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Sarcoglycanopathies: a novel predictive approach

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Davide Frumento at University of Genoa
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Abstract

Progressive Muscular Dystrophies (PMDs) are a heterogeneous family of neuromuscular diseases. Although they are considered as a rare diseases group, their severity and relatively high prevalence make them a suitable target for that kind of scientific research whose target is to give to the community a better quality of life. With this in mind, it is reasonable to think that a reliable predictive model is needed. Alas, since both PMDs subtypes prevalence and incidence among general population do not show significant statistical variations, it is not possible to base a predictive model on these data. However, the aim of this paper is to elaborate a novel approach in order to crack the code of PMDs unpredictability.
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Citation: Frumento D. Sarcoglycanopathies: A Novel Predictive Approach. GSL J Public Health Epidemiol. 2019; 2:112.
Sarcoglycanopathies: A Novel Predictive Approach
Davide Frumento
Department of Experimental Medicine, DIMES, University of Genoa, Genoa, Italy
*Corr esponding author: Davide Frumento, PhD, Section of Biochemistry,
Department of Experimental Medicine Viale Benedetto XV 1, 16132
Genova (GE), Italy. Tel: +393334310322; E-mail: davide.frumento@edu.
unige.it
Received: Feb 20, 2019; Accepted: Feb 26, 2019; Published: Feb 28,
2019
Introduction
Progressive Muscular Dystrophies (PMDs) are a heterogeneous
family of neuromuscular diseases. Investigations on these hereditary
disorders started a long time ago, in fact the rst accurate description
of Duchenne Muscular Dystrophy (DMD), was carried out in 1852 [1].
About a century later, some cases of progressive muscular dystrophy
were reported, although they were clinically non-discriminable
from DMD. However, such an obscure form of PMD was later
called “Duchenne-like” autosomal recessive muscular dystrophy [2].
Aerwards, researchers discovered that DMD is ascribable to mutations
in the dystrophin protein gene [3,4]. Both structural and functional
feature of transmembrane dystrophin proteins brought to the nding
of a class of dystrophin-associated proteins, that taken together form
a unique transmembrane Dystrophin-Glycoprotein Complex (DGC).
Within such a molecular complex, one more sub-framework was
discovered, namely a four subunits-one called sarcoglycan [5]. Under a
genetic point of view, the positive correlation between mutations within
the sarcoglycan complex gene and sarcoglycanopathies development
became clear.
Epidemiological aspects
Prevalence data about all types of sarcoglycanopathies have been
calculated only for a restricted number of nations. More specically,
in India 53.8% [6], in USA it is about 15% [7], in Mexico 14% [8], in
Italy 18.1% [9], United Kingdom 11.7% [10]. In Denmark, Germany
and the Czech Republic the muscular dystrophies prevalence is 22.3,
23, and 2.3% [11-13]. e percentages of each of such diseases shows
no statistically signicant variations for about all populations, except
for isolated ones, among which the founder eect is very relevant. e
most common form of LGMD (Limb Girdle Muscular Dystrophy),
regardless of the geographic area, is usually the 2D type. 2E and 2C
forms presence is generally balanced among patients [14]. e rarest
type is, in most nations, is 2F, while in India it comes aer 2C [6]. 2C is
also prevalent, among other forms, in North Africa [15,16].
Abstract
Progressive Muscular Dystrophies (PMDs) are a heterogeneous family of neuromuscular diseases. Although they are considered as a rare
diseases group, their severity and relatively high prevalence make them a suitable target for that kind of scientic research whose target is to give to
the community a better quality of life. With this in mind, it is reasonable to think that a reliable predictive model is needed. Alas, since both PMDs
subtypes prevalence and incidence among general population do not show signicant statistical variations, it is not possible to base a predictive
model on these data. However, the aim of this paper is to elaborate a novel approach in order to crack the code of PMDs unpredictability.
Novel insights
Under an epidemiological point of view, it is legit to put
sarcoglycanopathies among the group of rare diseases. Nevertheless,
they are worldwide acknowledged as serious genetic disorders, as
they deeply aect life quality at all levels of severity. Since it has been
demonstrated that signicant statistical variations between LGMDs
only occur among isolated populations (due to the founder eect), it is
reasonable to infer that predictive models are not feasible only taking
into account general population. e aim of this opinion paper is to
propose a backward-wise methodological approach. e idea consists
in mapping the ethnical background of LGMD patients among big
communities, so that it will be possible to identify the ethnogenetic
basis of these diseases. en, ascending only to antiquely originated
isolated communities; it will be relatively easy to calculate their internal
LGDMs type prevalence. With this in mind, the next step it will be to
ethnogenetically track the origin of patients among general population,
in order to identify the LGMD cases that aect individuals ethnically
linked to the above cited antiquely originated isolated communities and
nally design a reliable predictive model.
