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Publications

June 2024

June 4, 2024

Mutations in the SLC35C1 gene, contributing to significant differences in fucosylation patterns, may underlie the diverse phenotypic manifestations observed in leukocyte adhesion deficiency type II patients

Skurska E, Szulc B, Kreczko K, Olczak M. Int J Biochem Cell Biol., June 4, 2024

Congenital disorders of glycosylation (CDG) are a large family of genetic diseases resulting from defects in the synthesis of glycans and the attachment of glycans to macromolecules. The CDG known as leukocyte adhesion deficiency II (LAD II) is an autosomal, recessive disorder caused by mutations in the SLC35C1 gene, encoding a transmembrane protein of the Golgi apparatus, involved in GDP-fucose transport from the cytosol to the Golgi lumen. In this study, a cell-based model was used as a tool to characterize the molecular background of a therapy based on a fucose-supplemented diet.

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June 3, 2024

Novel compound heterozygous MPDU1 variants causing congenital disorders of glycosylation presenting with erythrokeratodermia variabilis

Wei Z, Mo R, Yang Y, Chen Z. J Dermatol., June 3, 2024

Congenital disorders of glycosylations (CDGs) are a class of inherited metabolic diseases. CDG-type If (OMIM: 609180), also known as mannose-P-dolichol utilization defect 1 (MPDU1)-CDG, is caused by defects in the MPDU1 gene. MPDU1-CDG patients typically present with neurodevelopmental delays, seizures, ichthyosiform dermatitis, hypotonia, facial dysmorphism, and eye defects.1 Here, we describe the first report of an MPDU1-CDG patient, presenting with erythrokeratodermia variabilis.

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June 1, 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. , June 1, 2024

Infantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies. 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. [...] 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.

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June 1, 2024

NANS-CDG: Expanding clinical insights with a novel patient with novel variants

Yoo S, Cheon CK. Am J Med Genet A., June 1, 2024

N-acetyl-d-neuraminic acid synthase-congenital disorder of glycosylation (NANS-CDG) is a rare autosomal recessive defect in the N-acetyl-neuraminic acid biosynthesis pathway. Herein, we report the first Korean NANS-CDG patient. A 10-year-old boy was referred to our clinic because of incidental radiographic findings indicating spondyloepimetaphyseal dysplasia. The patient had microcephaly, cavum septum pellucidum, and ventriculomegaly at birth, and at 10 years, a very short stature. He had a history of idiopathic chronic immune thrombocytopenia, central adrenal insufficiency, and hypothyroidism since infancy. The first unprovoked seizure occurred at the age of 2 years, and he was subsequently admitted to the hospital frequently because of respiratory infections and intractable seizures. Exome sequencing identified unreported biallelic variants of the NANS gene. Clinical and genetic confirmation of NANS-CDG highlights its expanding phenotypic and genotypic diversity.

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May 2024

May 30, 2024

A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis

Wilson MP, et al. Cell., May 30, 2024

Dolichol is a lipid critical for N-glycosylation as a carrier for activated sugars and nascent oligosaccharides. It is commonly thought to be directly produced from polyprenol by the enzyme SRD5A3. Instead, we found that dolichol synthesis requires a three-step detour involving additional metabolites, where SRD5A3 catalyzes only the second reaction. The first and third steps are performed by DHRSX, whose gene resides on the pseudoautosomal regions of the X and Y chromosomes. Accordingly, we report a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG). Of note, DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD+-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps. Thus, our work reveals unexpected complexity in the terminal steps of dolichol biosynthesis. Furthermore, we provide insights into the mechanism by which dolichol metabolism defects contribute to disease.

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May 17, 2024

Droplet Microfluidics with Capillary Electrophoresis for Glycan Biomarker Analysis

Liénard-Mayor T, Bricteux C, Tran NT, Bruneel A, Taverna M, Mai TD. Methods Mol Biol., May 17, 2024

Several glycoproteins are validated biomarkers of various diseases such as cancer, cardiovascular diseases, chronic alcohol abuse, or congenital disorders of glycosylation (CDG). In particular, CDG represent a group of more than 150 inherited diseases with varied symptoms affecting multiple organs. The distribution of glycans from target glycoprotein(s) can be used to extract information to help the diagnosis and possibly differentiate subtypes of CDG. Indeed, depending on the glycans and the proteins to which they are attached, glycans can play a very broad range of roles in both physical and biological properties of glycoproteins. For glycans in general, capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) has become a staple. Analysis of glycans with CE-LIF requires several sample preparation steps, including release of glycans from the target glycoprotein, fluorescent labeling of glycans, and purification of labeled glycans. Here, we describe the protocol for glycan sample treatment in a microfluidic droplet system prior to CE-LIF of labeled glycans. The microfluidic droplet approach offers full automation, sample, and reagent volume reduction and elimination of contamination from external environment.

