Mass Spectrometry Glycophenotype Characterization of ALG2-CDG Argentinean Patients with a New Genetic Variant in Homozygosis.

GABRIELA MAGALI PAPAZOGLU; MARISA CUBILLA; MARCELA PEREYRA; RAQUEL DODELSON DE KREMER; BELÉN PÉREZ; LUISA STURIALE; CARLA GABRIELA ASTEGGIANO

GLYCOCONJUGATE JOURNAL

SPRINGER

Lugar: Berlin; Año: 2021

0282-0080

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous disorders characterized by impaired signal transmission at the neuromuscular synapse. Five out of sixteen genes associated with CMS to date are involved in the N-linked glycosylation pathway. Human ALG2 encodes a α 1,3 mannosyltransferase that catalyzes the first steps in the synthesis of N-glycans in the endoplasmic reticulum. Variants in ALG2 were shown to cause a congenital disorder of glycosylation (CDGs) variant known as ALG2-CDG. To date, nine ALG2-CDG patients have been reported worldwide. ALG2-CDG is a rare autosomal recessive inherited disorder characterized by neurological involvement, convulsive syndrome of unknown origin, axial hypotonia, and mental and motor regression. In this study we used MALDI-TOF MS to define both total serum protein and transferrin (Tf) N-glycan phenotypes in three ALG2-CDG patients carrying, as determined by exome sequencing, a c.752G>T, p.Arg251Leu ALG2 missense variant in homozygous state. We observed increased heterogeneity of Tf glycoforms due to under-occupancy of glycosylation site(s) typical of a defective N-glycan assembly, and also minor N-glycan alterations consisting on increased amounts of hyposialylated N-glycans, along with a general increase in fucosylation, suggesting some implications on Golgi N-glycan processing. Our analysis on total serum N-glycome reflected the same alterations observed for serum Tf. These results highlight the importance of combining genomics and glycomics to identify specific diagnostic biomarkers and to aid the design of personalized treatment strategies for CDGs.