References
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voluntary muscles. Med Chir Trans 35: 73-84.
2. Kloepfer HW, Talley C (1958) Autosomal recessive inheritance of
Duchenne-type muscular dystrophy. Ann Hum Genet 22: 138-143.
3. Koenig M, Homan EP, Bertelson CJ et al. (1987) Complete
cloning of the Duchenne muscular dystrophy (DMD) cDNA and
preliminary genomic organization of the DMD gene in normal and
aected individuals. Cell 50: 509-517.
4. Homan EP, Brown RH Jr, Kunkel LM (1987) Dystrophin: the
protein product of the Duchenne muscular dystrophy locus. Cell
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5. Yoshida M, Suzuki A, Yamamoto H et al. (1994) Dissociation of
the complex of dystrophin and its associated proteins into several
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Citation: Frumento D. Sarcoglycanopathies: A Novel Predictive Approach. GSL J Public Health Epidemiol. 2019; 2:112.
GSL J Public Health Epidemiol. 2019; 2:112 | Page 2 of 2
Volume 2, Issue 1Frumento D
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limb-girdle muscular dystrophies in the Czech Republic. BMC
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13. Sveen ML, Schwartz M and Vissing J (2006) High prevalence and
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type 2I in Denmark. Ann Neurol 59: 808-815.
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correlations in 35 Brazilian families with sarcoglycanopathies
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Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals
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Severe childhood autosomal recessive muscular dystrophy (SCARMD) is a progressive muscle-wasting disorder common in North Africa that segregates with microsatellite markers at chromosome 13q12. Here, it is shown that a mutation in the gene encoding the 35-kilodalton dystrophin-associated glycoprotein, γ-sarcoglycan, is likely to be the primary genetic defect in this disorder. The human γ-sarcoglycan gene was mapped to chromosome 13q12, and deletions that alter its reading frame were identified in three families and one of four sporadic cases of SCARMD. These mutations not only affect γ-sarcoglycan but also disrupt the integrity of the entire sarcoglycan complex.
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Dissociation of the complex of dystrophin and its associated proteins into several groups by n-octyl β-D-glucoside
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  • Jul 1994
Dystrophin is purified as a complex with several proteins from the digitonin-solubilized muscle cell membrane. Most of dystrophin-associated proteins (DAPs) are assumed to form a large oligomeric transmembranous glycoprotein complex on the sarcolemma and link dystrophin with a basement membrane protein, laminin. In the present study, we found that the purified dystrophin-DAP complex was dissociated into several groups by n-octyl-beta-D-glucoside treatment. In particular, we found that the glycoprotein complex stated above was dissociated into two distinct groups: one composed of 156DAG and 43DAG (A3a) and the other composed of 50DAG, 35DAG and A3b. We confirmed by crosslinking and immunoaffinity chromatography that these two groups existed in a complexes. We thus concluded that the glycoprotein complex consists of these two subcomplexes. Furthermore, A3b and 43DAG, which had been formerly treated simply as the 43DAG doublets due to their similar electrophoretic mobilities in SDS/PAGE, were shown to be present in two different subcomplexes. Based on the analyses by two-dimensional gel electrophoresis, peptide mapping and immunoblotting, we concluded that A3b is a novel DAP different from 43DAG.
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Mild and severe muscular dystrophy caused by a single ??-sarcoglycan mutation
Article
  • Dec 1996
Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein gamma-sarcoglycan. The previous mutation analysis of gamma-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the gamma-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding gamma-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the gamma-sarcoglycan gene. These patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of alpha-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the gamma-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from gamma-sarcoglycan gene mutations.
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Sarcoglycanopathies in Dutch patients with autosomal recessive limb girdle muscular dystrophy
Article
  • Aug 2000
Within a group of 76 sporadic/autosomal recessive limb girdle muscular dystrophy (LGMD) patients we tried to identify those with LGMD type 2C-E. Muscle biopsy specimens of 40 index patients, who had 22 affected sibs, were analyzed immuno-histochemically for the presence of three subunits: alpha-, beta-, and gamma-sarcoglycans. Abnormal sarcoglycan expression was established in eight patients, with six affected sibs. In one patient gamma-sarcoglycan was absent, and both alpha- and beta-sarcoglycans were reduced. In the remaining seven patients gamma-sarcoglycan was (slightly) reduced, and alpha- and beta-sarcoglycans were absent or reduced. By DNA sequencing mutations were detected in one of the three sarcoglycan genes in all eight cases. Three patients had mutations in the alpha-, three in the beta-, and two in the gamma-sarcoglycan gene. The patients with sarcoglycanopathy comprised the more severely affected cases (P=0.04). In conclusion, sarcoglycanopathy was identified in 23 % (14/62) of the autosomal recessive LGMD patients.
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