|ZFIN ID: ZDB-PUB-050617-8|
Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies
Grewal, P.K., McLaughlan, J.M., Moore, C.J., Browning, C.A., and Hewitt, J.E.
|Source:||Glycobiology 15(10): 912-923 (Journal)|
|Registered Authors:||Moore, Chris|
|Keywords:||muscular dystrophy; dystroglycan; glycosyltransferase; Golgi|
|PubMed:||15958417 Full text @ Glycobiology|
Grewal, P.K., McLaughlan, J.M., Moore, C.J., Browning, C.A., and Hewitt, J.E. (2005) Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies. Glycobiology. 15(10):912-923.
ABSTRACTThe Large(myd) mouse has a loss of function mutation in the putative glycosyltransferase gene Large. Mutations in the human homologue (LARGE) have been described in a form of congenital muscular dystrophy (MDC1D). Other genes that encode known or putative glycosylation enzymes (POMT1, POMGnT1, fukutin and FKRP) are also causally associated with human congenital muscular dystrophies. All these diseases are associated with hypoglycosylation of the membrane protein alpha-dystroglycan and consequent loss of extracellular ligand binding. Hence, they are termed dystroglycanopathies. A paralogous gene for LARGE (LARGE2 or GYLTL1B) may also have a role in dystroglycan glycosylation. Using database interrogation and RT-PCR, we identified vertebrate orthologues of each of these genes in many vertebrates, including human, mouse, dog, chicken, zebrafish and pufferfish. However, within invertebrate genomes we were able to identify only single homologues. We suggest that vertebrate LARGE orthologues be referred to as LARGE1. RT-PCR, dot blot and Northern analysis indicated that LARGE2 has a more restricted tissue expression profile than LARGE1. Using epitope-tagged proteins, we show that both LARGE1 and LARGE2 localise to the Golgi apparatus. The high similarity between the LARGE paralogues suggests that LARGE2 may also act on dystroglycan. Over-expression of LARGE2 in mouse C2C12 myoblasts results in increased glycosylation of alpha-dystroglycan accompanied by an increase in laminin binding. Thus, there may be functional redundancy between LARGE1 and LARGE2. Consistent with this idea, we show that alpha-dystroglycan is still fully glycosylated in adult kidney (a tissue that expresses a high level of LARGE2 mRNA) of Large(myd) mutant mice.