The TBC1D8B gene is located on chromosome X at q22.3 and encodes the protein Tre2-Bub2-Cdc16 (TBC)1 domain family member 8B, which is a GTPase-activating protein for specific Rab GTPases, such as RAB11 that regulate vesicular trafficking of nephrin.
TBC1D8B was first reported in relation to X-linked early-onset steroid-resistant nephrotic syndrome in 2019 (Dorval et al., PMID: 30661770). The preferred disease name suggested for this disorder is ‘Nephrotic syndrome - TBC1D8B’. The mechanism of pathogenicity is known to be loss of function. Nephrotic syndrome - TBC1D8B is characterized in existing literature by significant protein loss in the urine causing generalized edema with variable age of onset ranging from the first few months of life to 19 years.
Nine variants (frameshift, nonsense and missense) have been reported in 8 probands in 3 publications (PMIDs: 30661770, 31732614, 35970429) and are included in this curation. A total of 6.3/12 pts. for genetic evidence was reached, considering case-level data.
This gene-disease association is also supported by animal models, expression studies, in vitro functional assays, and rescue assays. TBC1D8B is expressed on mature human glomeruli (PMID 30661770), interacts with nephrin which is reduced in mutant TBC1D8B (PMID 31732614), and TBC1D8B mutation in vitro increased podocyte motility, increased cell adhesion, and impaired vesicular trafficking (PMID 30661770). TBC1D8B knockout in zebrafish caused glomerular proteinuria, podocyte foot process effacement and pericardial edema (PMID 30661770). Lastly, TBC1D8B knockdown in zebrafish could be rescued using wild-type mRNA (PMID 30661770). A total of 5/6 pts. for experimental evidence was reached.
In summary, there is moderate evidence supporting the relationship between TBC1D8B and X-linked Nephrotic syndrome.
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