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PMID:22522421

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Citation

Roscioli, T, Kamsteeg, EJ, Buysse, K, Maystadt, I, van Reeuwijk, J, van den Elzen, C, van Beusekom, E, Riemersma, M, Pfundt, R, Vissers, LE, Schraders, M, Altunoglu, U, Buckley, MF, Brunner, HG, Grisart, B, Zhou, H, Veltman, JA, Gilissen, C, Mancini, GM, Delrée, P, Willemsen, MA, Ramadža, DP, Chitayat, D, Bennett, C, Sheridan, E, Peeters, EA, Tan-Sindhunata, GM, de Die-Smulders, CE, Devriendt, K, Kayserili, H, El-Hashash, OA, Stemple, DL, Lefeber, DJ, Lin, YY and van Bokhoven, H (2012) Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan. Nat. Genet. 44:581-5

Abstract

Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant a-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated a-dystroglycan. These results implicate ISPD in a-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates.

Links

PubMed PMC3378661 Online version:10.1038/ng.2253

Keywords

Animals; Brain/metabolism; Brain/pathology; Child, Preschool; Dystroglycans/metabolism; Embryo, Nonmammalian; Eye/metabolism; Eye/pathology; Glycosylation; Humans; Mannosyltransferases/genetics; Mannosyltransferases/metabolism; Muscle Fibers, Skeletal/metabolism; Muscle Fibers, Skeletal/pathology; Mutation/genetics; Walker-Warburg Syndrome/genetics; Zebrafish/embryology; Zebrafish/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:ISPD

involved_in

GO:0035269: protein O-linked mannosylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:ISPD

involved_in

GO:0048854: brain morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120629-1

P

Seeded From UniProt

complete

DANRE:ISPD

involved_in

GO:0060049: regulation of protein glycosylation

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120629-1

P

Seeded From UniProt

complete

DANRE:ISPD

involved_in

GO:0060049: regulation of protein glycosylation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110418-2,ZFIN:ZDB-MRPHLNO-120629-1

P

Seeded From UniProt

complete

DANRE:ISPD

involved_in

GO:0060049: regulation of protein glycosylation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110418-1,ZFIN:ZDB-MRPHLNO-120629-1

P

Seeded From UniProt

complete

DANRE:A3KP10

involved_in

GO:0060049: regulation of protein glycosylation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110418-1,ZFIN:ZDB-MRPHLNO-120629-1

P

Seeded From UniProt

complete

HUMAN:ISPD

involved_in

GO:0035269: protein O-linked mannosylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:A4QP37

involved_in

GO:0060049: regulation of protein glycosylation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110418-2,ZFIN:ZDB-MRPHLNO-120629-1

P

Seeded From UniProt

complete

DANRE:B8JMA5

involved_in

GO:0060049: regulation of protein glycosylation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110418-1,ZFIN:ZDB-MRPHLNO-120629-1

P

Seeded From UniProt

complete

DANRE:Q0PIP5

involved_in

GO:0060049: regulation of protein glycosylation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110418-2,ZFIN:ZDB-MRPHLNO-120629-1

P

Seeded From UniProt

complete

DANRE:Q0PIP6

involved_in

GO:0060049: regulation of protein glycosylation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110418-1,ZFIN:ZDB-MRPHLNO-120629-1

P

Seeded From UniProt

complete


See also

References

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