Alternative titles; symbols
SNOMEDCT: 725043006; ORPHA: 206564; DO: 0110292;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.1 | Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 3 | 613157 | Autosomal recessive | 3 | POMGNT1 | 606822 |
A number sign (#) is used with this entry because this form of limb-girdle muscular dystrophy-dystroglycanopathy (type C3; MDDGC3), also known as LGMDR15 and LGMD2O, is caused by homozygous mutation in the gene encoding protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGNT1; 606822) on chromosome 1p34.
Mutation in the POMGNT1 gene can also cause a severe congenital muscular dystrophy with brain and eye anomalies (type A3; MDDGA3; 253280) and congenital muscular dystrophy-dystroglycanopathy with impaired intellectual development (type B3; MDDGB3; 613151).
MDDGC3 is a rare form of autosomal recessive limb-girdle muscular dystrophy with normal cognition (Clement et al., 2008). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007).
For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
Clement et al. (2008) reported an Irish girl with limb-girdle muscular dystrophy. She first developed proximal limb muscle weakness at age 12 years, showing difficulty rising from a sitting position and climbing stairs. The weakness progressed rapidly; by the time the patient was 14 years old, it was more proximal than distal, with the neck, hip girdle, and shoulder abductor muscles particularly affected. She had positive Gowers sign and hypertrophy of the calves and quadriceps, with wasting of the hamstring and deltoid muscles. Other features included lordosis and tightening of the Achilles tendon. Muscle biopsy showed dystrophic changes with variable staining for glycosylated alpha-dystroglycan. She lost ambulation at age 19 years after a leg fracture. She also had myopia. Cognitive development and intelligence were normal. Clement et al. (2008) proposed the designation 'LGMD2M' for this phenotype.
Raducu et al. (2012) reported an 11-year-old Belgian boy with limb-girdle muscular dystrophy without brain or eye anomalies. He had slightly delayed initial motor development and unsteady stance at age 2 years. Examination showed 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. Ophthalmologic evaluation and brain MRI were normal.
In an Irish girl with limb-girdle muscular dystrophy and normal intellect, Clement et al. (2008) identified a homozygous mutation in the POMGNT1 gene (D556N; 606822.0013).
In an 11-year-old Belgian boy with limb-girdle muscular dystrophy without brain or eye anomalies, Raducu et al. (2012) identified a homozygous 9-bp duplication upstream of the transcriptional start site of the POMGNT1 gene (606822.0017). Transfection of the mutation in COS-7 and HEK293T cells resulted in a 75% decrease in promoter activity compared to wildtype. In vitro studies demonstrated that 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.
Clement, E. M., Godfrey, C., Tan, J., Brockington, M., Torelli, S., Feng, L., Brown, S. C., Jimenez-Mallebrera, C., Sewry, C. A., Longman, C., Mein, R., Abbs, S., Vajsar, J., Schachter, H., Muntoni, F. Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant. Arch. Neurol. 65: 137-141, 2008. [PubMed: 18195152] [Full Text: https://doi.org/10.1001/archneurol.2007.2]
Godfrey, C., Clement, E., Mein, R., Brockington, M., Smith, J., Talim, B., Straub, V., Robb, S., Quinlivan, R., Feng, L., Jimenez-Mallebrera, C., Mercuri, E., and 10 others. Refining genotype-phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 130: 2725-2735, 2007. [PubMed: 17878207] [Full Text: https://doi.org/10.1093/brain/awm212]
Raducu, M., Baets, J., Fano, O., Van Coster, R., Cruces, J. Promoter alteration causes transcriptional repression of the POMGNT1 gene in limb-girdle muscular dystrophy type 2O. Europ. J. Hum. Genet. 20: 945-952, 2012. [PubMed: 22419172] [Full Text: https://doi.org/10.1038/ejhg.2012.40]