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Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
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TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes
Julie C Van De Weghe1, Jessica L Giordano2, Inge B Mathijssen3
1Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
HGG Advances
|April 1, 2021
Summary
Genetic variants in TMEM218 cause Joubert-Meckel syndrome spectrum disorders, a group of ciliopathies. This discovery aids in diagnosing rare genetic conditions and understanding primary cilium function.
Area of Science:
- Genetics
- Cell Biology
- Developmental Biology
Background:
- Joubert-Meckel syndrome spectrum disorders are recessive ciliopathies stemming from primary cilium dysfunction.
- The primary cilium, an antenna-like organelle, is crucial for cellular signaling and is separated by the transition zone.
- Genetic causes remain unidentified in up to 30% of Joubert syndrome (JBTS) cases.
Purpose of the Study:
- To identify novel genetic causes of the Joubert-Meckel syndrome spectrum.
- To investigate the role of TMEM218 in ciliopathies.
Main Methods:
- Exome and targeted sequencing of 655 families with JBTS.
- Utilized MatchMaker Exchange to identify additional families with TMEM218 variants.
- Analyzed clinical features and functional data related to TMEM218.
Main Results:
- Identified biallelic TMEM218 variants in six families with ciliopathy phenotypes, including JBTS and Meckel syndrome.
- Four families had variants affecting the conserved amino acid position 115.
- Clinical features included molar tooth sign, occipital encephalocele, retinal dystrophy, and polycystic kidneys.
Conclusions:
- TMEM218 dysfunction is a significant cause of ciliopathy phenotypes within the Joubert-Meckel syndrome spectrum.
- This finding expands the genetic basis of JBTS and Meckel syndrome.
- Enables improved diagnostics, counseling, and therapeutic target identification for these rare disorders.
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