Alternative titles; symbols
SNOMEDCT: 719990003; ORPHA: 55596; DO: 0110306;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q21.22 | Muscular dystrophy, limb-girdle, autosomal dominant 3 | 609115 | Autosomal dominant | 3 | HNRNPDL | 607137 |
A number sign (#) is used with this entry because of evidence that autosomal dominant limb-girdle muscular dystrophy-3 (LGMDD3) is caused by heterozygous mutation in the HNRNPDL gene (607137) on chromosome 4q21.
Autosomal dominant limb-girdle muscular dystrophy-3 (LGMDD3) is characterized by slowly progressive proximal muscle weakness affecting the upper and lower limbs. Onset is usually in adulthood, but can occur during the teenage years. Affected individuals may also develop cataracts before age 50 (summary by Vieira et al., 2014).
For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (603511).
At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD1G was renamed LGMDD3.
Starling et al. (2004) reported a Brazilian family in which 12 members had a mild adult-onset form of autosomal dominant limb-girdle muscular dystrophy. Age at onset ranged from 30 to 47 years with proximal lower limb weakness in most patients, muscle cramps in 1 patient, and upper limb weakness in 1 patient. Nine of 10 patients eventually had upper limb weakness. With the exception of the youngest patient, all patients developed progressive and permanent restriction of finger and toe flexion and reduced range of movement in the interphalangeal joints. Normal strength was retained in the intrinsic hand muscles. Serum creatine kinase was increased in all but 2 patients, and muscle biopsy of 1 patient showed a myopathic pattern with rimmed vacuoles. All 5 patients and 3 unaffected family members older than 45 years had type II diabetes mellitus (125853). Vieira et al. (2014) noted that 2 members of the family reported by Starling et al. (2004) developed cataracts at 36 and 56 years of age, respectively. Skeletal muscle biopsy of a severely affected individual showed a clear myopathic pattern with necrotic fibers and rimmed vacuoles, as well as some neurogenic involvement, as evidenced by small angulated fibers, predominance of type II fibers, and fiber-type grouping.
Vieira et al. (2014) reported a large 4-generation Uruguayan family with autosomal dominant LGMD. Affected individuals presented between 15 and 53 years of age with proximal lower or upper limb weakness, including limitation of finger and toe flexion. Six of 11 clinically affected patients developed cataracts before age 50 years.
The transmission pattern of LGMDD3 in the families reported by Vieira et al. (2014) was consistent with autosomal dominant inheritance and incomplete penetrance.
In a family with autosomal dominant limb-girdle muscular dystrophy, Starling et al. (2004) identified the disease locus, termed LGMD1G, within a 9-cM (7 Mb) region between markers D4S2947 and D4S2409 on chromosome 4q21 (maximum 2-point lod score of 6.62 at theta = 0.0 for D4S2964).
In affected members of a Brazilian family and a Uruguayan family with LGMD1G, Vieira et al. (2014) identified 2 different heterozygous missense mutations affecting the same codon in the HNRNPDL gene (D378N, 607137.0001 and D378H, 607137.0002, respectively). The mutations were found by a combination of linkage analysis and whole-genome sequencing. Functional studies of the variants were not performed. Loss of the yeast homolog hrp1 had pronounced effects on both protein levels and cell localizations, demonstrating that its loss was detrimental to cell physiology. The loss of Hrp1 on the yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. Immunohistochemical studies of patient skeletal muscle showed higher variability in nuclear labeling of HNRNPDL compared to controls, with some nuclei showing a strong condensed signal and others showing a diffuse pattern around the nucleus. The findings implicated a role for RNA binding/processing proteins in muscle development and muscle disease.
Vieira et al. (2014) found that morpholino knockdown of hnrpdl in zebrafish resulted in body shape defects and twisted tails, as well as restricted movement and uncoordination, consistent with a myopathy. Myofibers isolated from mutant zebrafish were disorganized.
Starling, A., Kok, F., Passos-Bueno, M. R., Vainzof, M., Zatz, M. A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21. Europ. J. Hum. Genet. 12: 1033-1040, 2004. Note: Erratum: Europ. J. Hum. Genet. 13: 264 only, 2005. [PubMed: 15367920] [Full Text: https://doi.org/10.1038/sj.ejhg.5201289]
Straub, V., Murphy, A., Udd, B. 229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017. Neuromusc. Disord. 28: 702-710, 2018. [PubMed: 30055862] [Full Text: https://doi.org/10.1016/j.nmd.2018.05.007]
Vieira, N. M., Naslavsky, M. S., Licinio, L., Kok, F., Schlesinger, D., Vainzof, M., Sanchez, N., Kitajima, J. P., Gal, L., Cavacana, N., Serafini, P. R., Chuartzman, S., Vasquez, C., Mimbacas, A., Nigro, V., Pavanello, R. C., Schuldiner, M., Kunkel, L. M., Zatz, M. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum. Molec. Genet. 23: 4103-4110, 2014. [PubMed: 24647604] [Full Text: https://doi.org/10.1093/hmg/ddu127]