SLC35A1-CDG

What is SLC35A1?

SLC35A1 is the name of gene that encodes a protein called the CMP-sialic acid transporter. SLC35A1 resides in the Golgi membrane, where it quickly ushers in a sugar nucleotide fusion and oligosaccharide building block called CMP-sialic acid. SLC35A1 and SLC35A2 are close relatives. Mutations in either gene cause a Type 2 congenital disorder of glycosylation. (Check out the SLC35A2-CDG Disease page here).

Type 2 CDGs involve the later stages of N-linked glycosylation when proteins are transiting through the Golgi. Like an automated assembly line, a procession of enzymes adds and subtracts various flavors of sugar to and from newly made proteins, lengthening and pruning oligosaccharide appendages as proteins pass from one station to the next. In the case of SLC35A1-CDG, sialic acid building blocks are not incorporated onto the ends of oligosaccharide-linked proteins and lipids. This lack of sialylation has implications beyond SLC35A1-CDG involving the immune system, pathogen recognition and cancer. 

As is the case for almost all CDG genes, SLC35A1 is evolutionarily conserved in mice, zebrafish, flies and worms.

Clinical descriptions of SLC35A1-CDG

The first two SLC35A1-CDG patients were described over an eight-year span. The first published account of SLC35A1-CDG is 15 years old and presents the case of a child who was diagnosed posthumously (Martinez-Duncker et al., 2005). The next clinical report was published by Morava and colleagues after some genetic detective work singled out SLC35A1 as the culprit (Mohamed et al., 2013). While CDG patients in general experience coagulation defects because of hypoglycosylation of circulating clotting factors, SLC35A1-CDG patients also have reduced platelet cell function. Platelet clearance and life span appear to be particularly sensitive to sialylation defects (Kauskot et al., 2018).

A now young teenage girl from Germany was the third SLC35A1-CDG patient ever written up in Ng et al., 2017. Like many papers describing the workup of an undiagnosed CDG-1x patient, the story begins with unbiased whole exome sequencing followed by nomination of a casual gene followed by functional studies of the mutated gene in patient-derived fibroblasts. Because SLC35A1 is a transporter protein localized to Golgi, studies that assess the effects of mutations on protein function and intracellular location are relatively straightforward.

Figure 2 reproduced from Ng et al., 2017 showing the near complete loss of transporter functionality of SLC35A1-CDG patient fibroblasts (panel B, solid black line) compared to a control fibroblast.

In addition to its role in N-linked glycosylation, there is also evidence that SLC35A1 impacts O-linked mannosylation in a manner that does not involve its sialic acid transporter function. Therefore SLC35A1-CDG has hallmarks of both a congenital disorder of glycosylation and a muscular dystrophy-dystroglycanopathy (Riemersma et al., 2015).

Next steps for SLC35A1-CDG

The usual prescription for generating a portfolio of disease models is in order. Worm, fly, zebrafish and mouse SLC35A1-CDG disease models are all theoretically possible. A functional assay to measure CMP-sialic acid transport has already been worked out in patient fibroblasts and could be adapted for other systems.

The orthologs, or ancestral versions, of SLC35A1 across species.

In the absence of any animal models, it’s too premature to recommend specific therapeutic theses. Only a handful of SLC35A1 mutations have been described and so far there’s no rhyme or reason to their location in the SLC35A1 gene. There is a splicing mutation that in theory could be amenable to splice modulating antisense oligonucleotides but that would require an experimental n-of-1 approach.

The tiny SLC35A1-CDG community should seek out allies in other Type 2 CDG advocates. Joining forces and pooling resources to create disease models would be a useful exercise. Exploring rare-to-common connections with scientists who work on platelets could be another avenue to stimulate new research.

It was recently shown that SLC35A1 is required for influenza virus infectivity (Han et al., 2018). Turns out there’s a theme. SLC35A1 is also required for Enterovirus virus (Baggen et al., 2016) and Lassa virus (Jae et al., 2013) infectivity. Although in the case of SLC35A1-CDG, SLC35A1 transporter function needs to be augmented, the connection to viral infectivity can be exploited by the SLC35A1-CDG community to attract new researchers to the field, for example virologists, and to attract interest from potential industry collaborators and funders who see a broader application of SLC35A1-CDG disease modifiers to controlling or preventing viral infections.

The biotech company Cerecor is enrolling patients in a L-fucose oral therapy for SLC35A1-CDG. You can find more information about this trial on the Clinicians page.

References

Baggen J, Thibaut HJ, Staring J, Jae LT, Liu Y, Guo H, Slager JJ, de Bruin JW, van Vliet AL, Blomen VA, Overduin P, Sheng J, de Haan CA, de Vries E, Meijer A, Rossmann MG, Brummelkamp TR, van Kuppeveld FJ. (2016). Enterovirus D68 receptor requirements unveiled by haploid genetics. Proceedings of the National Academy of Sciences. 113: 1399-404.

Han J, Perez JT, Chen C, Li Y, Benitez A, Kandasamy M, Lee Y, Andrade J, tenOever B, Manicassamy B. (2018). Genome-wide CRISPR/Cas9 Screen Identifies Host Factors Essential for Influenza Virus Replication. Cell Reports. 23: 596-607.

Jae LT, Raaben M, Riemersma M, van Beusekom E, Blomen VA, Velds A, Kerkhoven RM, Carette JE, Topaloglu H, Meinecke P, Wessels MW, Lefeber DJ, Whelan SP, van Bokhoven H, Brummelkamp TR. (2013). Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry. Science. 340: 479-483.

Kauskot A, Pascreau T, Adam F, Bruneel A, Reperant C, Lourenco-Rodrigues MD, Rosa JP, Petermann R, Maurey H, Auditeau C, Lasne D, Denis CV, Bryckaert M, de Lonlay P, Lavenu-Bombled C, Melki J, Borgel D. (2018). A mutation in the gene coding for the sialic acid transporter SLC35A1 is required for platelet life span but not proplatelet formation. Haematologica. 103: e613-e617.

Martinez-Duncker I, Dupré T, Piller V, Piller F, Candelier JJ, Trichet C, Tchernia G, Oriol R, Mollicone R. (2005). Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter. Blood. 105: 2671-2676.

Mohamed M, Ashikov A, Guillard M, Robben JH, Schmidt S, van den Heuvel B, de Brouwer AP, Gerardy-Schahn R, Deen PM, Wevers RA, Lefeber DJ, Morava E. (2013). Intellectual disability and bleeding diathesis due to deficient CMP–sialic acid transport. Neurology. 81: 681-687.

Ng BG, Asteggiano CG, Kircher M, Buckingham KJ, Raymond K, Nickerson DA, Shendure J, Bamshad MJ; University of Washington Center for Mendelian Genomics, Ensslen M, Freeze HH. (2017). Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1. American Journal of Medical Genetics A. 173: 2906-2911.

Riemersma M, Sandrock J, Boltje TJ, Büll C, Heise T, Ashikov A, Adema GJ, van Bokhoven H, Lefeber DJ. (2015). Disease mutations in CMP-sialic acid transporter SLC35A1 result in abnormal α-dystroglycan O-mannosylation, independent from sialic acid. Human Molecular Genetics. 24: 2241-2246.

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