Publications

April 8, 2024

A complement C4-derived glycopeptide is a biomarker for PMM2-CDG

Garapati K et al. JC Insight., April 8, 2024

Diagnosis of PMM2-CDG, the most common congenital disorder of glycosylation (CDG), relies on measuring carbohydrate-deficient transferrin (CDT) and genetic testing. CDT tests have false negatives and may normalize with age. Site-specific changes in protein N-glycosylation have not been reported in sera in PMM2-CDG. Using multistep mass spectrometry-based N-glycoproteomics, we analyzed sera from 72 individuals to discover and validate glycopeptide alterations. We performed comprehensive tandem mass tag-based discovery experiments in well-characterized patients and controls. Next, we developed a method for rapid profiling of additional samples. Finally, targeted mass spectrometry was used for validation in an independent set of samples in a blinded fashion.

April 3, 2024

Neurodevelopmental defects in a mouse model of O-GlcNAc transferase intellectual disability

Authier F, Ondruskova N, Ferenbach AT, McNeilly A, van Aalten DMF. Dis Model Mech, MarchApril 3, 2024 28, 2024

O-GlcNAcylation is a protein modification that is critical for vertebrate development, catalysed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense mutations in OGT have recently been shown to segregate with a X-linked syndromic form of intellectual disability, OGT-linked Congenital Disorder of Glycosylation (OGT-CDG). Although OGT-CDG suggests a critical role of O-GlcNAcylation in neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant.

March 28, 2024

ELISA-based highly sensitive assay system for the detection of endogenous NGLY1 activity

Fujihira H, Sato K, Nishiuchi Y, Murase T, Matsuda Y, Yoshida Y, Kamei T, Suzuki T. Biochem Biophys Res Commun., March 28, 2024

Cytosolic peptide:N-glycanase (NGLY1, PNGase) is an enzyme that cleaves N-glycans from misfolded glycoproteins. In 2012, a human genetic disorder, NGLY1 deficiency, was first reported to be caused by mutations of the NGLY1 gene. Since then, there has been rapid progresses on NGLY1 biology, and gene therapy has been proposed as a promising therapeutic option for NGLY1 deficiency. While a plasma/urine biomarker has also been developed for this disease, detection of NGLY1 activity could be another viable option for early diagnosis of NGLY1 deficiency. Thus far, several in vitro and in cellulo NGLY1 assays have been reported, but those assay systems have several issues that must be addressed in order to develop an assay system compatible for routine clinical examination. Here, we show a facile, highly sensitive in vitro assay system that could be used to detect NGLY1 activity by utilizing its sequence editing function, i.e. conversion of glycosylated Asn into Asp, followed by a detection of newly generated epitope (HA)-tag by anti-HA antibody.

March 28, 2024

TRAPPC11-CDG muscular dystrophy: Review of 54 cases including a novel patient

Corona-Rivera JR et al. Mol Genet Metab., March 28, 2024

The trafficking protein particle (TRAPP) complex is a multisubunit protein complex that functions as a tethering factor involved in intracellular trafficking. TRAPPC11, a crucial subunit of this complex, is associated with pathogenic variants that cause a spectrum of disease, which can range from a limb girdle muscular dystrophy (LGMD) to developmental disability with muscle disease, movement disorder and global developmental delay (GDD)/intellectual disability (ID), or even a congenital muscular dystrophy (CMD). We reviewed the phenotype of all reported individuals with TRAPPC11-opathies, including an additional Mexican patient with novel compound heterozygous missense variants in TRAPPC11 (c.751 T > C and c.1058C > G), restricted to the Latino population.

March 27, 2024

Phosphomannomutase 2-congenital disorder of glycosylation presenting with very early onset inflammatory bowel disease

Comert M, Guler T, Ergani AC, Gumus M, Ozdemir EM, Artac H. Indian J Gastroenterol. , March 27, 2024

March 25, 2024

Promise of gene therapy for congenital neurologic disease due to GPI deficiency

Babushok DV, Sabatino DE. Mol Ther Methods Clin Dev., March 25, 2024

A recent study by Murakami et al. describes a novel genetic treatment for inherited glycophosphatidylinositol (GPI) deficiency (IGD) using adeno-associated virus (AAV)-based gene therapy. PIGA is an X-linked gene required for the first step of GPI anchor biosynthesis, a multistep process requiring at least 27 different genes. Disruption of PIGA or other genes in the GPI biosynthesis process leads to the loss of approximately 150 different GPI-anchored surface proteins (GPI-APs) in humans. [...]

March 22, 2024

Novel mutation of COG5 in a Taiwanese girl with congenital disorders of glycosylation manifesting as developmental delay

Wang YC, Niu DM, Chen LZ, Chen YR, Yang CF. Mol Genet Metab Rep., March 22, 2024

We are documenting the case of An 11-year-old girl who has been followed up at our out-patient clinic since birth with clinical presentations including intrauterine growth restriction, recurrent periodic fever in infancy, hypotonia, global developmental delay, liver function impairment with cirrhotic changes, and clinodactyly. Congenital abnormalities were suspected but a series of examinations including brain MRI, liver biopsy and muscle biopsy yielded insignificant findings. Whole genome sequencing (WGS) was conducted and revealed three novel mutations (c2T > G, c1826T > C, c.556-560delAGTAAinsCT) of the COG5 gene. A diagnosis of COG5-congenital disorders of glycosylation (COG5-CDG, or CDG IIi), with neurologic presentation was established.

March 18, 2024

Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature

Teutonico F et al. Neurogenetics., March 18, 2024

Mannosyl-oligosaccharide glucosidase - congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene.

March 16, 2024

Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center

Yüksel MF, Doğulu N, Yıldırım M, Köse E, Bektaş Ö, Eminoğlu FT, Teber S. Brain Dev., March 16, 2024

This study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years. [...] ost patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency.

March 14, 2024

Revisiting the immunopathology of congenital disorders of glycosylation: an updated review.

Pascoal C et al. Front Immunol., March 14, 2024

Glycosylation is a critical post-translational modification that plays a pivotal role in several biological processes, such as the immune response. Alterations in glycosylation can modulate the course of various pathologies, such as the case of congenital disorders of glycosylation (CDG), a group of more than 160 rare and complex genetic diseases. Although the link between glycosylation and immune dysfunction has already been recognized, the immune involvement in most CDG remains largely unexplored and poorly understood. In this study, we provide an update on the immune dysfunction and clinical manifestations of the 12 CDG with major immune involvement, organized into 6 categories of inborn errors of immunity according to the International Union of Immunological Societies (IUIS).