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FB2026_01
,
released March 12, 2026
This report describes nephrotic syndrome, type 20 (NPHS20), a steroid-resistant subtype of nephrotic syndrome which shows X-linked inheritance. The human gene implicated in this disease is TBC1D8B, a TBC family protein that may have Rab-GTPase activating ability. There is a single high-ranking ortholog of TBC1D8B in Drosophila, Tbc1d8-9, for which multiple genetic reagents have been generated, including an amorphic mutation, RNAi targeting constructs, alleles caused by insertional mutagenesis, overexpression constructs, and CRISPR/Cas9-based TKO constructs.
UAS constructs of the mouse ortholog of TBC1D8B, Mmus\Tbc1d8b, have been introduced into flies, including a construct carrying the wild-type gene and constructs carrying variants analogous to those associated with NPHS20 in human. See the 'Disease-Implicated Variants' table below. Functional complementation (heterologous rescue) of loss-of-function phenotypes of Dmel\Tbc1d8-9 by wild-type Mmus\Tbc1d8b has been demonstrated.
A moderate knockdown of Tbc1d8-9 in nephrocytes (podocyte-like cells) causes a reduction in nephrocyte function due to the loss of slit diaphragms. Stronger knockdown or complete loss of Tbc1d8-9, conversely, causes there to be ectopic, disorganized slit diaphragms. Knocking down Rab11, which binds to human TBC1D8B, also causes the loss of slit diaphragms, and abnormal clusters of slit diaphragm proteins. Overexpression of Rab11 causes ectopic protrusions of nephrin, a phenotype that is similar to but more mild than the Tbc1d8-9 loss-of-function phenotype.
[updated Sep. 2023 by FlyBase; FBrf0222196]
The nephrotic syndrome is characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. Approximately 20% of affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure (summary by Fuchshuber et al., 1996, pubmed:8606597). [From MIM:256300, 2016.06.13]
[NEPHROTIC SYNDROME, TYPE 20; NPHS20](https://omim.org/entry/301028)
[TBC1 DOMAIN FAMILY, MEMBER 8B; TBC1D8B](https://omim.org/entry/301027)
Steroid-resistant nephrotic syndrome (SRNS) commonly entails declining renal function, and represents the second most frequent cause of end-stage renal disease in patients manifesting before 25 years of age. (From Kampf et al. 2019, FBrf0244116.)
Nephrotic syndrome type 20 (NPHS20) is an X-linked renal disorder characterized by onset of steroid-resistant nephrotic syndrome and proteinuria in the first years of life in affected males. The disorder results in end-stage kidney disease and may cause death in childhood without renal transplantation. Carrier females may have a milder disorder with proteinuria or may be unaffected. Renal biopsy typically shows focal segmental glomerulosclerosis (FSGS) [] and effacement of podocyte foot processes (summary by Dorval et al. 2019, pubmed:30661770). [from MIM:301028, 2020.04.29. See also human health report FBhh0000617 about focal segmental glomerulosclerosis.]
After excluding relevant mutations in known SRNS genes, we identified hemizygous mutations of the gene TBC1 Domain Family Member 8B (TBC1D8B) in five individuals from five different families with nephrotic syndrome . All patients were male, and the available information was compatible with an X-linked inheritance. One heterozygous female carrier exhibited borderline proteinuria. From Kampf et al. 2019, FBrf0244116.)
The transmission pattern of NPHS20 in the families reported by Dorval et al. 2019 (pubmed:30661770) was consistent with X-linked inheritance. In 1 family, female mutation carriers were mildly affected, whereas in the other family, the female carrier was unaffected. [from MIM:301028, 2020.04.29.]
TBC1D8B is a member of the TBC domain protein family (Tre-2/Bub2/CDC16). Like other TBC proteins, TBC1D8B may function as a Rab-GTPase activating protein (Rab-GAP) by binding to specific Rab proteins and stimulating their GTPase activity. Interestingly, in addition to its Rab-GAP (TBC) domain, TBC1D8B contains one GRAM domain repeated two times, which allows binding to lipid rafts, critical elements of SD signaling in podocytes. TBC1D8B also possesses an EF-Hand domain localized at the C-terminal extremity. A second isoform of TBC1D8B results from alternative splicing events in intron 11 and leads to a shorter 632-amino acid protein, lacking the C-terminal extremity of the Rab-GAP domain and the entire EF-like domain. However, the catalytic residues (Arg534 and Glu574) are present in both protein isoforms. (From Dorval et al. 2019, pubmed:30661770.)
Many to one: four human genes to one Drosophila gene.
Single, high-scoring ortholog for TBC1D8B. Drosophila Tbc1d8-9 is orthologous to four human paralogs: TBC1D8, TBC1D8B, TBC1D9, and TBC1D9B.