Skip to Content

Publications

June 2022

June 19, 2022

N-Glycosylation Deficiency Reduces the Activation of Protein C and Disrupts the Endothelial Barrier Integrity

Pascreau T et al. Thromb Haemost., June 19, 2022

Phosphomannomutase 2 (PMM2) deficiency is the most prevalent congenital disorder of glycosylation. It is associated with coagulopathy, including protein C deficiency. Since all components of the anticoagulant and cytoprotective protein C system are glycosylated, we sought to investigate the impact of an N-glycosylation deficiency on this system as a whole. To this end, we developed a PMM2 knockdown model in the brain endothelial cell line hCMEC/D3. [...] Taken as a whole, our results show that the partial loss of PMM2 in hCMEC/D3 cells is associated with impaired activation of protein C and a relative increase in barrier permeability.

READ MORE

June 18, 2022

ALG8-CDG: molecular and phenotypic expansion suggests clinical management guidelines

Albokhari D et al. J Inherit Metab Dis., June 18, 2022

Congenital disorders of glycosylation are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid glycan biosynthesis. These disorders mostly manifest with multi-system involvement. Individuals with ALG8-CDG commonly present with hypotonia, protein-losing enteropathy, and hepatic involvement. Here, we describe seven unreported individuals diagnosed with ALG8-CDG based on biochemical and molecular testing and we identify nine novel variants in ALG8, bringing the total to 26 individuals with ALG8-CDG in the medical literature. In addition to the typical multisystem involvement documented in ALG8-CDG, our cohort includes the two oldest patients reported and further expands the phenotype of ALG8-CDG to include stable intellectual disability, autism spectrum disorder and other neuropsychiatric symptoms. We further expand the clinical features in a variety of organ systems including ocular, musculoskeletal, dermatologic, endocrine, and cardiac abnormalities and suggest a comprehensive evaluation and monitoring strategy to improve clinical management.

READ MORE

June 16, 2022

Disorder of fucosylation in an iranian patient caused by two novel variants in FCSK

Manoochehri J et al. Eur J Med Genet., June 16, 2022

athogenic variants in FCSK cause Congenital Disorder of Glycosylation with Defective Fucosylation-2 (FCSK-CDG; MIM: 618,324). It is a rare autosomal recessive genetic disease caused by defects in the L-fucose kinase, which is necessary for the fucose salvage pathway. Herein, we report two novel variants in an Iranian patient, the fourth individual with FCSK-CDG described in the literature. [...] The proband, a four-and-a-half year old Iranian male born to consanguineous parents, manifested Intellectual disability, growth delay, ophthalmic abnormalities, seizures, speech disorder, and feeding difficulties.

READ MORE

June 7, 2022

Case Report: A Novel Compound Heterozygous Gene Mutation of Dolichol Kinase Deficiency (DOLK-CDG)

Yu S, Zhang Y, Chen Z, Song J, Wang C. Endocr Metab Immune Disord Drug Targets., June 7, 2022

Congenital disorder of glycosylation caused by mutation of the DOLK(DOLK-CDG) is a group of rare autosomal recessive diseases with early onset age and poor prognosis. DOLK-CDG can cause dysfunction of multiple systems and organs such as heart, skin, nerves and bones. We report a child with DOLK-CDG diagnosed and treated in the Affiliated Hospital of Qingdao University. [...] This mutation is new mutation and not included in the human gene mutation library. The discovery of the novel mutation broadened the mutation spectrum of DOLK. At the same time, we sorted out the DOLK-CDG gene mutation sites and related clinical manifestations reported by August 2021 through literature review.

READ MORE

June 4, 2022

A rare cause of infantile achalasia: GMPPA-congenital disorder of glycosylation with two novel compound heterozygous variants

Geiculescu I, Dranove J, Cosper G, Edmondson AC, Morava-Kozicz E, Carter LB. Am J Med Genet A., June 4, 2022

Achalasia is rare in the pediatric population and should prompt clinicians to consider genetic disorders associated with this condition. While AAA syndrome (also known as Allgrove or Triple A syndrome) is commonly considered, GMPPA-congenital disorder of glycosylation (CDG) should also be in the differential diagnosis. We report a 9-month-old female born to nonconsanguineous parents with achalasia and alacrima found to have two novel compound heterozygous variants in the GMPPA gene associated with GMPPA-CDG. This rare disorder is commonly associated with developmental delay and intellectual disability. We discuss management of this disorder including the importance of confirming a genetic diagnosis and summarize reported cases.

