The beta-sarcoglycanopathy PDF Print E-mail

 

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LIMB-GIRDLE MUSCULAR DYSTROPHIES   (LGMD)

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. The clinical course is characterized by great variability, ranging from severe forms with rapid onset and progression to very mild forms allowing affected people to have fairly normal life spans and activity levels (see reviews by Nigro et al 2011; and Guglieri et al. 2008).

Sixteen loci have been so far identified, six autosomal dominant and ten autosomal recessive. Linkage analyses indicate that there is further genetic heterogeneity both for dominant and for recessive LGMD. The dominant forms (LGMD1) are generally milder and relatively rare, representing less than 10% of all LGMD (Mathews and Moore. 2003). The autosomal recessive forms (LGMD2) are much more common, having a cumulative prevalence of 1:15,000 with a number of geographical differences (Nigro, 2003). The product of ten autosomal recessive LGMD genes has so far been identified (Zatz et al 2003). Several genes involved in LGMD code for sarcoglycan proteins that together with dystrophin and dystroglycans contribute to form the so called Dystrophin-Glycoprotein Complex (DGC), a multisubunit protein complex that spans the sarcolemma and provides structural linkage between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells (Ervasti and Sonnemann 2008).

There are at least four sarcoglycan genes named alpha-, beta-, gamma-, and delta that when mutated are associated with sarcoglycanopathies (Sandonà and Betto, 2009). Here, we will focus on one of these genes, more precisely the beta-sarcoglycan gene (SGCB).

 

THE BETA-SARCOGLYCANOPATHY   (LGMD2E)

It has been shown that SGCB expresses a 43-kD component of the dystrophin-glycoprotein complex and is involved in a form of LGMD, designated LGMD2E (Bonnemann et al 1995; Lim et al 1995). Symptoms of the disease very greatly from person to person, even among people in the same family. LGMD2E is often associated with severe symptoms that can be fatal by the late teens, although some people with the disease have a mild course or are nearly asymptomatic. People with LGMD2E commonly develop symptoms before the age of 10, although in some cases, symptoms do not appear until later. In people with LGMD2E, the muscles of the hip, shoulder, and abdomen progressively weaken, often to a point where a wheelchair becomes necessary. This typically happens between the ages of 10 and 15. In people with LGMD2E, muscles attached to the scapula, a bone that connects the arm with the collar bone, do not work properly, causing a wing-like shape to the upper back. The calf muscles are often enlarged as well, a symptom known as calf hypertrophy. A minority of people with LGMD2E (about 20%) experience a weakening of the heart muscles (Fanin et al 2003; Barresi et al. 2000). However, involvement of the heart muscles is less common in type 2E than in other forms of limb girdle muscular dystrophy.

Functional studies have shown that beta-sarcoglycan co-localizes with the DGC at the sarcolemma and is predominantly expressed in muscle. The SGCB gene contains 6 exons and spans a relatively short genomic DNA regions of about 13.5 kb. Different type of mutation have been identified and mapped in the SGCB gene, and correlate with LGMD2E. Most of them are point mutations including: missense mutations resulting in amino acid substitutions; nonsense mutations that cause premature stop of the protein synthesis; frameshift mutations due to single base insertions or to short insertions/deletions generating out of frame non functional proteins (Bonnemann et al 1998; Bonnemann et al 1996). Importantly, as in the case of other sarcoglycans of the DGC, impairment in the expression of one component can affect expression and stability of the other sarcoglycans. Western blot analyses have shown that patients with reduced expression of beta sarcoglycan often display reduction or even total absence of the other sarcoglycans (Fanin and Angelini 2002). This suggests that the stoichiometry of the complex is finely regulated and tightly controlled. This aspect is extremely important and has strong implications in the design of possible gene therapy strategies. Simplistically, the endogenous defect may be correct by expressing the wild type protein in the LGMD2E muscle cells. However, due to the complex control of the stoichiometry of the DGC complex, the simple overexpression of the SGCB protein may be inadequate to re-establish a functional DGC. An excess of the SGCB protein may lead to formation of incomplete DGC that most likely will generate non-functional complexes. To avoid this kind of problems, the SGCB gene therapy construct should retain the tight expression control of the endogenous gene. To achieve this objective it is, however, crucial to identify the cis and trans regulatory elements that coordinate such control. As far as we know, very little information, if none, has been accrued about the transcription and post-transcriptional regulation of this gene.

Then LGMD 2E is transmitted as an autosomal recessive form and is caused by mutation in the gene encoding beta-sarcoglycan that is located on chromosome 4q12. LGMD 2E is characterized by scapular winging and calf hypertrophy. Age of onset is usually between 2 years and the mid-teenage years. Cardiac involvement occurs in about 20% of cases. Serum creatine kinase (CK) activity is always elevated. The overall prevalence of primary sarcoglycanopathies in northeast Italy was estimated to be 1/200,000. No specific treatment is known and many patients receive physical therapy to prevent worsening of contractures. *Author: Dr A. van der Kooi (October 2004)*.

In Italy some children follow a steroid therapy according to a protocol provided for Duchenne muscular dystrophy. Deflazocort in a low dosage is used in the pharmaceutical form of Deflan and Flantadin. Vitamin D (Didrogyl) and calcium (Calcium Sandoz) are also administered. Patients have the right to have medicine exemption, the specialist has to fill in the form for medicine prescript related to rare diseases.

Distinguishing mark of this disease is the fact that it is caused by a very small gene, made up of only 6 exons. Other sarcoglycanopathies have bigger genes too :

 

Number of patients with beta-sarcoglycanopathy mutation in exon specified

 

Exon   1

 

130

 

Exon  2

 

33

 

Exon  3

 

133

 

Exon  4

 

44

 

Exon  5

 

8

 

Exon  6

 

5

For more information LOVD (Leiden Open Variation Database)

 

Genomic organization of the beta-sarcoglycan gene.

Filled in boxes signify coding regions, open boxes refer to untranslated regions.

Exons are designatedE1–E6. Intron numbering follows exon numbering.

Approximate intron sizes are indicated in kilobases (kb).

 


For this reason, the gene of beta-sarcoglycanopathy is particularly suitable for the application of gene therapy.

From the data collected in the Leiden database LOVD, people suffering from beta-sarcoglycanopathy are estimated at 355 worldwide (as of August 30, 2011). Of these 130 have a mutation on the exon 1 and 133 on the 3 one. The mutations are less frequent on other exons. In Italy there are 45 cases reported in the north-east of the country, of which 23 have the exact same mutation on the exon 3. The data on the spatial distribution and type of mutation are shown in detail in the statistics.

 
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