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General Information
Name
congenital disorder of glycosylation, type IIc
FlyBase ID
FBhh0000044
Overview

This report describes congenital disorders of glycosylation, type IIc (designated as CDG2C by OMIM but more recently designated SLC35C1-CDG in the literature), which is a subtype of congenital disorders of glycosylation, type II; CDG2C exhibits autosomal recessive inheritance. The human gene implicated in this disease is SLC35C1, which encodes the GDP-fucose transporter. There is a single high-scoring fly ortholog, nac, for which loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Multiple UAS constructs of the human Hsap\SLC35C1 gene have been introduced into flies. Heterologous rescue (functional complementation) has been demonstrated.

Variant(s) implicated in human disease tested (as transgenic human gene, SLC35C1): the R147C variant form of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R125C in the fly nac gene (corresponds to R147C in the human SLC35C1 gene).

Loss-of-function mutations of Dmel\nac are viable, but female-sterile; scalloped wing and behavioral phenotypes are observed. Mutants show alteration or loss of a neuron-specific glycoconjugate; staining by anti-HRP antibodies in imaginal and adult neural tissue is eliminated. Experiments in Drosophila have implicated reduction in Notch signalling activity as a partial explanation for the pathogenesis of CDG2C.

[updated Apr. 2017 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: congenital disorders of glycosylation, type II
Symptoms and phenotype
Specific Disease Summary: congenital disorder of glycosylation, type IIc
OMIM report

[CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIc; CDG2C](https://omim.org/entry/266265)

Human gene(s) implicated

[SOLUTE CARRIER FAMILY 35, MEMBER C1; SLC35C1](https://omim.org/entry/605881)

Symptoms and phenotype

CDG2C is characterized by moderate to severe mental and growth retardation, mild dysmorphism, and impaired neutrophil mobility, the latter resulting in immunodeficiency. Administration of oral fucose is an effective therapy in some cases of CDG2C but not in others. [from OMIM:266265, OMIM:605881; 15.07.21]

Clinical symptoms of CDG2C (SLC35C1-CDG) include immunodeficiency, craniofacial dysmorphism, and severe psychomotor and mental retardation. Patients have recurrent bacterial infections with unusually high leukocytosis. (Goreta et al., 2012, pubmed:22838182, Jaeken, 2013: pubmed:23622397).

CDG2C is characterized by moderate to severe mental and growth retardation, mild dysmorphism, and impaired neutrophil mobility, the latter resulting in immunodeficiency. Administration of oral fucose is an effective therapy for the immunodeficiency in some cases of CDG2C but not in others. [from OMIM:266265, OMIM:605881; 15.07.21]

Genetics

CDG2C is an autosomal recessive disorder caused by a defect in Hsap\SLC35C1, the GDP-fucose transporter. Several mutations in highly conserved transmembrane domains of Hsap\SLC35C1 have been characterized: R147C, T308R (which presented with a more severe growth defect and mental retardation than R147C), E31X, and 501CTT, a 3bp deletion. Compound heterozygotes with the E31X and 501CTT mutations retain some fucosylation activity and do not show the Bombay blood type phenotype or the leukocytosis. [from OMIM:266265; 15.07.21]

CDG2C is an autosomal recessive disorder caused by a defect in Hsap\SLC35C1, the GDP-fucose transporter.

Cellular phenotype and pathology
Molecular information

CDG2C is caused by defects in the GDP-fucose transporter, which leads to defects in the processing of protein-bound glycans in the Golgi. Specifically, certain proteins are hypofucosylated. sialyl-Lewis X, a fucose-containing ligand of the selectin family of cell adhesion molecules necessary for the recruitment of neutrophils to infection sites, is missing in the neutrophils of CDG2C patients, leading to the immunodeficiency phenotype. (Goreta et al., 2012, pubmed:22838182, Jaeken, 2013: pubmed:23622397).

CDG2C is member of a group of disorders that involve defects in the processing of protein-bound glycans. The transport of GDP-fucose into Golgi vesicals is reduced resulting in a global decrease in the fucosylation of plasma glycoproteins. The immune defect of CDG2C is due to type II leukocyte adhesion deficiency resulting from lack of CD15 (also known as Lewis X), a fucose-containing, cell surface glycoprotein that is the ligand of E and P selectins. In addition, patients lack the red cell H antigen, a fucosylated glycoprotein, which is the precursor molecule of the A, B, and O blood groups and therefore exhibit the Bombay blood type. SLC35C1 encodes a GDP-fucose transporter which is 364 aa long and has 10 transmembrane domains. [from OMIM:266265, OMIM:605881; 15.07.21]

External links
Disease synonyms
CDG2C
CDG IIc
CDG-IIC
CDG-IIc
CDGIIc
LAD2
LADII
leukocyte adhesion deficiency, type II
Rambam-Hasharon syndrome
RHS
SLC35C1-CDG
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human SLC35C1 (1 Drosophila to 1 human). Dmel\nac shares 52% identity and 72% similarity with human SLC35C1.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (0 groups)
      Alleles Reported to Model Human Disease (Disease Ontology) (1 alleles)
      Models Based on Experimental Evidence ( 1 )
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      Modifiers Based on Experimental Evidence ( 0 )
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      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
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      Publicly Available Stocks
      Selected Drosophila transgenes
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      RNAi constructs available
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      Selected Drosophila classical alleles
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      Publicly Available Stocks
      loss of function allele
      loss of function allele
      loss of function allele
      Delta2-3 transposase
      References (11)