READ MORE

June 2, 2022

An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency

Hope KA, Berman AR, Peterson RT, Chow CY. PLoS Genet., June 2, 2022

NGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in the N-glycanase 1 (NGLY1) gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used a Drosophila model of NGLY1 deficiency to conduct an in vivo, unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules partially rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators.[...]  This study reveals the importance of the serotonin pathway in NGLY1 deficiency, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease.

READ MORE

June 2, 2022

A Community-Led Approach as a Guide to Overcome Challenges for Therapy Research in Congenital Disorders of Glycosylation

Francisco R, Brasil S, Pascoal C, et al. Int J Environ Res Public Health., June 2, 2022

Congenital Disorders of Glycosylation (CDG) are a large family of rare genetic diseases for which effective therapies are almost nonexistent. To better understand the reasons behind this, to analyze ongoing therapy research and development (R&D) for CDG, and to provide future guidance, a community-led mixed methods approach was organized during the 4th World Conference on CDG for Families and Professionals. [...] The multiple challenges and solutions identified administrative/regulatory, communication, financial, technical, and biological issues, which are directly related to three fundamental aspects of therapy R&D, namely data, sample, and patient management. 

READ MORE

May 2022

May 31, 2022

Compound heterozygous variants in MAN2B2 identified in a Chinese child with congenital disorders of glycosylation

Tian Q, Shu L, Shu C, Xi H, Ma N, Mao X, Wang H. Eur J Hum Genet., May 31, 2022

Congenital disorders of glycosylation (CDG) are a group of inherited disorders. It is characterized by multi-organ dysfunction with significant morbidity and mortality. MAN2B2-CDG caused by pathogenic variants in the MAN2B2 gene was a rare CDG. To date, only one case of MAN2B2-CDG was reported. The representative clinical features were immune deficiency, dysmorphic facial features, coagulopathy, and severe developmental delay. More cases are needed to support the pathogenesis of MAN2B2 variation and elucidate its clinical heterogeneity. In this study, we described the clinical presentations of a CDG proband with compound heterozygous variants in MAN2B2.

READ MORE

May 26, 2022

Differential Effects of D-Galactose Supplementation on Golgi Glycosylation Defects in TMEM165 Deficiency

Durin Z et al. Front Cell Dev Biol., May 26, 2022

[...] In the present study, we demonstrate the differential impact of D-Gal or MnCl2 supplementation effects on the Golgi glycosylation defects caused by TMEM165 deficiency. Whereas MnCl2 supplementation unambiguously fully rescues the N- and O-linked as well as GAG glycosylations in TMEM165-deficient cells, D-Gal supplementation only rescues the N-linked glycosylation, without any effects on the other Golgi-related glycosylation types. According to these results, we would recommend the use of MnCl2 for TMEM165-CDG therapy.

READ MORE

May 20, 2022

Specific N-glycans regulate an extracellular adhesion complex during somatosensory dendrite patterning

Rahman M, Ramirez-Suarez NJ, Diaz-Balzac CA, Bülow HE. EMBO Rep., May 20, 2022

N-glycans are molecularly diverse sugars borne by over 70% of proteins transiting the secretory pathway and have been implicated in protein folding, stability, and localization. Mutations in genes important for N-glycosylation result in congenital disorders of glycosylation that are often associated with intellectual disability. Here, we show that structurally distinct N-glycans regulate an extracellular protein complex involved in the patterning of somatosensory dendrites in Caenorhabditis elegans. Specifically, aman-2/Golgi alpha-mannosidase II, a conserved key enzyme in the biosynthesis of specific N-glycans, regulates the activity of the Menorin adhesion complex without obviously affecting the protein stability and localization of its components. AMAN-2 functions cell-autonomously to allow for decoration of the neuronal transmembrane receptor DMA-1/LRR-TM with the correct set of high-mannose/hybrid/paucimannose N-glycans.

READ MORE
LOAD MORE