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November 2022

November 25, 2022

Antisense oligonucleotide induced pseudoexon skipping and restoration of functional protein for Fukuyama muscular dystrophy caused by a deep-intronic variant

Enkhjargal S, et al. Hum Mol Genet., November 25, 2022

Fukuyama congenital muscular dystrophy (FCMD) is an autosomal recessive disorder caused by fukutin (FKTN) gene mutations. FCMD is the second most common form of childhood muscular dystrophy in Japan, and the most patients possess a homozygous retrotransposal SINE-VNTR-Alu insertion in the 3'-untranslated region of FKTN. A deep-intronic variant (DIV) was previously identified as the second most prevalent loss-of-function mutation in Japanese patients with FCMD. [...] Patients with FCMD carrying the DIV present a more severe symptoms, and currently, there is no radical therapy available for this disorder. In the present study, we describe in vitro evaluation of antisense oligonucleotide mediated skipping of pseudoexon inclusion and restoration of functional FKTN protein. 


November 24, 2022

Congenital disorder of glycosylation with defective fucosylation 2 (FCSK gene defect): The third report in the literature with a mild phenotype

Al Tuwaijri A, et al. Mol Genet Genomic Med., November 24, 2022

Congenital disorders of glycosylation (CDG) are a group of heterogeneous disorders caused by abnormal lipid or protein glycosylation. Variants in the FCSK gene have been reported to cause CDG. Defective FCSK-induced CDG (FCSK-CDG) has only been reported previously in three unrelated children. [...] In this study, we genetically and clinically examined a 3-year-old proband with resolved infantile spasms and normal development. WES revealed a rare biallelic missense variant (c.3013G>C; p.Val1005Leu) in FCSK.


November 23, 2022

A rare case of SRD5A3-CDG in a patient with ataxia and telangiectasia: A case report

Nabavizadeh SH, et al. Clin Case Rep. , November 23, 2022

Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is an extremely rare congenital disease. Common manifestations are developmental delay, intellectual disability, ophthalmological abnormalities, cerebellar abnormalities, ataxia, and hypotonia. Here, we discuss a seven-year-old boy with SRD5A3-CDG (homozygous variant c.57G>A [p.Trp19Ter]), featuring the unprecedented finding of telangiectasia.


November 22, 2022

Glycan quality control in and out of the endoplasmic reticulum of mammalian cells

Harada Y et al. FEBS J., November 22, 2022

The endoplasmic reticulum (ER) is equipped with multiple quality control systems (QCS) that are necessary for shaping the glycoproteome of eukaryotic cells. These systems facilitate the productive folding of glycoproteins, eliminate defective products, and function as effectors to evoke cellular signaling in response to various cellular stresses. These ER functions largely depend on glycans, which contain sugar-based codes that, when needed, function to recruit carbohydrate-binding proteins that determine the fate of glycoproteins. [...] This review summarizes the current state of our knowledge of the mechanisms underlying glycan QCS in mammals and its physiological and pathological roles in embryogenesis, tumor progression, and congenital disorders associated with abnormal glycosylation


November 21, 2022

GLUT1 is a Highly Efficient L-Fucose Transporter

Ng BG, Sosicka P, Xia Z, Freeze HH. J Biol Chem., November 21, 2022

Understanding L-fucose metabolism is important because it is used as a therapy for several congenital disorders of glycosylation. Exogenous L-fucose can be activated and incorporated directly into multiple N- and O-glycans via the fucose salvage/recycling pathway. However, unlike for other monosaccharides, no mammalian L-fucose transporter has been identified. Here, we functionally screened nearly 140 annotated transporters and identified GLUT1 (SLC2A1) as an L-fucose transporter. We confirmed this assignment using multiple approaches to alter GLUT1 function including, chemical inhibition, siRNA knockdown, and gene knockout. Collectively, all methods demonstrate that GLUT1 contributes significantly to L-fucose uptake and its utilization at low micromolar levels.


November 19, 2022

Prenatal ultrasound findings associated with PIGW variants: One more piece in the FRYNS syndrome puzzle? PIGW-related prenatal findings.

