Alternative titles; symbols
SNOMEDCT: 725907002; ORPHA: 424261; DO: 0110289;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q25.2 | ?Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures | 617072 | Autosomal recessive | 3 | TOR1AIP1 | 614512 |
A number sign (#) is used with this entry because of evidence that autosomal recessive myopathy with rigid spine and distal joint contractures (MRRSDC) is caused by homozygous mutation in the TOR1AIP1 gene (614512) on chromosome 1q25. One such family has been reported.
Autosomal recessive myopathy with rigid spine and distal joint contractures (MRRSDC) is characterized by onset of slowly progressive muscle weakness in the first or second decades of life. There is initial involvement of the proximal lower limbs, followed by distal upper and lower limb muscle weakness and atrophy. Other features include joint contractures, rigid spine, and restricted pulmonary function; some patients may have mild cardiac involvement (summary by Kayman-Kurekci et al., 2014).
Kayman-Kurekci et al. (2014) reported 3 patients from a consanguineous Turkish family with a myopathic disorder. Detailed clinical features were only available for 2 sibs, whose phenotype varied somewhat. The 29-year-old sister had onset of proximal muscle weakness at age 7 years. As a young adult, she could walk, but could not rise from the floor. She had a thin appearance with flexion contractures of the proximal and distal interphalangeal hand joints, as well as mild spinal rigidity in the cervical region. She had restricted pulmonary function, but normal cardiac function; serum creatine kinase was normal. Her 36-year-old brother had onset at age 17 years of proximal weakness of the lower limbs, which progressed to marked distal muscle weakness and atrophy affecting the upper and lower limbs within a few years, resulting in an inability to walk long distances. He also developed contractures, with spine, ankle, and hand involvement. Serum creatine kinase was increased, and EMG showed a myopathic pattern. The brother also had cardiac involvement, with mild diastolic and systolic dysfunction and an ejection fraction of 57%. Pulmonary function was moderately restricted. Neither patient had elbow contractures. Skeletal muscle biopsies in both patients showed mild dystrophic changes, including variation in fiber size, increased internal nuclei, atrophic fibers, and increased endomysial connective tissue. There were no rimmed vacuoles. Electron microscopic studies showed nuclear fragmentation and deformation, chromatin clump formation, and naked chromatin resulting from karyoplasmic leakage into the sarcoplasmic compartment. Sewry and Goebel (2014) commented that the ultrastructural features of the nuclei identified by Kayman-Kurekci et al. (2014) were nonspecific, and that some of the material may have represented lipofuscin rather than DNA. Kayman-Kurekci et al. (2014) responded that no autofluorescence was detected and that some of the fibers may have contained lipofuscin, but that the material they identified was extruded chromatin; these authors also corrected the legend in figure 3(C) in the original article to designate a degenerated nucleus and not naked chromatin.
The transmission pattern of MRRSDC in the family reported by Kayman-Kurekci et al. (2014) was consistent with autosomal recessive inheritance.
In 3 members of a consanguineous Turkish family with MRRSDC, Kayman-Kurekci et al. (2014) identified a homozygous truncating mutation in the TOR1AIP1 gene (614512.0001). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. Linkage analysis excluded other known LGMD2 loci. Skeletal muscle samples from 1 patient showed a 5-fold decrease in TOR1AIP1 mRNA compared to controls. Western blot analysis showed absence of the wildtype 66.3-kD TOR1AIP1 protein (LAP1B), but increased amounts of a 50-kD protein compared to controls. Expression of LULL1 (TOR1AIP2; 614513) was also increased compared to controls. Skeletal muscle biopsy showed dystrophic changes and a substantial loss of LAP1B immunostaining, although there appeared to be LAP1B in the endomysial regions, which likely represented the 50-kD isoform.
Kayman-Kurekci, G., Korkusuz, P., Dincer, P. Response (to Sewry and Gobel). (Letter) Neuromusc. Disord. 24: 1122 only, 2014. [PubMed: 25193337] [Full Text: https://doi.org/10.1016/j.nmd.2014.08.001]
Kayman-Kurekci, G., Talim, B., Korkusuz, P., Sayar, N., Sarioglu, T., Oncel, I., Sharafi, P., Gundesli, H., Balci-Hayta, B., Purali, N., Serdaroglu-Oflazer, P., Topaloglu, H., Dincer, P. Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies. Neuromusc. Disord. 24: 624-633, 2014. [PubMed: 24856141] [Full Text: https://doi.org/10.1016/j.nmd.2014.04.007]
Sewry, C. A., Goebel, H. H. Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies. (Letter) Neuromusc. Disord. 24: 1122 only, 2014. [PubMed: 25193335] [Full Text: https://doi.org/10.1016/j.nmd.2014.07.007]