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Updated: May 27, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Biallelic TEDC1 variants cause a new syndrome with severe growth impairment and endocrine complications
Noriko Miyake1,2, Kentaro Shiga3, Yuya Hasegawa4
1Department of Human Genetics, National Center for Global Health and Medicine, Tokyo, Japan. nomiyake@ri.ncgm.go.jp.
Insights
Genetic variants in TEDC1 cause severe developmental disorders, including growth impairment and microcephaly, by disrupting centriole function and cell proliferation. This study identifies novel loss-of-function mutations in TEDC1, impacting human health and validating findings in zebrafish models.
Area of Science:
- Genetics
- Cell Biology
- Developmental Biology
Background:
- Centrioles are crucial for cell division and cilia formation.
- TEDC1 (Tektin 1) and TEDC2 (Tektin 2) are essential for centriole stability.
- Dysfunctional centrioles are implicated in various human diseases.
Purpose of the Study:
- To investigate the genetic basis of a severe developmental disorder characterized by microcephaly, growth impairment, and multiple congenital anomalies.
- To elucidate the functional consequences of identified genetic variants in TEDC1.
- To establish a disease model for studying TEDC1-related disorders.
Main Methods:
- Whole exome sequencing to identify causative genetic variants.
- In vitro studies using patient-derived cells to assess protein function and cell cycle progression.
- CRISPR/Cas9 gene editing in zebrafish to create a tedc1 knockout model.
Main Results:
- Identified compound heterozygous loss-of-function variants in TEDC1 in affected siblings.
- Demonstrated that TEDC1 variants lead to impaired centriole stability, cell cycle abnormalities, and cilia defects.
- The zebrafish model recapitulated key features of the human disorder, including growth impairment, cranial bone dysplasia, and sterility.
Conclusions:
- Biallelic loss-of-function variants in TEDC1 cause a severe developmental syndrome in humans.
- TEDC1 is essential for centriole function, cell proliferation, and normal development.
- The identified zebrafish model is valuable for further research into TEDC1-related disorders.
Abstract:
We encountered two affected male patients born to non-consanguineous parents, who presented with prenatal-onset severe growth impairment, primary microcephaly, developmental delay, adrenal insufficiency, congenital glaucoma, delayed bone aging, craniosynostosis, congenital tracheal stenosis, and primary hypogonadism. By exome sequencing, we identified compound heterozygous TEDC1 variants (NM_001134877.1 c.[104-5C>G];[787delG] p.[?];[(Ala263LeufsTer29)] in both affected siblings. We confirmed that the splice site variant, c.104-5C>G, leads to no TEDC1 protein production via nonsense-mediated mRNA decay. The frameshift variant located in the last coding exon, c.787delG, produces a C-terminally truncated protein, which impairs the binding with TEDC2. Thus, both variants are thought to be loss-of-function. TEDC1 and TEDC2 are both required for centriole stability and cell proliferation. Our in vitro experiments using patient-derived cells revealed cell cycle abnormality. Our in vivo study using tedc1-/- zebrafish generated by CRISPR/Cas9 successfully recapitulated the growth impairment and cranial bone dysplasia as seen in our patients. The tedc1-/- mutant zebrafish were sterile and did not have developed gonads. Furthermore, we showed that biallelic TEDC1 deletion causes cilia abnormalities through defective acetylated tubulins.
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