Ronzoni L et al. Prenat Diagn., November 19, 2022

We describe the prenatal ultrasound findings and autopsy of three fetuses with multiple congenital anomalies (MCA) whose diagnostic workup suggested the same genetic etiology. We conducted a literature review to corroborate the molecular results and find evidence that the identified variants are responsible for the phenotype seen. [...] Based on the phenotypic overlap between the prenatal findings in our three cases and other cases with pathogenic variants in other genes involved in GPIBDs, we speculate that the variants identified in the three fetuses are likely causal of their phenotype and that the PIGWclinical spectrum might extend to MCA, mainly involving brain, skeletal and genitourinary systems. Moreover, we suggest that also PIGW could be involved in Fryns/Fryns-like phenotypes.


November 18, 2022

Chemical Therapies for Congenital Disorders of Glycosylation

Sosicka P, Ng BG, Freeze HH. ACS Chem Biol., November 18, 2022

Congenital disorders of glycosylation (CDG) are ultrarare, genetically and clinically heterogeneous metabolic disorders. Although the number of identified CDG is growing rapidly, there are few therapeutic options. Most treatments involve dietary supplementation with monosaccharides or other precursors. These approaches are relatively safe, but in many cases, the molecular and biochemical underpinnings are incomplete. Recent studies demonstrate that yeast, worm, fly, and zebrafish models of CDG are powerful tools in screening repurposed drugs, ushering a new avenue to search for novel therapeutic options. Here we present a perspective on compounds that are currently in use for CDG treatment or have a potential to be applied as therapeutics in the near future.


November 16, 2022

The O-GlcNAc cycling in neurodevelopment and associated diseases

Wenzel DM, Olivier-Van Stichelen S. Biochem Soc Trans., November 16, 2022

Proper neuronal development is essential to growth and adult brain function. Alterations at any step of this highly organized sequence of events, due to genetic mutations or environmental factors, triggers brain malformations, which are leading causes of diseases including epilepsy, intellectual disabilities, and many others. The role of glycosylation in neuronal development has been emphasized for many years, notably in studying human congenital disorders of glycosylation (CDGs). [...] In this review, we give an overview of the role of O-GlcNAcylation in this critical physiological process and emphasize the consequences of its dysregulation.


November 13, 2022

Rare multiple congenital anomalies-hypotonia-seizures syndrome type 1 (MCAHS1) – The clinical and molecular summary

Bukowska-Olech E et al. Eur J Med Genet., November 13, 2022

Multiple congenital anomalies-hypotonia-seizures syndrome type 1 (MCAHS1) is a rare autosomal recessive genetic disease belonging to glycosylphosphatidylinositols biosynthesis defects (GPIBD), a group of recessive disorders characterized by intellectual disability, hypotonia, and seizures. [...]  Here, we have reported a male patient presenting with hypotonia, intellectual disability, and epilepsy, who underwent whole exome sequencing (WES). The analysis revealed the presence of two deleterious variants in PIGN that encodes GPI ethanolamine phosphate transferase-1 - one novel (c.1247_1251delAAGTG; p.Glu416Glyfs*22), and one that has been previously reported in the medical literature (c.1434+5G > A) resulting in MCAHS1. 


November 10, 2022

Homozygous truncating variant in MAN2A2 causes a novel congenital disorder of glycosylation with neurological involvement

Mahajan S, et al. J Med Genet., November 10, 2022

Enzymes of the Golgi implicated in N-glycan processing are critical for brain development, and defects in many are defined as congenital disorders of glycosylation (CDG). Involvement of the Golgi mannosidase, MAN2A2 has not been identified previously as causing glycosylation defects. [...] Our findings show that pathogenic variants in MAN2A2 cause a novel autosomal recessive CDG with neurological involvement and facial dysmorphism. Here, we also present the development of a cell-based complementation assay to assess the pathogenicity of MAN2A2 variants, which can also be extended to MAN2A1 variants for future diagnosis.