Expanding the molecular and clinical phenotypes of FUT8‐CDG

Ng, Bobby G.; Dastsooz, Hassan; Silawi, Mohammad; Habibzadeh, Parham; Jahan, Shima Bahram; Fard, Mohammad Ali Farazi; Halliday, Benjamin J.; Raymond, Kimiyo; Ruzhnikov, Maura R.Z.; Tabatabaei, Zahra; Taghipour‐Sheshdeh, Afsaneh; Brimble, Elise; Robertson, Stephen; Faghihi, Mohammad Ali; Freeze, Hudson H.

doi:10.1002/jimd.12221

Cited by 28 publications

(18 citation statements)

References 21 publications

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“…FUT8 gene disruption in mice causes postnatal semi-lethality with emphysema-like changes in the lungs and extracellular matrix destruction (44,45), severe growth retardation (14), defects in antigen presentation and immune response (5), aberrant B-cell development (9), defects in T-cell receptor signaling (10,46) impaired synaptic plasticity (47), schizophrenialike symptoms (48), and enhanced neuroinflammation (49). Patients with FUT8-CDG harboring defects in the FUT8 gene also present a similar spectrum of clinical symptoms (50,51).…”

Section: Introductionmentioning

confidence: 99%

Characterizing human α-1,6-fucosyltransferase (FUT8) substrate specificity and structural similarities with related fucosyltransferases

Boruah

Kadirvelraj

Liu

et al. 2020

Journal of Biological Chemistry

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Mammalian Asn-linked glycans are extensively processed as they transit the secretory pathway to generate diverse glycans on cell surface and secreted glycoproteins. Additional modification of the glycan core by α-1,6-fucose addition to the innermost GlcNAc residue (core fucosylation) is catalyzed by an α-1,6-fucosyltransferase (FUT8). The importance of core fucosylation can be seen in the complex pathological phenotypes of FUT8 null mice, which display defects in cellular signaling, development, and subsequent neonatal lethality. Elevated core fucosylation has also been identified in several human cancers. However, the structural basis for FUT8 substrate specificity remains unknown. Here, using various crystal structures of FUT8 in complex with a donor substrate analog, and with four distinct glycan acceptors, we identify the molecular basis for FUT8 specificity and activity. The ordering of three active site loops corresponds to an increased occupancy for bound GDP, suggesting an induced-fit folding of the donor binding subsite. Structures of the various acceptor complexes were compared with kinetic data on FUT8 active site mutants and with specificity data from a library of glycan acceptors to reveal how binding site complementarity and steric hindrance can tune substrate affinity. The FUT8 structure was also compared with other known fucosyltransferases to identify conserved and divergent structural features for donor and acceptor recognition and catalysis. These data provide insights into the evolution of modular templates for donor and acceptor recognition among GT-B fold glycosyltransferases in the synthesis of diverse glycan structures in biological systems.

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Section: Introductionmentioning

confidence: 99%

Characterizing human α-1,6-fucosyltransferase (FUT8) substrate specificity and structural similarities with related fucosyltransferases

Boruah

Kadirvelraj

Liu

et al. 2020

Journal of Biological Chemistry

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“…FUT8 is a fucosyltransferase essential for neurodevelopment that has also been studied in relation to the immune system and cancer (Schneider et al, 2017). Biallelic mutations in FUT8 were reported in seven individuals with neurological impairment (Ng et al, 2018, Ng et al, 2020. Similarly, subgroup 6, characterized by auditory hypo-sensitivity paired with auditory ltering scores in the different from typically developing children range as well as taste hyper-sensitivity paired with de nitely different taste and smell sensitivity scores, was associated with variants in SHANK1.…”

Section: Discussionmentioning

confidence: 94%

Cluster Analysis of Short Sensory Profile Data Reveals Sensory-based Subgroups in Autism Spectrum Disorder

