TBC1D23 – Pontocerebellar Hypoplasia, Type 11

Pontocerebellar hypoplasia type 11 (PCH11) is an autosomal recessive neurodevelopmental disorder caused by biallelic variants in TBC1D23. In a Chinese family, a novel homozygous frameshift variant, c.511_512del (p.Phe171GlnfsTer8), was identified in the single affected individual, who exhibited profound pontocerebellar hypoplasia, thinning of the corpus callosum, global developmental delay (HP:0001263), and severe motor and language impairment (PMID:40581672).

Mechanistic studies in a zebrafish model demonstrated that the mutant transcript escapes nonsense-mediated decay to ~50% of wild-type levels, and in vitro assays showed the truncated TBC1D23 protein to have increased stability, aberrant cytoplasmic localization instead of Golgi targeting, and an inhibitory effect on cell proliferation, consistent with a primary loss-of-function exacerbated by cytotoxicity (PMID:40581672). Structural analyses of the TBC1D23 C-terminal Pleckstrin homology fold revealed PtdIns(4)P and FAM21 binding surfaces critical for endosome-to-TGN trafficking; patient-derived mutations in these interfaces disrupt neuronal growth in zebrafish, linking trafficking defects to PCH pathogenesis (PMID:31624125; PMID:37903274).

Overall, evidence is limited to a single family with concordant cellular and animal model data supporting a loss-of-function mechanism for PCH11. Additional unrelated cases and segregation analyses are needed to confirm the clinical validity. Key take-home: screening for TBC1D23 LoF variants can facilitate diagnosis of PCH11 and guide mechanistic research.

References

• Human genomics • 2025 • Identification and functional analysis of a novel TBC1D23 pathogenic variant in a Chinese family with pontocerebellar hypoplasia PMID:40581672
• Proceedings of the National Academy of Sciences of the United States of America • 2019 • Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH PMID:31624125
• Proceedings of the National Academy of Sciences of the United States of America • 2023 • FAM91A1-TBC1D23 complex structure reveals human genetic variations susceptible for PCH PMID:37903274

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