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May 14, 2024

Destabilization and Degradation of a Disease-Linked PGM1 Protein Variant

Gouliaev F, Jonsson N, Gersing S, Lisby M, Lindorff-Larsen K, Hartmann-Petersen R. Biochemistry., May 14, 2024

PGM1-linked congenital disorder of glycosylation (PGM1-CDG) is an autosomal recessive disease characterized by several phenotypes, some of which are life-threatening. Research focusing on the disease-related variants of the α-D-phosphoglucomutase 1 (PGM1) protein has shown that several are insoluble in vitro and expressed at low levels in patient fibroblasts. Due to these observations, we hypothesized that some disease-linked PGM1 protein variants are structurally destabilized and subject to protein quality control (PQC) and rapid intracellular degradation. Employing yeast-based assays, we show that a disease-associated human variant, PGM1 L516P, is insoluble, inactive, and highly susceptible to ubiquitylation and rapid degradation by the proteasome. In addition, we show that PGM1 L516P forms aggregates in S. cerevisiae and that both the aggregation pattern and the abundance of PGM1 L516P are chaperone-dependent. Finally, using computational methods, we perform saturation mutagenesis to assess the impact of all possible single residue substitutions in the PGM1 protein. These analyses identify numerous missense variants with predicted detrimental effects on protein function and stability. We suggest that many disease-linked PGM1 variants are subject to PQC-linked degradation and that our in silico site-saturated data set may assist in the mechanistic interpretation of PGM1 variants.

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May 14, 2024

Rare Genetic Developmental Disabilities: Mabry Syndrome (MIM 239300) Index Cases and Glycophosphatidylinositol (GPI) Disorders.

Thompson MD, Knaus A. Genes., May 14, 2024

The case report by Mabry et al. (1970) of a family with four children with elevated tissue non-specific alkaline phosphatase, seizures and profound developmental disability, became the basis for phenotyping children with the features that became known as Mabry syndrome. Aside from improvements in the services available to patients and families, however, the diagnosis and treatment of this, and many other developmental disabilities, did not change significantly until the advent of massively parallel sequencing. As more patients with features of the Mabry syndrome were identified, exome and genome sequencing were used to identify the glycophosphatidylinositol (GPI) biosynthesis disorders (GPIBDs) as a group of congenital disorders of glycosylation (CDG). [...] We discuss the longevity of the Mabry syndrome index patients in the context of the utility of pyridoxine treatment of seizures and evidence for putative glycolipid storage in patients with HPMRS3. From the perspective of the laboratory innovations made that enabled the identification of the HPMRS phenotype in Dr. Mabry's patients, the need for treatment innovations that will benefit patients and families affected by developmental disabilities is clear.

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May 14, 2024

Prenatal Diagnosis of Fryns Syndrome through Identification of Two Novel Splice Variants in the PIGN Gene-A Case Series

Marchetto A, et al. Life. , May 14, 2024

Fryns syndrome (FS) is a multiple congenital anomaly syndrome with different multisystemic malformations. These include congenital diaphragmatic hernia, pulmonary hypoplasia, and craniofacial dysmorphic features in combination with malformations of the central nervous system such as agenesis of the corpus callosum, cerebellar hypoplasia, and enlarged ventricles. We present a non-consanguineous northern European family with two recurrent cases of FS: a boy with multiple congenital malformations who died at the age of 2.5 months and a female fetus with a complex developmental disorder with similar features in a following pregnancy. g variants as the underlying pathomechanism for the development of FS in two patients.

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May 10, 2024

Normal transferrin glycosylation does not rule out severe ALG1 deficiency

Bosnyak I, Sadek M, Ranatunga W, Kozicz T, Morava E. JIMD, May 10, 2024

ALG1-CDG is a rare, clinically variable metabolic disease, caused by the defect of adding the first mannose (Man) to N-acetylglucosamine (GlcNAc2)-pyrophosphate (PP)-dolichol to the growing oligosaccharide chain, resulting in impaired N-glycosylation of proteins. N-glycosylation has a key role in functionality, stability, and half-life of most proteins. Therefore, congenital defects of glycosylation typically are multisystem disorders. Here we report a 3-year-old patient with severe neurological, cardiovascular, respiratory, musculoskeletal and gastrointestinal symptoms. [...] Reviewing the literature, we found 86 reported ALG1-CDG patients, but only one with normal transferrin analysis. Based on our results we would like to highlight the importance of multiple approaches in diagnosing ALG1-CDG, as normal serum transferrin glycosylation or other biomarkers with normal expression levels can occur.

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