TSEN54 – Pontocerebellar Hypoplasia Type 2A

Pontocerebellar hypoplasia type 2A (PCH2A) is an autosomal recessive neurodevelopmental and neurodegenerative disorder defined by cerebellar and pontine hypoplasia, progressive microcephaly, profound global developmental delay (HP:0012736), choreoathetosis (HP:0001266), and intractable epilepsy (HP:0001250).

Genetic analyses in three Israeli Arab patients from two sibships (two siblings and their first cousin) demonstrated homozygosity for the recurrent missense variant p.Ala304Ser in TSEN54, establishing a founder effect in this population ([PMID:32629522]) and accounting for 3 probands across one extended kindred. Segregation analysis confirmed variant segregation in 2 additional affected relatives within the family ([PMID:32629522]).

TSEN54 pathogenic variants underlie PCH2A via an autosomal recessive inheritance pattern. The variant spectrum is dominated by missense changes such as p.Ala304Ser. A synonymous variant, c.1170G>A (p.Val390=), has also been reported in TSEN54-related PCH in an Iranian consanguineous family, expanding the allelic heterogeneity ([PMID:32697043]).

Functional studies in zebrafish morphants revealed that tsen54 knockdown causes loss of brain structural definition and increased neuronal apoptosis, phenocopying PCH pathology; these defects were partially rescued by co-injection of human TSEN54 mRNA, supporting a loss-of-function mechanism ([PMID:21273289]).

Complementary invertebrate models in Drosophila showed that Tsen54 mutants exhibit reduced brain lobe size, increased cell death, impaired locomotion, and reduced viability, closely mirroring human PCH phenotypes ([PMID:35132432]). Yeast genetic suppressor screens further implicate TSEN54 in tRNA processing–independent essential functions, demonstrating its broader role in neuronal viability and supporting haploinsufficiency as a disease mechanism ([PMID:36943791]).

In aggregate, genetic and experimental data converge on a loss-of-function mechanism for TSEN54 in PCH2A, with robust segregation, recurrent founder mutation, and consistent model phenotypes. TSEN54 variant analysis is clinically actionable for diagnosis and genetic counseling in PCH2A. Key Take-home: TSEN54 testing should be prioritized in patients with cerebellar hypoplasia, early epilepsy, and profound global developmental delay.

References

• Neuropediatrics • 2020 • Evolution of EEG Findings in Pontocerebellar Hypoplasia Type 2A: Normal EEG in the First Few Months followed by Abnormal Tracing over the Years. PMID:32629522
• Human Molecular Genetics • 2011 • Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia. PMID:21273289
• Biology Open • 2022 • Mutations in Drosophila tRNA processing factors cause phenotypes similar to Pontocerebellar Hypoplasia. PMID:35132432
• Genetics • 2023 • An unknown essential function of tRNA splicing endonuclease is linked to the integrated stress response and intron debranching. PMID:36943791

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