Loss of ciliary transition zone protein TMEM107 leads to heterotaxy in mice

Shylo, Natalia A.; Emmanouil, Elli; Ramrattan, Dylan; Weatherbee, Scott D.

doi:10.1016/j.ydbio.2019.12.014

Cited by 7 publications

(7 citation statements)

References 73 publications

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“…The application on case-control based mother-infant pairs from NBDPS identified several candidate genes associated with CHD. The possible roles of TMEM107, CTC1 and other genes in biological process related to CHD were supported by evidence from previous literatures (Berg et al, 2003;Booth & Charchar, 2017;Chen et al, 2013;Christopher et al, 2012;Klena et al, 2017;Mangino et al, 2012;Narasimhan & Roy, 2015;Shylo et al, 2016;Shylo et al, 2020;Taketazu et al, 2006). Our study provides an alternative approach to investigate MFG interaction, especially for rare variants, and the findings add to the growing knowledge of genetic etiology of CHD.…”

Section: Discussionsupporting

confidence: 82%

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A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

Huang,

Lyu,

Liu

et al. 2023

Genetic Epidemiology

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The risk of congenital heart defects (CHDs) may be influenced by maternal genes, fetal genes, and their interactions. Existing methods commonly test the effects of maternal and fetal variants one‐at‐a‐time and may have reduced statistical power to detect genetic variants with low minor allele frequencies. In this article, we propose a gene‐based association test of interactions for maternal–fetal genotypes (GATI‐MFG) using a case‐mother and control‐mother design. GATI‐MFG can integrate the effects of multiple variants within a gene or genomic region and evaluate the joint effect of maternal and fetal genotypes while allowing for their interactions. In simulation studies, GATI‐MFG had improved statistical power over alternative methods, such as the single‐variant test and functional data analysis (FDA) under various disease scenarios. We further applied GATI‐MFG to a two‐phase genome‐wide association study of CHDs for the testing of both common variants and rare variants using 947 CHD case mother–infant pairs and 1306 control mother–infant pairs from the National Birth Defects Prevention Study (NBDPS). After Bonferroni adjustment for 23,035 genes, two genes on chromosome 17, TMEM107 (p = 1.64e−06) and CTC1 (p = 2.0e−06), were identified for significant association with CHD in common variants analysis. Gene TMEM107 regulates ciliogenesis and ciliary protein composition and was found to be associated with heterotaxy. Gene CTC1 plays an essential role in protecting telomeres from degradation, which was suggested to be associated with cardiogenesis. Overall, GATI‐MFG outperformed the single‐variant test and FDA in the simulations, and the results of application to NBDPS samples are consistent with existing literature supporting the association of TMEM107 and CTC1 with CHDs.

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Section: Discussionsupporting

confidence: 82%

“…TMEM107 was also found to influence the risk of CHD. For example, animal studies showed that the functional loss of TMEM107 led to heterotaxy in mice (Shylo et al, 2020). Among the human fetus with complex CHDs, 16% of them are diagnosed with heterotaxy clinically (Berg et al, 2003; Taketazu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

Huang,

Lyu,

Liu

et al. 2023

Genetic Epidemiology

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“…Primary cilia defect in different organs in Tmem107 −/− embryos have been previously reported ( Cela et al, 2018 ; Shylo et al, 2020 ). However, the potential ciliary anomalies in the retina of these animals remain elusive.…”

Section: Resultsmentioning

confidence: 80%

“…Previous analysis of Tmem107 −/− animals revealed reduced ciliogenesis in mesenchymal cells associated with altered morphology of primary cilia ( Cela et al, 2018 ; Shylo et al, 2020 ). These findings corroborated the results previously reported in Tmem107 schlei mice and in fibroblasts derived from human patients ( Christopher et al, 2012 ; Shaheen et al, 2015 ; Shylo et al, 2016 ).…”

Section: Discussionmentioning

confidence: 96%

Role of ciliopathy protein TMEM107 in eye development: insights from a mouse model and retinal organoid

Dubaic,

Peskova,

Hampl

et al. 2023

Life Sci. Alliance

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Primary cilia are cellular surface projections enriched in receptors and signaling molecules, acting as signaling hubs that respond to stimuli. Malfunctions in primary cilia have been linked to human diseases, including retinopathies and ocular defects. Here, we focus on TMEM107, a protein localized to the transition zone of primary cilia. TMEM107 mutations were found in patients with Joubert and Meckel–Gruber syndromes. A mouse model lackingTmem107exhibited eye defects such as anophthalmia and microphthalmia, affecting retina differentiation.Tmem107expression during prenatal mouse development correlated with phenotype occurrence, with enhanced expression in differentiating retina and optic stalk. TMEM107 deficiency in retinal organoids resulted in the loss of primary cilia, down-regulation of retina-specific genes, and cyst formation. Knocking out TMEM107 in human ARPE-19 cells prevented primary cilia formation and impaired response toSmoothenedagonist treatment because of ectopic activation of the SHH pathway. Our data suggest TMEM107 plays a crucial role in early vertebrate eye development and ciliogenesis in the differentiating retina.

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“…The non‐motile structural components of cilia such as centrosomal proteins, IFTs, and transition zone components also affect cardiac left–right asymmetry establishment (Gorivodsky et al., 2009 ; Houde et al., 2006 ; Lee et al., 2015 ; Murcia et al., 2000 ; Shylo et al., 2020 ; C. Wu et al., 2014 ). Takeda et al.…”

Section: Lro Cilia and Cardiac Asymmetrymentioning

confidence: 99%

Functions of cilia in cardiac development and disease

Shaikh Qureshi,

Hentges

2023

Annals of Human Genetics

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Errors in embryonic cardiac development are a leading cause of congenital heart defects (CHDs), including morphological abnormalities of the heart that are often detected after birth. In the past few decades, an emerging role for cilia in the pathogenesis of CHD has been identified, but this topic still largely remains an unexplored area. Mouse forward genetic screens and whole exome sequencing analysis of CHD patients have identified enrichment for de novo mutations in ciliary genes or non‐ciliary genes, which regulate cilia‐related pathways, linking cilia function to aberrant cardiac development. Key events in cardiac morphogenesis, including left–right asymmetric development of the heart, are dependent upon cilia function. Cilia dysfunction during left–right axis formation contributes to CHD as evidenced by the substantial proportion of heterotaxy patients displaying complex CHD. Cilia‐transduced signaling also regulates later events during heart development such as cardiac valve formation, outflow tract septation, ventricle development, and atrioventricular septa formation. In this review, we summarize the role of motile and non‐motile (primary cilia) in cardiac asymmetry establishment and later events during heart development.

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Loss of ciliary transition zone protein TMEM107 leads to heterotaxy in mice

Cited by 7 publications

References 73 publications

A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

A gene‐based association test of interactions for maternal–fetal genotypes identifies genes associated with nonsyndromic congenital heart defects

Role of ciliopathy protein TMEM107 in eye development: insights from a mouse model and retinal organoid

Functions of cilia in cardiac development and disease

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