Summary
In their 2008 study “Mutations in the tRNA splicing endonuclease cause pontocerebellar hypoplasia”, Budde et al. demonstrated the genetic cause of PCH2 through genomic analysis. The underlying change is located on chromosome 17q25, specifically in the TSEN54 gene.
Study design and results
Budde et al. examined 58 patients with PCH from European countries, Brazil, and Israel. Of these, 52 participants were classified as having PCH2 based on symptoms and MRI findings.
Genomic analysis revealed that individuals with PCH2 carry mutations on chromosome 17q25. By narrowing down the affected region, the researchers were able to identify the causative mutation:
a homozygous missense variant in the TSEN54 gene (TSEN54 919G˃T).
The team proposed that a single “founder mutation” most likely explains why the majority of PCH2 patients carry the same genetic variant. They estimated that this mutation first appeared at least 11–16 generations ago.On the protein level, this mutation leads to the substitution of alanine with serine at position 307. It is therefore referred to as TSEN54 A307S.
Causative mutation in PCH4?
Mutations in the same gene region have also been identified as the cause of PCH4. Additional mutations have been reported in some patients, but all are linked to the TSEN complex.
Conclusion
This study provided the first evidence that mutations in genes essential for cytoplasmic tRNA splicing can cause human disease. By precisely describing the causative mutation for PCH2, the study opened new opportunities for further research, as well as offering options for affected families, including prenatal diagnosis and determination of carrier status in unaffected siblings.
Note: Further information about the TSEN54 gene, its function, and its implications can be found here.
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