The LARGE gene is thought to encode a putative glycosyltransferase because of its typical topology. However, no enzyme activity has been demonstrated yet, although the gene apparently supports the functional maturation of alpha-dystroglycan by glycosylation when it is transfected into cells. A novel homologous gene to LARGE was identified and named LARGE2. LARGE2 recombinant was co-expressed with alpha-dystroglycan in human embryonic kidney 293T cells to determine its activity to support the maturation of a-dystroglycan. The alpha-dystroglycan co-transfected with LARGE2 was more highly glycosylated than that co-transfected with LARGE. Pull-down experiments demonstrated binding activity of LARGE2 as well as LARGE toward of.-dystroglycan. LARGE2 was found to support the maturation of alpha-dystroglycan more effectively than LARGE. Both of them are ubiquitously expressed in many tissues, except the brain where LARGE2 was not expressed at all. This compensatory function can explain the residual functionally glycosylated alpha-dystroglycan in a patient with MDC1D whose LARGE genes are congenitally null. (c) 2005 Elsevier Inc. All rights reserved.