Lyons-Warren

Wan

2021

Preprint

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Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social interactions and communication. Additional features include restricted, repetitive patterns of behaviors, and differences in sensory processing. The clinical presentation of patients with ASD is heterogeneous, likely reflecting multiple underlying etiologies. Heterogeneity in presentation and treatment response are barriers to development of precise therapeutic approaches. Therefore, identification of clinically meaningful subgroups within ASD is critical to develop targeted interventions. We hypothesized that sensory features can be used to identify clinically recognizable subgroups with shared underlying etiologies. Methods: Subjects included 378 individuals with a clinical diagnosis of ASD who contributed Short Sensory Profile (SSP) data assessing the frequency of sensory behaviors and whole genome sequencing results to the Autism Speaks’ MSSNG database. To determine if the SSP could be used to subgroup individuals with ASD, we performed cluster analysis on responses to all 38 questions, followed by an independent cluster analysis using only a subset of questions selected specifically to assay hyper- and hypo-sensitivity to sensory stimulation. Cross-validation of the resulting clusters determined the final subgroups. To test for shared underlying etiologies, we correlated variant frequency across subgroups for each of 24,896 genes. Variant frequency included any variation in each gene regardless of the type of variant. To be significantly associated with a subgroup, a gene variant frequency had to be greater than four standard deviations (SD) from the mean frequency for all subgroups and 3 SD different from each subgroup.Results: We identified seven distinct sensory-based ASD subgroups. Subgroup 1, characterized by atypical scores in all sensory areas, was not associated with any genes. Subgroups 2, 4 and 6 were significantly associated with four to six genes each. Subgroups 3, 5 and 7 were enriched for 126, 12 and 50 genes, respectively. Limitations: This study was performed using retrospective data that did not include other phenotypic data such as age, comorbidities, or measures of disease severity. All those likely contribute to the variability of the identified subgroupsConclusions: These results support the use of sensory features to identify ASD subgroups with shared genetic mechanisms.

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“…due to hypofucosylation), present serologically with the Bombay (0h) blood group, whereby at least some of the SLC35C1-CDG patients can be distinguished from other patients described in the context of defects in the fucose metabolism. (Frydman et al, 1992;L€ ubke et al, 2001;Etzioni et al, 2002;Ng et al, 2018b;Ng et al, 2020;Park et al, 2020). An exception is POFUT1-CDG, which mainly manifests by reticulate hyperpigmentation after puberty known as Dowling-Degos disease 2 (Li et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

A spoonful of L‐fucose—an efficient therapy for GFUS‐CDG, a new glycosylation disorder

et al. 2021

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Congenital disorders of glycosylation are a genetically and phenotypically heterogeneous family of diseases affecting the co-and posttranslational modification of proteins. Using exome sequencing, we detected biallelic variants in GFUS (NM_003313.4) c.[632G>A]; [659C>T] (p.[Gly211Glu];[Ser220Leu]) in a patient presenting with global developmental delay, mild coarse facial features and faltering growth. GFUS encodes GDP-L-fucose synthase, the terminal enzyme in de novo synthesis of GDP-L-fucose, required for fucosylation of N-and O-glycans. We found reduced GFUS protein and decreased GDP-L-fucose levels leading to a general hypofucosylation determined in patient's glycoproteins in serum, leukocytes, thrombocytes and fibroblasts. Complementation of patient fibroblasts with wild-type GFUS cDNA restored fucosylation. Making use of the GDP-L-fucose salvage pathway, oral fucose supplementation normalized fucosylation of proteins within 4 weeks as measured in serum and leukocytes. During the follow-up of 19 months, a moderate improvement of growth was seen, as well as a clear improvement of cognitive skills as measured by the Kaufmann ABC and the Nijmegen Pediatric CDG Rating Scale. In conclusion, GFUS-CDG is a new glycosylation disorder for which oral L-fucose supplementation is promising.

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Expanding the molecular and clinical phenotypes of FUT8‐CDG

Cited by 28 publications

References 21 publications

Characterizing human α-1,6-fucosyltransferase (FUT8) substrate specificity and structural similarities with related fucosyltransferases

Characterizing human α-1,6-fucosyltransferase (FUT8) substrate specificity and structural similarities with related fucosyltransferases

Cluster Analysis of Short Sensory Profile Data Reveals Sensory-based Subgroups in Autism Spectrum Disorder

A spoonful of L‐fucose—an efficient therapy for GFUS‐CDG, a new glycosylation disorder

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