Objectives: DGKE mutations can lead to hemolysis and thrombus in patients with atypical hemolytic uremic syndrome (aHUS). However, the sequence variants of DGKE in Chinese patients with aHUS have not been reported, and the protein function and crystal structure of DGKE remain unresolved. Methods: Targeted exome sequencing was accomplished in one affected patient from each family using the Illumina NextSeq 500 platform. Protein modeling and functional analysis in DGKE were also performed to understand the impact of identified variants on the phenotype. Results: We report a novel compound heterozygous mutation in the DGKE gene in a Chinese consanguineous family in which a child was diagnosed with aHUS, which includes a c.231C>G missense mutation and a c.790_791delTG frameshift mutation derived from his father and mother, respectively. Our bioinformatic analysis suggested that the allelic mutations at different sites in DGKE yield abnormal crystal structures and conformations, leading to dysregulation of its downstream signaling. Conclusions: Our study further expands the spectrum of the sequence variants reported in the DGKE gene and also indicates that different races may have different DGKE variants. Moreover, the altered structures and conformations, caused by DGKE mutations, disrupt the binding of DGKE with its partners, and leading to the occurrence of aHUS.

Mutations in the human GREB1L (growth regulation by estrogen in breast cancer 1-like) gene are associated with congenital anomalies of the kidneys and urinary tracts (CAKUT). However, its precise function and molecular mechanisms remain poorly understood. This study aimed to explore the role of Greb1l deficiency on pronephros development in zebrafish ( Danio rerio ) and to elucidate its potential molecular mechanisms. We created Greb1l-deficient zebrafish models using CRISPR/Cas9 and morpholino oligonucleotide (MO)-based methods. Maternal-zygotic greb1l homozygous mutants (MZ greb1l ^−/− ) exhibited human-like phenotypes, including a cystic pronephros, abnormal reproduction, pericardial edema, and skeletal deformities. Moreover, there was a significant increase in both cell proliferation and apoptosis in the cystic proximal tubules of the pronephros, indicating a disruption of cellular homeostasis. Transcriptomic sequencing of 5 dpf MZ greb1l ^−/− mutants revealed that the differentially expressed genes (DEGs) were significantly enriched in the cell cycle, apoptosis, and MAPK signaling pathway. Further functional validation confirmed a significant downregulation in the phosphorylation levels of key MAPK pathway proteins ERK, JNK, and p38 in the Greb1l-deficient model. By treating with the MAPK activator lipopolysaccharide (LPS), we restored the pathway’s activity, significantly rescuing the pronephric cyst phenotype and alleviating the cell proliferation/apoptosis imbalance caused by Greb1l deficiency. Our findings demonstrate that Greb1l plays a vital role in the morphogenesis of pronephric tubules, contributing to cellular equilibrium through modulation of the MAPK signaling pathway. This study sheds light on the underlying molecular mechanisms of GREB1L-associated congenital kidney diseases.

Variants in the LAGE3 gene can lead to Galloway-Mowat syndrome (GAMOS), a rare genetic disease. Currently, there have been a total of 6 reported cases worldwide, all occurring in children under the age of 3 years old. The main features of LAGE3 variants include early-onset nephrotic syndrome, microcephaly, developmental delay, and neurological abnormalities, with a poor prognosis. However, there are few reports on mild clinical manifestations and prognosis associated with LAGE3 variants. Here, we report two brothers, aged 9 and 5 years old respectively, from a family, both presenting with nephrotic syndrome with different types of renal pathology. They both had a high-arched palate and were treated with steroids and tacrolimus, resulting in negative urine protein. Genetic sequencing revealed that both siblings carried a hemizygous variant in the LAGE3 gene: c.389T > G (p.V130G). However, neither of them exhibited the typical features of microcephaly, developmental delay, or neurological abnormalities associated with LAGE3 gene variants. Currently, both siblings have normal renal function and are being regularly followed up with a good prognosis. This report is the first to document patients with LAGE3 variants who do not exhibit microcephaly, developmental delay, or neurological abnormalities. Additionally, it is the first case where proteinuria manifested at an older age and had a positive prognosis. The two siblings represent the 7th and 8th cases of children with LAGE3 variants, expanding the genotype and phenotype spectrum of LAGE3 variants, providing new insights for clinical diagnosis and risk assessment.