Alternative titles; symbols
SNOMEDCT: 726614009; ORPHA: 280333; DO: 0110293;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21.31 | Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9 | 613818 | Autosomal recessive | 3 | DAG1 | 128239 |
A number sign (#) is used with this entry because of evidence that this form of limb-girdle muscular dystrophy-dystroglycanopathy (type C9; MDDGC9), also known as LGMDR16 and LGMD2P, is caused by homozygous or compound heterozygous mutation in the gene encoding alpha-dystroglycan (DAG1; 128239) on chromosome 3p21.
Mutation in the DAG1 gene can also cause the more severe disorder congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A9, MDDGA9; 616538).
MDDGC9 is an autosomal recessive muscular dystrophy showing onset in early childhood. It is part of a group of similar disorders resulting from defective glycosylation of DAG1, collectively known as 'dystroglycanopathies' (summary by Hara et al., 2011).
For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
Dincer et al. (2003) reported a 16-year-old Turkish girl with autosomal recessive limb-girdle muscular dystrophy and severe mental retardation. She had delayed motor development and achieved walking at age 3 years, but showed unsteady gait and difficulties climbing stairs, which progressed to a waddling gait with Gowers sign. She had mild enlargement of the calves, ankle contractures, and increased lumbar lordosis. At age 16, she used only 2-word sentences and had an IQ of 50. Laboratory studies showed increased serum creatine kinase; brain MRI was normal. Skeletal muscle biopsy showed dystrophic changes and decreased labeling for glycosylated alpha-dystroglycan.
Clinical Variability
Dong et al. (2015) reported a 7-year-old boy, born of unrelated Japanese parents, with a very mild form of muscular dystrophy manifest only as asymptomatic increased serum creatine kinase. The patient was found to have increased serum creatine kinase incidentally during an episode of tonsillitis. He had no symptomatic muscle weakness, but did have calf pseudohypertrophy. Skeletal muscle biopsy showed features of muscular dystrophy, including regenerating fibers, internal nuclei, and mild endomysial fibrosis. There was negative staining with an antibody for the glycoepitope of DAG1, and Western blot analysis showed decreased glycosylation of alpha-dystroglycan compared to controls.
The transmission pattern of MDDGC9 in the family reported by Dincer et al. (2003) was consistent with autosomal recessive inheritance.
In a Turkish woman with limb-girdle muscular dystrophy and severe cognitive impairment reported by Dincer et al. (2003), Hara et al. (2011) identified a homozygous mutation in the DAG1 gene (T192M; 128239.0001). Functional expression analysis in vitro and in mice indicated that the mutation decreased LARGE (603590)-mediated posttranslational O-mannosyl glycosylation of DAG1, interfering with its receptor function and laminin binding in skeletal muscle and brain.
In a 7-year-old Japanese boy with a very mild form of MDDGC9 presenting only as asymptomatic increased serum creatine kinase, Dong et al. (2015) identified compound heterozygous missense mutations in the DAG1 gene (V74I, 128239.0002 and D111N, 128239.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were found at a low frequency in the dbSNP, 1000 Genomes Project, and HapMap databases. Transfection of either mutation into DAG1-null cells did not restore alpha-dystroglycan immunoreactivity. Beta-dystroglycan was unaffected, indicating that the mutations did not influence expression of dystroglycan, but did cause a defect in posttranslational modification.
Hara et al. (2011) demonstrated that mice with a homozygous T190M mutation in the Dag1 gene, which corresponds to the human T192M mutation (128239.0001), developed muscular dystrophy and neurologic motor impairment reminiscent of the human disorder.
Tabebordbar et al. (2013) designated this disorder 'limb-girdle muscular dystrophy 2P (LGMD2P).'
Dincer, P., Balci, B., Yuva, Y., Talim, B., Brockington, M., Dincel, D., Torelli, S., Brown, S., Kale, G., Haliloglu, G., Gerceker, F. O., Atalay, R. C., Yakicier, C., Longman, C., Muntoni, F., Topaloglu, H. A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan. Neuromusc. Disord. 13: 771-778, 2003. [PubMed: 14678799] [Full Text: https://doi.org/10.1016/s0960-8966(03)00161-5]
Dong, M., Noguchi, S., Endo, Y., Hayashi, Y. K., Yoshida, S., Nonaka, I., Nishino, I. DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of alpha-dystroglycan. Neurology 84: 273-279, 2015. [PubMed: 25503980] [Full Text: https://doi.org/10.1212/WNL.0000000000001162]
Hara, Y., Balci-Hayta, B., Yoshida-Moriguchi, T., Kanagawa, M., Beltran-Valero de Bernabe, D., Gundesli, H., Willer, T., Satz, J. S., Crawford, R. W., Burden, S. J., Kunz, S., Oldstone, M. B. A., Accardi, A., Talim, B., Muntoni, F., Topaloglu, H., Dincer, P., Campbell, K. P. A dystroglycan mutation associated with limb-girdle muscular dystrophy. New Eng. J. Med. 364: 939-946, 2011. [PubMed: 21388311] [Full Text: https://doi.org/10.1056/NEJMoa1006939]
Tabebordbar, M., Wang, E. T., Wagers, A. J. Skeletal muscle degenerative diseases and strategies for therapeutic muscle repair. Annu. Rev. Path. 8: 441-475, 2013. [PubMed: 23121053] [Full Text: https://doi.org/10.1146/annurev-pathol-011811-132450]