Adult-onset female focal segmental glomerulosclerosis with nephrotic syndrome caused by a TBC1D8B variant: a case report

ABSTRACT

We report the case of a 49-year-old Chinese woman with nephrotic syndrome, characterized by normal kidney function but poor response to hormonal and immunosuppressive therapy, indicative of steroid-resistant nephrotic syndrome. Through renal biopsy, the patient was diagnosed as havingfocal segmental glomerulosclerosis (perihilar type), and subsequent whole-exome sequencing identified a pathogenic frameshift variant concerning the TBC domain of the TBC1D8B gene. This patient represents the first late-onset Chinese female who was found to carry a novel, pathogenic variant in the gene TBC1D8B.

BACKGROUND

Histological characteristics of focal segmental glomerulosclerosis (FSGS) encompass focal and segmental sclerosis, alongside foot process effacement. FSGS commonly presents as proteinuria and has the potential to advance into nephrotic syndrome (NS). FSGS is classified into three categories based on its etiology: primary, secondary, and hereditary. Hereditary FSGS is primarily attributed to pathogenic variants in genes encoding podocyte-associated proteins, including nephrin, which is located within the narrow-slit diaphragm. These pathogenic variants induce both morphological and functional aberrations in podocytes [1].

TBC1D8B, located on the X chromosome, is a recently discovered single-gene locus associated with hereditary FSGS. Pathogenic variants in this gene primarily lead to FSGS in male patients at an early age [2]. The protein encoded by this gene plays a crucial role in regulating specific Rab GTPases, including Rab11b, which are responsible for vesicle transport. As a result, it contributes to the regulation of nephrin, a key protein involved in maintaining the glomerular filtration barrier [1]. Through whole-exome sequencing, we have identified a female patient with late-onset adult FSGS who carries a pathogenic frameshift variant in the TBC region of the TBC1D8B gene.

CASE REPORT

We present a case of a 49-year-old female patient who came to our clinic after being diagnosed with proteinuria for 3 years. Originally, her urinary protein levels were noted to be 2+–3+ 3 years ago. Six months prior to her visit, a 24-hour urine protein test showed a level of 3.21 g, with serum albumin (Alb) measured at 26.1 g/l, and serum creatinine recorded at 50.6 μmol/l. Despite undergoing 3 months of treatment with prednisone and cyclophosphamide (CTX), the patient did not achieve remission of her NS and subsequently discontinued these medications. Seventeen days prior to her current admission to the hospital, she experienced a worsening of pitting edema in both lower extremities. Additionally, she has a history of hypertension for the past 9 months, which is currently managed with irbesartan 150 mg/day, maintaining her blood pressure at 130/80 mmHg (Supplementary Table 1).

A renal biopsy was performed, yielding the following results. Immunofluorescence examination revealed the presence of IgM 2+ mesangial granular deposition and C3 2+ small vessel wall granular deposition, with IgA and IgG being negative. Light microscopy examination of the biopsy specimen revealed a total of 20 glomeruli, among which four glomeruli exhibited ischemic sclerosis (20%) and three glomeruli showed partial sclerosis accompanied by plasma exudation (15%). The remainder of the glomeruli exhibited mild mesangial cell proliferation and increased mesangial matrix, segmental aggravation, and a small amount of endothelial cell hyperplasia. Additionally, one glomerulus demonstrated segmental sclerosis around the blood vessel, as well as adhesion between the capsule and balloon and periglomerular fibrosis. Further observation under light microscopy revealed focal interstitial fibrosis of the kidney (15%) and atrophy of the renal tubules. Electron microscopy demonstrated that ∼60–70% of the glomerular capillary wall had fused without electron-dense deposition (Fig. 1a–d).

Figure 1:

(a) Renal biopsy specimens reveal granular deposits of IgM in the mesangial regions as shown by immunofluorescence (×200, 25 μm). (b) Electron microscopy images of renal biopsy specimens show podocyte foot process effacement (8000, 2 μm). (c) Light microscopy of renal biopsy specimens with PAS staining shows the patient has perihilar variant FSGS (×400, 50 μm). (d) Light microscopy of renal biopsy specimens with Masson's trichrome staining, showing a different plane of the same glomerulus as in (c) with PAS staining (×400, 50 μm). (e) Whole-exome sequencing results identifying the pathogenic NM_017752.3 (TBC1D8B) c.2089delA variant in a patient diagnosed with FSGS. (f) Schematic representation of the pathogenic variant in the exon of the TBC1D8B gene and its corresponding protein localization. GRAM, rab-like GTPase activators and myotubularin domain; TBC, Tre-2-Bub2-Cdc16 domain; aa, amino acid. (g) Pedigree chart illustrating the presence of the TBC1D8B c.2089delA pathogenic variant in a patient with FSGS.

Whole-exome sequencing analysis detected a heterozygous pathogenic frameshift variant in the TBC1D8B gene (NM_017752.3), specifically c.2089delA (p.Asp698Metfs6). This variant is absent from the total population in the gnomAD database (v.2.1.1) and is not present in ClinVar. Additionally, we have uploaded the variant to ClinVar (SCV005200508). This variant results in the premature appearance of a stop codon during protein synthesis (Fig. 1e, f, Supplementary Table 2). Further investigation of the patient's pedigree revealed that both parents had passed away, with an unknown history of kidney disease. The patient lacks any siblings. Subsequently, the patient's 25-year-old daughter underwent a urine test, which yielded normal results (Fig. 1g). The patient was then administered oral treatment consisting of irbesartan at a dosage of 75 mg/day, dapagliflozin at a dosage of 10 mg/day, and finerenone at a dosage of 10 mg/day. Following a 6-month follow-up period, the patient experienced partial remission of NS, with serum creatinine levels remaining within the normal range (Supplementary Table 3).

DISCUSSION

To the best of our knowledge, this is the first case reporting a pathogenic frameshift variant in the TBC domain of an X-linked heterozygous TBC1D8B gene in a Chinese female with late-onset FSGS. Previous studies have shown that most pathogenic variants in the TBC1D8B gene are located outside the TBC domain (Fig. 1f). Other studies have reported that hormone and immunosuppressant drugs do not effectively treat patients carrying pathogenic variant in the TBC1D8B gene, resulting in progression to kidney failure, except for one patient with a pathogenic variant in the TBC region who maintained normal kidney function [1–5]. TBC1D8B-associated nephropathy is recognized as an X-linked recessive disorder. Previous studies have predominantly reported TBC1D8B-associated nephropathy have been in males with hemizygous variants. Interestingly, our study presents a case of a female patient with a heterozygous pathogenic variant in the TBC1D8B gene, whose clinical presentation and renal pathology align with FSGS. This suggests that even females carrying a heterozygous pathogenic variant in TBC1D8B may be at risk of developing podocytopathy. Additionally, further research is needed to explore whether other factors may contribute to the development of FSGS in such cases. However, due to the limited number of cases, further observational studies are necessary to characterize treatment and prognosis in patients. Milosavljevic et al. have suggested that variations at different sites of TBC1D8B show varying degrees of severity in the renal slit membrane protein phenotype [3]. These studies further confirm the significant role of pathogenic variants in the TBC1D8B gene in FSGS. In the future, investigating the molecular roles and effects of these variations could help establish personalized and targeted treatment approaches for patients.

CONFLICT OF INTEREST STATEMENT

None declared.

ETHICAL APPROVAL

This study conformed to the Declaration of Helsinki and was approved by the ethics committee of Beijing Anzhen Hospital, Capital Medical University, approval number 2024027X.

PATIENT CONSENT

The patient gave informed consent to publish this case.