De novo truncating variants of TRIM8 and atypical neuro-renal syndrome: a case report and literature review

The TRIM8 gene is located on human chromosome 10 and encodes a protein with 551 amino acids. The protein is an E3 ubiquitin ligase that participates in biological processes such as cell signaling, proliferation, differentiation, autophagy, immunity, and tumor growth. Its dysfunction is closely related to cancer, inflammation, and autoimmune diseases [1, 2]. TRIM8 is widely expressed in human tissues, especially in the central nervous system, kidney, and eyes [3]. Therefore, variants in the TRIM8 may damage the nervous and renal systems. Eight reports have described neurological and renal system diseases associated with TRIM8 variants, and all of them were de novo truncating variants in the last exon of TRIM8 [4‐11]. A total of 22 cases have been reported in the literature, and all of them were observed in children. Among them, three cases involved only neurological diseases (mainly epilepsy with psychomotor retardation), two cases involved renal diseases only, and two cases involved renal diseases accompanied by mild psychomotor retardation (no seizures). The other 15 cases involved obvious symptoms in the neurological and renal systems. The main manifestations of renal lesions are nephrotic-range proteinuria, and most cases eventually progress to end-stage renal disease. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS), and only one case involved FSGS with renal tubular damage. Most reported cases included specific facial features (such as long philtrum, straight eyebrows, sunken eyes, microcephaly, micrognathia, broad forehead, broad nasal bridge, upper-slanted palpebral fissures, thin lips, large ear lobes, and low-set ears). This study presents a case of one boy who had a de novo truncating variation in the last exon of TRIM8. Notably, this type of variant has not been reported before. Of all the previously reported variants, the variant involved in this case was the closest to the C-terminal. We reviewed the characteristics of previously reported cases of neuro-renal syndrome caused by a TRIM8 variant and found that when the TRIM8 variant is closer to the C-terminal, the renal damage is more severe and the nervous system damage is less severe [4‐11]. Our findings provide a new understanding of neuro-renal syndrome caused by TRIM8 variant. It also reminds us to pay attention to eye damage in addition to kidney and nervous system damage.

A 6-year-old boy presented to our hospital because of urinary incontinence with urgent urination for 3 years. He had astigmatism and myopia. He had no history of convulsions. His physical growth, intelligence, and motor development were normal. There was no family history of consanguineous marriage, kidney disease, or hereditary disease. The physical examination revealed specific facial features, including low-set ears, micrognathia, thin lips, wide eye distance, stubby neck, and large ear lobes. His blood pressure was normal. There was no edema in his body. All other results of the physical examination were normal. The urine examination showed massive proteinuria at the nephrotic level. The blood examination indicated that he had hyperlipidemia, that the lowest level of his serum albumin was 25.3 g/L, and that his estimated glomerular filtration rate suggested stage 3 chronic kidney disease. Urinary ultrasound suggested reduced volume and hydronephrosis in both kidneys. The urodynamic examination showed decreased bladder compliance and poor detrusor contraction. Brain magnetic resonance imaging showed that the bilateral frontal extracerebral space was widened, the left ventricle was fuller than the right ventricle, and a cystoid cerebrospinal fluid signal was observed in the cisterna magna and was considered to be an arachnoid cyst. The Wechsler Intelligence Scale result was normal. After excluding tuberculosis, hepatitis B, systemic lupus erythematosus, diabetes, tumors, and other diseases, he was administered sufficient prednisone, captopril, dipyridamole, and multivitamins orally for 28 days. There was no remission in the proteinuria and serum creatinine levels, but the urinary incontinence symptoms disappeared after treatment with Solifenacin. A further renal biopsy showed diffuse fusion of the foot process and microvilli, but no significant thickening of the glomerular basement membrane was observed using electron microscopy. Using light microscopy, eight glomeruli were observed; of these, six had glomerular sclerosis and one was an incomplete glomerulus with suspected segmental sclerosis. The renal tubules showed cystic dilatation. No capillary endothelial cell proliferation, mesangial cell proliferation, inflammatory infiltration, necrotizing lesions, crescent, or thrombotic microangiopathy was observed. These pathological changes suggested FSGS with sclerosis and cystic dilatation of renal tubules (Fig. 1).

We performed whole exome sequencing and found a novel de novo truncating variant in the last exon of TRIM8 (Chr10:104,416,939;NM_030912.2:c.1484G > A;p.Trp495*). This variant leads to the early termination of protein translation encoded by TRIM8. There were no additional kidney or nervous-related pathogenic gene variations that could be found in the proband. According to the criteria for classifying pathogenic variants in the guide of sequence variation [12], the variant was classified as pathogenic. Sanger sequencing showed that the variant and other variants were not detected in his parents, suggesting that the variation was a de novo variant in the patient himself (Fig. 2).

