ClinVar

In an 11-year-old Belgian boy with limb-girdle muscular dystrophy without brain or eye anomalies (MDDGC3; 613157), Raducu et al. (2012) identified a homozygous 9-bp duplication (-83_-75dup) upstream of the transcriptional start site of the POMGNT1 gene in the 5-prime flanking region. Each unaffected parent was heterozygous for the mutation, which was not found in 200 control individuals. Transfection of the mutation in COS-7 and HEK293T cells resulted in a 75% decrease in promoter activity compared to wildtype. Electrophoretic mobility shift assay (EMSA) revealed binding sites for several transcription factors in this region. The mutation generated an additional binding site for the transcriptional repressor ZNF202 (603430), resulting in the downregulation of POMGNT1 gene expression and, ultimately, defective glycosylation. The patient had slightly delayed initial motor development and had unsteady standing at age 2 years. He had muscle weakness, slight generalized amyotrophy, a positive Gowers sign, and lack of reflexes. At age 7 to 8 years, he had lumbar hyperlordosis, difficulties in climbing stairs, and weakness of the shoulder muscles. Laboratory studies showed a mild elevation of serum creatine kinase, and muscle biopsy showed dystrophic changes and defects in alpha-dystroglycan staining.