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

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.

Endosome-to-TGN Trafficking: Organelle-Vesicle and Organelle-Organelle Interactions

“…Two human TBC1D23 isoforms are described so far, which differ by one exon (exon 15). As a result, the longer isoform including this exon encodes a protein with 699 residues, and the shorter one encodes 684 residues (Marin-Valencia et al, 2017). TBC1D23 contains three functional domains: an N-terminal TBC domain, a Rhodanese-like domain in the middle, and an C-terminal domain which is shown to be structurally similar to a Pleckstrin homology (PH) domain (Figure 3A; Wang et al, 2018;Huang et al, 2019).…”

“…For instance, TBC1D5 is a GAP for both Rab7a and Rab7b, and functions to regulate retromer-dependent trafficking, and to regulate late endosomal and lysosomal functions (Figure 3A; Mukhopadhyay et al, 2007;Seaman et al, 2009;Jia et al, 2016;Borg Distefano et al, 2018;Jimenez-Orgaz et al, 2018;Kvainickas et al, 2019). In contrast, TBC1D23 lacks both essential catalytic residues, and is catalytically inactive (Marin-Valencia et al, 2017). Proteins with a rhodanese domain can possess sulphurtransferase (such as TSTD1) or phosphatase (such as CDC25) activity (Bordo and Bork, 2002).…”

Endosomal receptor trafficking: Retromer and beyond

“…The interaction between the WDR11 complex and TBC1d23 is proposed to promote the tethering of vesicles to the TGN; however, the exact mechanism remains to be elucidated. Intriguingly, homozygous mutation in TBC1d23 has been recently linked with pontocerebellar hypoplasia, a developmental disorder characterized by impaired growth of the pons and cerebellum, furthering emphasizing the importance of vesicular trafficking in neuronal development and function.…”

Clinical genetics and genomic medicine in Qatar

“…Importantly, these studies have lent themselves to translational work that have helped dissect the underlying biological causes of disease. A few of many recent examples include TBC1D23 (OMIM 617687) and pontocerebellar hypoplasia (Marin-Valencia et al, 2017); SLC7A5 (OMIM 600182) and autism spectrum disorder (Tarlungeanu et al, 2016); TMTC3 (OMIM 617218) and cobblestone lissencephaly (Jerber et al, 2016); MBOAT7 (OMIM 606048) and autism with seizures and intellectual disability (Johansen et al, 2016). In addition to gene/condition-specific work, larger studies that incorporate statistical analyses of the underlying genomic architecture of the population have also yielded novel gene discovery techniques (Scott et al, 2016).…”