The pathogenesis of a TRIM8 variant leading to neurological and renal system diseases is still unclear. The TRIM8 protein is an E3 ubiquitin ligase widely involved in JAK-STAT, NF-κB, γ-interferon, and other signaling pathways [2, 7, 13‐15]. The TRIM8 protein normally localizes to the nuclear bodies of renal podocytes and neuronal cells, whereas the TRIM8 gene variant causes TRIM8 protein to be mislocalized to the nucleoplasm, resulting in protein truncation clustering. Therefore, abnormal nuclear localization may cause the early termination of TRIM8 protein translation, thus interfering with the normal transmission of the aforementioned cellular signal pathways [4, 16‐18].

Among the previously reported 22 patients with nervous and renal system diseases caused by the TRIM8 variant, 17 patients (77%) had both nervous and renal system diseases, three patients (14%) had only nervous system diseases, and two patients (9%) had only renal system diseases. The average age at the time of onset for patients with nervous system involvement is 2.4 years, and most of them present with epilepsy and psychomotor retardation. The average age at the time of onset for patients with renal system involvement is 4.5 years. Renal diseases occur at the same time as or after nervous system diseases. During the early stage, most patients have asymptomatic proteinuria; later, they have nephrotic-range proteinuria. Only a few patients have typical nephrotic syndrome during the early stage. Most patients with renal diseases eventually experience progression to end-stage renal disease. Renal biopsies were performed for 17 of the 22 previously reported patients; two had mesangial glomerulonephritis, two had diffuse mesangial sclerosis, and 13 had FSGS. Of all the patients who underwent renal biopsy, only one case was associated with renal tubular damage (An additional table file shows this in more detail (see Additional file 1)). Weng et al. performed a gene sequencing analysis of 2501 patients with steroid-resistant nephrotic syndrome, 9057 patients with epilepsy, and 48,556 control subjects, and detected TRIM8 variants in 12 patients (one was previously reported by Warren [7]). They confirmed that TRIM8 is a single pathogenic gene for renal disease in these patients, and almost all of these patients presented with epilepsy and psychomotor retardation; therefore, it was called neuro-renal syndrome.

We reported a patient with nephrotic proteinuria, specific facial features, and neurogenic bladder, and the whole exon sequencing indicated TRIM8 variant. Specific facial features, including low-set ears, large ear lobes, micrognathia, and thin lips have been observed in previous cases. Only one patient with enuresis has been reported, but the urodynamic examination was not performed. Our patient had decreased bladder compliance, poor detrusor contraction, and increased residual urine volume in the bladder. Symptoms of the neurogenic bladder were relieved after treatment with Solifenacin. We consider that the neurogenic bladder may be related to the slight involvement of the nervous system caused by TRIM8 variant. However, he had no seizures or no obvious physical, intellectual, or motor development abnormalities. This symptomatology is consistent with the patients reported by Shirai (case 9 in Additional file 1) and Li (case 22 in Additional file 1) who did not have epilepsy and psychomotor developmental abnormalities, and had only renal disorders as the prominent manifestation [5, 11]. Patients reported by Weng (case 20 in Additional file 1) and Li (case 21 in Additional file 1) had nephrotic-range proteinuria with mild psychomotor retardation, but no seizures [4, 11]. We found that the five patients with no severe neurological symptoms reported by Shirai, Li, Weng, as well as the current case, all shared one common feature: their TRIM8 variant sites were closer to the C-terminal and all the protein truncation sites were more than 480. Regarding the remaining 18 patients, the protein truncation sites were between 367 and 460 (Fig. 3). Additionally, the variant site of the present patient is closest to the C-terminal, and this has not been reported previously. Therefore, we inferred that when the TRIM8 variants are closer to the C-terminal, the renal lesions are more prominent and there are fewer neurologic lesions. The pathological changes caused by TRIM8 variants may not show the typical triad of neuro-renal syndrome (epilepsy, psychomotor retardation, and nephrotic-range proteinuria), and they may be characterized only by renal or nervous system diseases. The reason may be related to the different sites of protein truncation caused by the aforementioned TRIM8 variants. However, the specific molecular mechanism of this genotype–phenotype correlation requires further study.

Interestingly, no previous studies found a relationship between TRIM8 variants and ocular lesions. Our patient had myopia and astigmatism. McClatchey reported one patient with strabismus, and Weng et al. reported one patient with hyperopia and astigmatism and one patient with amblyopia and astigmatism [4, 6]. This suggests that, in addition to renal and nervous system diseases, attention should be focused on ocular lesions of patients with a TRIM8 variant. The lesions may be related to the highest expression of TRIM8 in the central nervous tissue, kidney, and eye.

In conclusion, we reported a patient with a de novo truncating variant of TRIM8 with a variant site closest to the C-terminal and nephrotic-range proteinuria but without epilepsy and psychomotor retardation. Additionally, unlike most of the previously reported cases, the renal biopsy did not show renal tubule damage. However, our patient had FSGS with cystic dilatation of the renal tubules. We also reviewed the literature reporting the TRIM8 variant causing neurological and renal diseases and found an interesting phenomenon: the closer the TRIM8 variant is to the C-terminal, the more likely it is to cause renal diseases; however, the neurological diseases will not be obvious. Our study provides a new understanding of neuro-renal syndrome caused by TRIM8 variant. However, this must be confirmed by accumulating more cases and further genetic and molecular studies.