL: www.clinicaltrials.gov
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congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia
Circulation, 2007Co-Authors: Marcus P Kennedy, Sharon D Dell, Heymut Omran, Margaret W Leigh, Lucy Morgan, Paul L Molina, Blair V Robinson, Susan L Minnix, Heike Olbrich, Thomas SeverinAbstract:Background— Primary ciliary dyskinesia (PCD) is a recessive genetic disorder that is characterized by sinopulmonary disease and reflects abnormal ciliary structure and function. Situs inversus totalis occurs in ≈50% of PCD patients (Kartagener’s syndrome in PCD), and there are a few reports of PCD with heterotaxy (Situs Ambiguus), such as cardiovascular anomalies. Advances in diagnosis of PCD, such as genetic testing, allow the systematic investigation of this association. Methods and Results— The prevalence of heterotaxic defects was determined in 337 PCD patients by retrospective review of radiographic and ultrasound data. Situs solitus (normal Situs) and Situs inversus totalis were identified in 46.0% and 47.7% of patients, respectively, and 6.3% (21 patients) had heterotaxy. As compared with patients with Situs solitus, those with Situs abnormalities had more ciliary outer dynein arm defects, fewer inner dynein arm and central apparatus defects (P<0.001), and more mutations in ciliary outer dynein arm...
Whitney E Wolf - One of the best experts on this subject based on the ideXlab platform.
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laterality defects other than Situs inversus totalis in primary ciliary dyskinesia insights into Situs Ambiguus and heterotaxy
Chest, 2014Co-Authors: Adam J Shapiro, Stephanie D Davis, Thomas W Ferkol, Sharon D Dell, Margaret Rosenfeld, Kenneth N Olivier, Scott D Sagel, Carlos Milla, Maimoona A Zariwala, Whitney E WolfAbstract:BACKGROUND Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), Situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied. METHODS In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) Situs solitus (SS), (2) SI, or (3) Situs Ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD. RESULTS Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9%), 125 (41.0%), and 37 (12.1%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6% and 2.3% with SA plus complex or simple cardiac defects, respectively; 4.6% with SA but no cardiac defect; and 2.6% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P CONCLUSIONS At least 12.1% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects. TRIAL REGISTRY ClinicalTrials.gov ; No.: NCT00323167; URL: www.clinicaltrials.gov
Thomas Severin - One of the best experts on this subject based on the ideXlab platform.
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congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia
Circulation, 2007Co-Authors: Marcus P Kennedy, Sharon D Dell, Heymut Omran, Margaret W Leigh, Lucy Morgan, Paul L Molina, Blair V Robinson, Susan L Minnix, Heike Olbrich, Thomas SeverinAbstract:Background— Primary ciliary dyskinesia (PCD) is a recessive genetic disorder that is characterized by sinopulmonary disease and reflects abnormal ciliary structure and function. Situs inversus totalis occurs in ≈50% of PCD patients (Kartagener’s syndrome in PCD), and there are a few reports of PCD with heterotaxy (Situs Ambiguus), such as cardiovascular anomalies. Advances in diagnosis of PCD, such as genetic testing, allow the systematic investigation of this association. Methods and Results— The prevalence of heterotaxic defects was determined in 337 PCD patients by retrospective review of radiographic and ultrasound data. Situs solitus (normal Situs) and Situs inversus totalis were identified in 46.0% and 47.7% of patients, respectively, and 6.3% (21 patients) had heterotaxy. As compared with patients with Situs solitus, those with Situs abnormalities had more ciliary outer dynein arm defects, fewer inner dynein arm and central apparatus defects (P<0.001), and more mutations in ciliary outer dynein arm...