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

doi:10.1016/j.ajhg.2017.07.015

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

Am J Hum Genet. 2017 Sep 7;101(3):441-450. doi: 10.1016/j.ajhg.2017.07.015. Epub 2017 Aug 17.

Authors

Isaac Marin-Valencia¹, Andreas Gerondopoulos², Maha S Zaki³, Tawfeg Ben-Omran⁴, Mariam Almureikhi⁴, Ercan Demir⁵, Alicia Guemez-Gamboa¹, Anne Gregor¹, Mahmoud Y Issa³, Bart Appelhof⁶, Susanne Roosing¹, Damir Musaev⁷, Basak Rosti⁸, Sara Wirth⁷, Valentina Stanley⁷, Frank Baas⁶, Francis A Barr², Joseph G Gleeson⁹

Affiliations

¹ Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
² Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
³ Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, 12311 Cairo, Egypt.
⁴ Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, 3050 Doha, Qatar.
⁵ Gazi University, Department of Pediatric Neurology, 06500 Ankara, Turkey.
⁶ Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
⁷ Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
⁸ Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA; Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
⁹ Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA; Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA. Electronic address: jogleeson@ucsd.edu.

Abstract

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.

Keywords: TBC1D23; ataxia; intellectual disability; microcephaly; pontocerebellar hypoplasia.

MeSH terms

Adolescent
Animals
Cerebellar Diseases / genetics*
Cerebellar Diseases / pathology
Child
Child, Preschool
Female
GTPase-Activating Proteins / genetics*
HeLa Cells
Homozygote*
Humans
Male
Microcephaly / genetics*
Microcephaly / pathology
Mutation*
Pedigree
Phenotype
Zebrafish / genetics
Zebrafish / growth & development

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

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