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Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
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Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder
Aram Niaz1, Jia Truong2, Annabel Manoleras3
1Rare Diseases Functional Genomics, Kids Research, The Children's Hospital at Westmead and Children's Medical Research Institute, Westmead, NSW, Australia.
Blood Advances
|April 27, 2022
Summary
Functional analysis of TERT gene variants is crucial for diagnosing telomere biology disorders (TBDs). Compound heterozygous variants in TERT can reveal interallelic effects impacting telomerase function and disease severity.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Telomere biology disorders (TBDs) are inherited conditions causing bone marrow failure due to mutations in telomere maintenance genes.
- Evaluating the pathogenicity of TBD variants is challenging due to variable penetrance and genetic anticipation.
Observation:
- A patient with compound heterozygous TERT variants presented with severe Hoyeraal-Hreidarsson syndrome, while parents were asymptomatic.
- One TERT variant (L557P) impaired RNA binding, and another (K1050E) affected DNA binding and processivity.
Findings:
- Molecular modeling and biochemical analyses revealed functional interactions between the two TERT alleles.
- Wild-type hTERT partially rescued the processivity defect caused by the K1050E variant, but L557P did not.
Implications:
- This study elucidates a mechanistic link between RNA binding and processivity in telomerase function.
- Functional characterization of compound heterozygous variants is essential for accurate TBD diagnosis and understanding interallelic effects.
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