Association of ACTN4 Gene Mutation with Primary Nephrotic Syndrome in Children in Guangxi Autonomous Region, China.

Objective: To investigate the association between ACTN4 gene mutation and primary nephrotic syndrome (PNS) in children in Guangxi Autonomous Region, China. Methods: The high-throughput sequencing technology was used to sequence ACTN4 gene in 155 children with PNS in Guangxi Autonomous Region in China, with 98 healthy children serving as controls. Twenty-three exon-specific capture probes targeting ACTN4 were designed and used to hybridize with the genomic DNA library. The targeted genomic region DNA fragments were enriched and sequenced. The protein levels of ACTN4 in both case and control groups were quantified using ELISA method. Results: Bioinformatics analysis revealed five unique ACTN4 mutations exclusively in patients with PNS, including c.1516G>A (p.G506S) on one exon in 2 patients, c.1442 + 10G>A at the splice site in 1 patient, c.1649A>G (p.D550G) on exon in 1 patient, c.2191-4G>A at the cleavage site in 2 patients, and c.2315C>T (p.A772V) on one exon in 1 patient. The c.1649A>G (p.D550G) and c.2315C>T (p.A772V) were identified from the same patient. Notably, c.1649A>G (p.D550G) represents a novel mutation in ACTN4. In addition, three other ACTN4 polymorphisms occurred in both case and control groups, including c.162 + 6C>T (1 patient in case group and 2 patients in control group), c.572 + 11G>A (1 patient in case group and 2 patients in control group), and c.2191-5C>T (4 patients in the case group and 3 patients in control group). The serum ACTN4 concentration in the case group was markedly higher, averaging 544.7 ng/mL (range: 264.6-952.6 ng/mL), compared with 241.20 ng/mL (range: 110.75-542.35 ng/mL) in the control group. Conclusion: Five ACTN4 polymorphisms were identified among children with PNS in Guangxi Autonomous Region, China, including the novel mutation c.1649A>G. The lower serum levels of α-actinin-4 in the case group suggest that this protein might play a protective role in PNS.

Phenotype-Genotype Correlations in Three Different Cases of Adult-Onset Genetic Focal Segmental Glomerulosclerosis.

This study highlights the importance of a combined diagnostic approach in the diagnosis of rare diseases, such as adult-onset genetic FSGS. We present three adult patient cases evaluated with kidney biopsy for proteinuria, chronic kidney disease, and hypertension, which were suggestive of adult-onset genetic FSGS. Renal biopsy samples and formalin-fixed, paraffin-embedded fetal kidneys were evaluated using standard light microscopical stainings, direct immunofluorescence on cryostat sections, and electron microscopy. Clinical exome sequencing was performed for each case, and 45 FSGS-related genes were analyzed. Identifying mutations in the PAX2, ACTN4, and COL4A5 genes have prompted a re-evaluation of the previous histopathological examinations. The PAX2 mutation led to a thinner nephrogenic zone and decreased number of glomeruli, resulting in oligohydramnios during fetal development and oligomeganephronia and adaptive focal-segmental glomerulosclerosis in adulthood. The ACTN4 mutation caused distinct electron-dense aggregates in podocyte cell bodies, while the COL4A5 mutation led to segmental sclerosis of glomeruli with marked interstitial fibrosis and tubular atrophy. The identification of specific mutations and their histopathological consequences can lead to a better understanding of the disease and its progression, as well as potential treatment options.

Analysis of the association of NPHS2 and ACTN4 genes polymorphism with nephrotic syndrome in Egyptian children.

BACKGROUND: One of the most common kidney illnesses in developing countries is pediatric nephrotic syndrome (PNS), which is frequently associated with dyslipidemia and edema. The rapid discovery of genes related to NS has aided in the understanding of the molecular mechanics of glomerular filtration. The goal of this study is to determine the relationship between NPHS2 and ACTN4 in PNS youngsters. METHODS: A study with 100 NS children and 100 healthy matched volunteers was conducted. Genomic DNA was extracted from peripheral blood. Single-nucleotide polymorphisms were genotyped using ARMS-PCR. RESULTS: A substantial decline in the level of albumin was found in NS cases (P < 0.001) Further on, a significantly difference in T.C and TG level between healthy and NS patient. Molecular study showed a highly significant difference of NS patients from controls regarding NPHS2 rs3829795 polymorphic genotypes as the GA heterozygous genotype shows highly significant difference from controls (P < 0.001) as well as GA + AA genotypes (P < 0.001) in comparison with GG genotype. Regarding rs2274625, The GA heterozygous genotype showed no statistically significant difference between genotypes and alleles with NS (P = 0.246). Association of AG haplotype NPHS2 rs3829795-rs2274625 haplotypes found a significant association with the risk of developing NS (P = 0.008). Concerning the ACTN4 rs121908415 SNP, there was no link between this mutation and NS children. CONCLUSION: The correlation of AG haplotype NPHS2 rs3829795-rs2274625 haplotypes identified a strong association with the likelihood of getting NS, according to our findings. There was no connection found between the ACTN4 rs121908415 SNP and NS children.

Alpha-actinin-4 (ACTN4) gene amplification is a predictive biomarker for adjuvant chemotherapy with tegafur/uracil in stage I lung adenocarcinomas.

Although adjuvant tegafur/uracil (UFT) is recommended for patients with completely resected stage I non-small-cell lung cancer (NSCLC) in Japan, only one-third of cases has received adjuvant chemotherapy (ADJ) according to real-world data. Therefore, robust predictive biomarkers for selecting ADJ or observation (OBS) without ADJ are needed. Patients who underwent complete resection of stage I lung adenocarcinoma with or without adjuvant UFT were enrolled. The status of ACTN4 gene amplification was analyzed by FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were carried out. Formalin-fixed, paraffin-embedded samples from 1136 lung adenocarcinomas were submitted for analysis of ACTN4 gene amplification. Ninety-nine (8.9%) of 1114 cases were positive for ACTN4 gene amplification. In the subgroup analysis of patients aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009-0.806; P = .032). The difference in RFS between the ADJ group and the OBS group was not significant in ACTN4-negative cases (all ages: HR, 1.214; 95% CI, 0.848-1.738; P = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side-effects of ADJ, and saving medical costs.

Rapid progression to end-stage renal disease in a child with a sporadic ACTN4 mutation.

Mutations of ACTN4 cause an autosomal dominant form of focal segmental glomerulosclerosis (FSGS). Presentation usually occurs in the teenage years or later with symptoms of mild proteinuria and slowly progressive renal dysfunction leading to end-stage renal disease (ESRD). We report a 5-year-old female patient who was diagnosed with nephrotic syndrome and did not respond to 6 weeks of oral glucocorticoid therapy. Renal biopsy showed a collapsing variant of FSGS and genetic studies revealed a heterozygous disease-causing mutation in the ACTN4 gene (c.784C>T, p.Ser262Phe). No mutations were found in the NPHS2, TRPC6, and INF2 genes, nor did her parents have any mutations for FSGS. She developed ESRD 6 months after presentation. Although a disease-causing ACTN4 mutation was identified, the contribution of additional polymorphisms in other genes is not known. Such additional polymorphisms may represent yet unidentified epigenetic factors that contributed to the aggressive nature of this child's disease progression. A literature review has revealed only two similar case reports.