bims-meglyc 2023-12-03 papers

Transl Res. 2023 Nov 25. pii: S1931-5244(23)00185-8. [Epub ahead of print]

Efficacy of oral manganese and D-galactose therapy in a patient bearing a novel TMEM165 variant.

Zoé Durin, Alexandre Raynor, François Fenaille, Sophie Cholet, Sandrine Vuillaumier-Barrot, Jean-Meidi Alili, Joël Poupon, Nouzha Djebrani Oussedik, Caroline Tuchmann-Durand, Jennifer Attali, Romain Touzé, Thierry Dupré, Elodie Lebredonchel, Marlyse Angah Akaffou, Dominique Legrand, Pascale de Lonlay, Arnaud Bruneel, François Foulquier.

TMEM165-CDG has first been reported in 2012 and manganese supplementation was shown highly efficient in rescuing glycosylation in isogenic KO cells. The unreported homozygous missense c.928G>C; p.Ala310Pro variant leading to a functional but unstable protein was identified. This patient was diagnosed at 2 months and displays a predominant bone phenotype and combined defects in N-, O- and GAG glycosylation. We administered for the first time a combined D-Gal and Mn2+ therapy to the patient. This fully suppressed the N-; O- and GAG hypoglycosylation. There was also striking improvement in biochemical parameters and in gastrointestinal symptoms. This study offers exciting therapeutic perspectives for TMEM165-CDG.

Keywords: Golgi, glycosylation; TMEM165, Manganese, galactose

DOI: https://doi.org/10.1016/j.trsl.2023.11.005

Biophys J. 2023 Nov 28. pii: S0006-3495(23)04100-0. [Epub ahead of print]

N-Glycosylation-dependent regulation of immune-specific tetraspanins CD37 and CD53.

Sjoerd van Deventer, Ilse A Hoogvliet, Merel van de Voort, Frank Arnold, Martin Ter Beest, Annemiek B van Spriel.

Tetraspanin proteins play an important role in many cellular processes as they are key organizers of different receptors on the plasma membrane. Most tetraspanins are highly glycosylated at their large extracellular loop, however, little is known about the function of tetraspanin glycosylation in immune cells. In this study we investigated the effects of glycosylation of CD37 and CD53, two tetraspanins important for cellular and humoral immunity. Broad and cell-specific repertoires of N-glycosylated CD37 and CD53 were observed in human B cells. We generated different glycosylation mutants of CD37 and CD53 and analyzed their localization, nanoscale plasma membrane organization and partner protein interaction capacity. Abrogation of glycosylation in CD37 revealed the importance of this modification for CD37 surface expression, whereas surface expression of CD53 was unaffected by its glycosylation. Single-molecule dSTORM microscopy revealed that the nanoscale organization of CD53 was not dependent on glycosylation. CD37 interaction with its partner proteins CD53 and CD20 was affected by glycosylation in a localization-dependent way, whereas its interaction with IL6Rα was independent of glycosylation. Surprisingly, glycosylation was found to inhibit the interaction between CD53 and its partner proteins CD45, CD20 and to a lesser extent CD37. Together, our data show that glycosylation affects the interaction capacity of immune-specific tetraspanins CD37 and CD53, which adds another layer of regulation to immune membrane organization.

DOI: https://doi.org/10.1016/j.bpj.2023.11.3399

Life Sci. 2023 Nov 26. pii: S0024-3205(23)00938-4. [Epub ahead of print]336 122303

Glycosylation: A new signaling paradigm for the neurovascular diseases.

Dapinder Kaur, Heena Khan, Amarjot Kaur Grewal, Thakur Gurjeet Singh.

A wide range of life-threatening conditions with complicated pathogenesis involves neurovascular disorders encompassing Neurovascular unit (NVU) damage. The pathophysiology of NVU is characterized by several features including tissue hypoxia, stimulation of inflammatory and angiogenic processes, and the initiation of intricate molecular interactions, collectively leading to an elevation in blood-brain barrier permeability, atherosclerosis and ultimately, neurovascular diseases. The presence of compelling data about the significant involvement of the glycosylation in the development of diseases has sparked a discussion on whether the abnormal glycosylation may serve as a causal factor for neurovascular disorders, rather than being just recruited as a secondary player in regulating the critical events during the development processes like embryo growth and angiogenesis. An essential tool for both developing new anti-ischemic therapies and understanding the processes of ischemic brain damage is undertaking pre-clinical studies of neurovascular disorders. Together with the post-translational modification of proteins, the modulation of glycosylation and its enzymes implicates itself in several abnormal activities which are known to accelerate neuronal vasculopathy. Despite the failure of the majority of glycosylation-based preclinical and clinical studies over the past years, there is a significant probability to provide neuroprotection utilizing modern and advanced approaches to target abnormal glycosylation activity at embryonic stages as well. This article focuses on a variety of experimental evidence to postulate the interconnection between glycosylation and vascular disorders along with possible treatment options.

Keywords: Glycosylation; Neuroprotection; Neurovascular disorders; Stroke

DOI: https://doi.org/10.1016/j.lfs.2023.122303

Heart. 2023 Dec 01. pii: heartjnl-2023-323126. [Epub ahead of print]

Genetic syndromes associated with congenital heart disease.

Valeria E Duarte, Michael N Singh.

Congenital heart defects are the most common type of birth defect, affecting 1% of live births. The underlying cause of congenital heart disease is frequently unknown. However, advances in human genetics and genome technologies have helped expand congenital heart disease pathogenesis knowledge during the last few decades. When the cardiac defects are part of a genetic syndrome, they are associated with extracardiac conditions and require multidisciplinary care and surveillance. Some genetic syndromes can have subtle clinical findings and remain undiagnosed well into adulthood. Each syndrome is associated with specific congenital and acquired comorbidities and a particular clinical risk profile. A timely diagnosis is essential for risk stratification, surveillance of associated conditions and counselling, particularly during family planning. However, genetic testing and counselling indications can be challenging to identify in clinical practice. This document intends to provide an overview of the most clinically relevant syndromes to consider, focusing on the phenotype and genotype diagnosis, outcome data, clinical guidelines and implications for care.

Keywords: Congenital heart disease

DOI: https://doi.org/10.1136/heartjnl-2023-323126