Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia

Isaac Marin-Valencia, Andreas Gerondopoulos, Maha S. Zaki, Tawfeg Ben-Omran, Mariam Almureikhi, Ercan Demir, Alicia Guemez-Gamboa, Anne Gregor, Mahmoud Y. Issa, Bart Appelhof, Susanne Roosing, Damir Musaev, Basak Rosti, Sara Wirth, Valentina Stanley, Frank Baas, Francis A. Barr, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.

Original languageEnglish
Pages (from-to)441-450
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number3
StatePublished - 7 Sep 2017
Externally publishedYes


  • TBC1D23
  • ataxia
  • intellectual disability
  • microcephaly
  • pontocerebellar hypoplasia


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