ギャロウェイ・モワト症候群

L Antigen Family Member 3 (LAGE3) is a core component of the KEOPS complex, mutations of which are implicated in Galloway-Mowat syndrome (GAMOS). The KEOPS complex is known to function in telomere maintenance and tRNA N6-threonylcarbamoyladenosine (t6A) modification. However, whether the KEOPS complex also contributes to chromosomal DNA regulation through additional mechanisms remains elusive. Here, we find that LAGE3 and the other four components of KEOPS localize to the stalled forks and protect the nascent DNA strand from degradation under DNA replication stress. TurboID-mediated proximity labeling identifies the MRE11 nuclease as a LAGE3-interacting partner, and LAGE3 deficiency leads to unscheduled stalled forks degradation in an MRE11 nuclease-dependent manner. Similarly, TP53RK, another KEOPS subunit, also exhibits a protective role at stalled forks. In vitro experiments demonstrate that the KEOPS complex prefers to bind to a ds-ssDNA junction, then directly limits MRE11 to degrade nascent DNA. In addition, GAMOS-associated LAGE3 mutations disrupt KEOPS complex assembly, preventing its recruitment to stalled replication forks and consequently leading to unscheduled fork resection and genome instability under DNA replication stress. Collectively, our findings reveal that LAGE3 acts as a stalled fork protector to prevent genome instability during DNA replication stress, providing new insights into GAMOS pathogenesis.

INTRODUCTION: Galloway-Mowat syndrome (GAMOS) is a rare genetic disorder that is characterized by microcephaly and neurological and renal abnormalities. Ten types of GAMOS exist based on the underlying implicated gene. The purpose of this study was to investigate the phenotypic and genotypic spectrum of GAMOS in Kuwait. METHODS: We queried the Kuwait Medical Genetic Center database for subjects with neuro-renal or neurological phenotypes and pathogenic variants in any of the ten known genes associated with GAMOS. RESULTS: We identified eight subjects from five unrelated families with biallelic pathogenic WDR73 variants and a diagnosis of GAMOS type 1 (GAMOS1). All subjects had global developmental delay, microcephaly, tone abnormalities and impaired activities of daily living. Renal features were observed in more than half of the subjects (5/8 subjects) and included proteinuria, nephrotic syndrome, and end-stage renal disease (ESRD). More than half of the subjects (5/8 subjects) died by 5-10 due to ESRD, including one of which who died due to unknown cause while the rest (ages 3-5 years) are still living with no renal features.Two possible founder variants were identified, including c.287 G>A;p.Arg96Lys in three unrelated families of Kuwaiti, Iraqi, and/or Syrian ancestry, and c.767 G>A;p.Arg256Gln in two unrelated families of Kuwaiti or Syrian ancestry. CONCLUSION: GAMOS1 is the most prevalent form of GAMOS in Kuwait, likely due to the presence of two WDR73 regional founder variants. These findings contribute to the global understanding of GAMOS and highlight the important contribution of regional genetic studies in diverse populations to rare disease research.

Galloway-Mowat syndrome is a rare autosomal recessive genetic disorder that is highly underrecognized. The phenotype is heterogeneous, but it is now widely accepted that early-onset nephrotic syndrome and microcephaly with brain malformation are characteristic features of Galloway-Mowat syndrome. It has been phenotypically defined as the presence of primary microcephaly, developmental delay, seizure tendency, and early-onset nephrotic syndrome. Rarely, congenital syphilis or other intrauterine infections can cause congenital nephrotic syndrome, a relatively uncommon illness in children with genetic reasons linked to podocin gene abnormalities. This syndrome is characterized by gyral and myelin anomalies in MRI, early onset of nephrotic syndrome, microcephaly, developmental delay, fascio-skeletal dysmorphism, along with end-stage renal disease. Here, the authors report a case of a 10-month-old male infant who was admitted for clinical symptomatology suggestive of nephrotic syndrome and delay in achieving key developmental milestones and, on examination, had failure to thrive with microcephaly. Following a thorough assessment of the child, a homozygous missense variant in exon 9 of the OSGEP gene was discovered on genetic analysis by whole-exome sequencing. This variant is suggestive of Galloway-Mowat syndrome type 3 and results in an amino acid substitution of proline for alanine at codon 286. Our index case emphasizes the importance of detailed evaluation so as to apprise and prognosticate the parents of a child having a rare and nearly fatal condition by the utilization of genetic analysis.

BACKGROUND: Galloway-Mowat syndrome type 3 (GAMOS3) is a rare autosomal recessive disorder characterized by the co-occurrence of renal and neurological abnormalities in early childhood, caused by OSGEP gene variants. AIM: This study aims to characterize the genetic and phenotypic spectrum of GAMOS3 and evaluate correlations from prenatal imaging features to lifelong neurological and renal manifestations. METHOD: We retrospectively reviewed the medical records of cases genetically diagnosed with OSGEP-associated GAMOS3 at our center between January 2016 and August 2024. Additionally, a systematic review of reported cases in literature was conducted. The clinical validity of the gene-disease relationship between OSGEP and GAMOS3 was also evaluated in accordance with the ClinGen Gene-Disease Clinical Validity Curation Framework. RESULTS: The postnatal renal and neurological dysfunction was associated with prenatal manifestations, indicating disease progression. Prominent prenatal features included fetal growth restriction (FGR), microcephaly, oligohydramnios and abnormal cranial imaging. Notably, FGR worsened with advancing gestation, predominantly affecting fetal head and abdominal growth while sparing long bones. Fetal central nervous system magnetic resonance imaging revealed uncommon findings such as abnormal sulcation and increased T2 signal in the white matter, suggestive of myelination defects or leukoencephalopathy. Trio-based medical exome sequencing identified novel variants in the OSGEP gene within this cohort, expanding the known genetic spectrum of GAMOS3. Furthermore, the gene-disease relationship between OSGEP and GAMOS3 was conclusively validated as 'Definitive' according to clinical-genetic criteria. CONCLUSIONS: This study provides a comprehensive overview of the clinical phenotypes and genetic spectrum of GAMOS3, spanning from the prenatal period throughout the life course.

BACKGROUND: Galloway-Mowat syndrome (GAMOS, OMIM: 251300) is a rare autosomal recessive (AR) neurodevelopmental disease, characterized by the combination of early-onset nephrotic syndrome and various central nervous system anomalies. The WD repeat-containing protein 73 (WDR73, OMIM: 616144) gene was the first gene found to be implicated in GAMOS1. METHODS: An AR family with parental consanguinity underwent comprehensive clinical and genetic analyses. In this study, the variant identified by whole exome sequencing was confirmed by Sanger sequencing and cosegregation analysis. A literature review was conducted to summarize previously reported cases of GAMOS1 caused by mutations in the WDR73 gene. RESULTS: The proband with GAMOS1 was a 3-year-old boy with normal renal function and typical characteristics of GAMOS1, including idiopathic nystagmus, agenesis of genitalia, persistent axial hypotonia, mild cerebellar atrophy, thinning of the corpus callosum, and brainstem hypoplasia. A novel homozygous frameshift mutation c.972_973dupCT (p.F325Sfs * 10) in the exon 8 of the WDR73 gene was identified in the proband. We summarized thirty-six previously reported GAMOS1 cases caused by mutations in the WDR73 gene. CONCLUSION: We identified a novel homozygous frameshift mutation (c.972_973dupCT) in the WDR73 gene, causing AR GAMOS1 in a Chinese consanguineous family. The results are essential for further confirming the pathogenicity of WDR73 gene mutations and expanding the manifestation spectrum of GAMOS1.