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MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 7; LGMDR7

MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 7; LGMDR7

Alternative titles; symbolsMUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2G; LGMD2GFor a general description and a discussion of genetic heterogeneity of autosomal reces...

Alternative titles; symbols

  • MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2G; LGMD2G

For a general description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).

▼ Nomenclature
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, LGMD2G was renamed LGMDR7.

▼ Clinical Features
Moreira et al. (1997) reported a family of Italian ancestry in which several members were affected with a unique form of limb-girdle muscular dystrophy. The unaffected parents had a total of 8 offspring, of whom 6 were affected. The mean age at onset was 12.5 years, which was when the patients showed difficulty with walking, running, and climbing stairs. At about the same time, they were unable to perform ankle dorsiflexion. Difficulty with walking on the heels appeared before difficulty with walking on the toes. Extraocular and facial muscles were spared in all patients. Although neck muscles were only very mildly affected or not affected, proximal muscle atrophy was marked in the upper limbs and both proximal and distal muscle atrophy was evident in the lower limbs. Tendon reflexes were abolished, without involvement of sensory and cranial nerves or of coordination. Foot drop was a feature common to all 5 patients. Four of the 6 affected sibs were in a wheelchair. No evidence of cardiac disease was detected. Creatine kinase (CK) levels were elevated 3- to 17-fold in the first stages of the disease, but decreased as the patients aged to almost normal levels in those patients already in a wheelchair.

Moreira et al. (2000) reported 2 additional affected families. In 9 affected patients from a new family and the family reported by Moreira et al. (1997), the age at onset ranged from 9 to 15 years, with marked weakness in the distal muscles of the legs and proximal involvement. Of these 9 patients, 5 lost the ability to walk in their third or fourth decade, whereas the remaining 4 were capable of walking at ages 22 to 44 years. Their serum creatine kinase levels were slightly increased, and rimmed vacuoles were observed in their muscle biopsies. Heart involvement was observed in 3 of 6 affected members of 1 family. In a third family, age at onset, typically characterized by difficulty in walking and climbing stairs, ranged from 2 to 15 years. All of the affected had pronounced calf hypertrophy (1 asymmetric), and their CK levels were increased 10- to 30-fold. The findings indicated phenotypic heterogeneity.

▼ Mapping
Through a genomewide search on a family with limb-girdle muscular dystrophy, Moreira et al. (1997) demonstrated linkage to a 3-cM region on chromosome 17q11-q12. They suggested that this form, which clinically resembled autosomal recessive Kugelberg-Welander disease (253400), should be classified as LGMD2G.

▼ Molecular Genetics
In affected members of the family with LGMD2G reported by Moreira et al. (1997), Moreira et al. (2000) identified compound heterozygosity for 2 mutations in the TCAP gene (604488.0001; 604488.0002). Affected members from 2 additional families with LGMD2G were homozygous for a TCAP mutation (604488.0001).

▼ Animal Model
Zhang et al. (2009) cloned tcap in zebrafish and showed that it is functionally conserved. The Tcap protein appeared in the sarcomeric Z disc, and reduction of Tcap resulted in muscular dystrophy-like phenotypes including reduced muscle mass, deformed muscle structure, and impaired swimming ability. A defective interaction between the sarcomere and plasma membrane was detected, which was further underscored by the disrupted development of the T-tubule system. Zebrafish tcap exhibited a variable expression pattern during somitogenesis. The variable expression was inducible by stretch force, and the expression level of Tcap was negatively regulated by integrin-link kinase (ILK; 602366), a protein kinase that is involved in stretch sensing signaling. The authors suggested that the pathogenesis in LGMD2G may be due to a disruption of sarcomere-tubular interaction, but not of sarcomere assembly per se. Zhang et al. (2009) hypothesized that the transcription level of TCAP may be regulated by the stretch force to ensure proper sarcomere-membrane interaction in striated muscle.

Markert et al. (2010) generated knockout mice carrying a null mutation in the Tcap gene and described skeletal muscle function in 4- and 12-month-old affected mice. Muscle histology of Tcap-null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin (MSTN; 601788), showed that deletion of Tcap was accompanied by increased protein levels of myostatin. The Tcap-null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wildtype controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus or soleus muscles.

Tags: 17q12