Tumor suppressive role of the antimicrobial lectin REG3A targeting the O-GlcNAc glycosylation pathway Nicolas Moniaux, Nicolas Geoffre, Alice Deshayes, Alexandre Dos Santos, Sylvie Job, et al. Hepatology, 2025 Background and Aims: Antimicrobial proteins of the regenerating family member 3 alpha (REG3A) family provide a first line of protection against infections and transformed cells. Their expression is inducible by inflammation, which makes their role in cancer biology less clear since an immune-inflammatory context may preexist or coexist with cancer, as occurs in HCC. The aim of this study is to clarify the role of REG3A in liver carcinogenesis and to determine whether its carbohydrate-binding functions are involved. Approach and Results: This study provides evidence for a suppressive role of REG3A in HCC by reducing O-GlcNAcylation in 2 mouse models of HCC, in vitro cell studies, and clinical samples. REG3A expression in hepatocytes significantly reduced global O-GlcNAcylation and O-GlcNAcylation of c-MYC in preneoplastic and tumor livers and markedly inhibited HCC development in REG3A-c-MYC double transgenic mice and mice exposed to diethylnitrosamine. REG3A modified O-GlcNAcylation without altering the expression or activity of O-linked N-acetylglucosaminyltransferase, O-linked N-acetylglucosaminyl hydrolase, or glutamine fructose-6-phosphate amidotransferase. Reduced O-GlcNAcylation was consistent with decreased levels of UDP-GlcNAc in precancerous and cancerous livers. This effect was linked to the ability of REG3A to bind glucose and glucose-6 phosphate, suggested by a REG3A mutant unable to bind glucose and glucose-6 phosphate and alter O-GlcNAcylation. Importantly, patients with cirrhosis with high hepatic REG3A expression had lower levels of O-GlcNAcylation and longer cancer-free survival than REG3A-negative cirrhotic livers. Conclusions: REG3A helps fight liver cancer by reducing O-GlcNAcylation. This study suggests a new paradigm for the regulation of O-GlcNAc signaling in cancer-related pathways through interactions with the carbohydrate-binding function of REG3A.
Early-onset phenotype in a patient with an intermediate allele and a large SCA1 expansion: a case report Guillaume Baille, Nicolas Geoffre, Anna Wissocq, Pauline Planté-Bordeneuve, Eugénie Mutez, et al. BMC Neurology, 2024 Background Spinocerebellar ataxia type 1, is a rare neurodegenerative disorder with autosomal dominant inheritance belonging to the polyglutamine diseases. The diagnosis of this disease requires genetic testing that may also include the search for CAT interruption of the CAG repeat tract. Case presentation One 23-years-old patient suffers from a severe ataxia, with early-onset and rapid progression of the disease. His father might have been affected, but no molecular confirmation has been performed. The genetic results were negative for the Friedreich’s ataxia, spinocerebellar ataxia type 2, 3, 6, 7 and 17. The numbers of CAG repeats in the ATXN1 gene was assessed by fluorescent PCR, tripled-primed PCR and enzymatic digestion for the search of sequence interruption in the CAG repeats. The patient carried one pathogenic allele of 61 CAG and one intermediate allele of 37 CAG in the ATXN1 gene. Both alleles were uninterrupted. Conclusions We report a rare case of spinocerebellar ataxia type 1 with an intermediate allele and a large SCA1 expansion. The determination of the absence of CAT interruption brought crucial information concerning this molecular diagnosis, the prediction of the disease and had practical consequences for genetic counseling.
Late-onset Kjellin syndrome: Diagnosis of SPG11 on fundus examination Vincent Brock, Anna Wissocq, Nicolas Geoffre, Caroline Marks, Vincent Canel, et al. European Journal of Ophthalmology, 2024 Introduction Spastic paraplegia (SPG) is a heterogenous group of neurodegenerative disorders, that may include ocular involvement. Here we report the clinical data of a patient with late-onset Kjellin syndrome, a peculiar form of hereditary SPG with macular dystrophy. Materials and Methods Clinical, functional and multimodal retinal imaging data were collected. Genetic testing was performed by Whole Exome Sequencing (WES). Results A 52-year-old female patient with SPG of unknown origin was referred for a progressive visual acuity loss. Multimodal fundus imaging revealed a peculiar macular dystrophy. Given the specific association of macular dystrophy and SPG, a Kjellin syndrome was suspected and genetic testing performed. WES revealed biallelic pathogenic variants in SPG11, co-segregating with disease in the family. Conclusion Careful ophthalmological examination prompted the diagnosis and guided molecular testing. This case underlines the importance of a neuro-ophthalmologic assessment in patients with SPG.
