Muscular Dystrophies Are Group Of Disorder Biology Essay

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DMD/BMD is an X-linked recessive genetic neuromuscular disorder with prevalence rate of 1/3500 in males. It affects predominantly males due to presence of single X chromosome rendering males susceptible to the disease. Mutation in dystrophin gene is the major risk factor for the emergence, pathology and progression of the disease. DMD patients have characteristic feature of progressive muscular weakness due to failure in mechanical support of dystrophin protein resulting in blemished sarcolemmal elasticity and causing death by respiratory and cardiac failure in twenties [2]. Becker's muscular dystrophy is a milder form of DMD with late age of onset and less severe progression.

Limb girdle muscular dystrophy (LGMD) is an autosomal muscular dystrophy which usually affects limb girdle muscles of hips and shoulders with characteristic of heterogeneity. More than 15 different types of LGMD subtypes are reported according to their pattern of inheritance and affected genes. LGMD subtypes are classified as their mode of autosomal dominant (LGMD1) and recessive (LGMD2) inheritance patterns. Myotilin gene (MYOT) encodes myotilin protein which maintains sarcomeric integrity and respective function and it has been found to be affected in LGMD1A [3]. Anoctamin5 (ANO5) is another risk factor in LGMD which functions as chloride channel activated by calcium. CAV3 gene encodes caveolin-3 protein which is a structural protein of caveolae membranes in cardiac and skeleton striated muscles leading to LGMD-1C phenotype when mutated [4]. LMNA gene mutation creates LGMD-1B phenotype. DYSF gene which includes 58 exons and spans approximately 233kb of genomic DNA encodes dysferlin protein with function of skeletal muscle repair leading to LGMD2B and other muscular dystrophies.

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Increased levels of creatine kinase (CK), positive Gower's sign, calf hypertrophy and progressive muscle weakness can be considered as inclusion criteria for the study. Creatine kinase enzyme plays a crucial role by forming high energy phosphate phosphocreatine in skeletal muscle. Elevated creatine kinase indicates muscle damage before disease onset. Gower's sign is the inability of patient to walk up due to proximal muscle weakness [5].

Muscular Dystrophies in India:

Among all muscular dystrophy cases in INDIA, DMD/BMD and LGMD is of greater prevalence. Different studies of dystrophin screening in INDIA reports higher prevalence of dystrophy in ethnic hindu and muslim east Indian patients[6]. According to Nalini et al. (2008) among 23 patients of dysferlinopathies 23% were identified later as LGMD cases and khadilkar et al. (2004) identified same as 14.5 % among 14 patients. LGMD prevalence was reported as higher as 54% in different studies among all sarcoglycanopathies [7]. It is interesting to understand the factors which predispose Indians to mutations at the DMD locus or to mutations of the dystrophin gene that cause Duchenne rather than Becker muscular dystrophy (BMD)? In considering possible mechanisms, the probable increased occurrence of mixed marriages among the ancestors of DMD patients has been implied. An explanation for the propensity to DMD mutations in Indians could be the presence of repetitive elements in the wild type gene, predisposing to mismatching and thereby to a pathogenic deletion or duplication (Roddie et al., 1992).

Genetic admixture is implied in the lower frequency of DMD among patients of South African mixed ancestry to Indians, but a greater frequency to that of Whites (Ballo et al., 1994). Some deletions are common in all populations and some are rare in others is striking (Onengut et al., 2000). Frequency of intragenic deletion varies according to ethnic populations among different Indian regions. Multiplex PCR based diagnosis of DMD was extensively used as a technique to identify the deletion or duplication which can only detect hot spots of the 79 exons of DMD gene untill MLPA emerged as a alternative tool. The natural history of DMD is heterogeneous, with interpatient variability in disease progression, motor, respiratory, and cardiac involvement (Desguerre et al, 2009). It is believed that genetic modifiers (multigenic polymorphisms remote from the dystrophin gene) or environmental factors influence variability in disease progression and response to steroids (Pegoraro et al., 2011). The identification of genetic modifiers also provides insights into disease pathogenesis (Collaco et al., 2008). Variability in dystrophin protein levels between patients with the same deletion; could stem from the differences of individual intronic breakpoints in patients, which may affect alternative splicing and/or translation efficiency. Other explanations for intra and intergroup variability could be the differential stability of the internally deleted dystrophins (Krieger et al., 2010; Henderson et al., 2011) and/or the endogenous splicing of other exons. Other genetic modifiers of dystrophin translation efficiency could also be involved in these discrepancies. Different molecular background in populations can produce different deletion mutations as a result of population specific intronic sequences that predispose individuals to preferential deletion breakpoints (Hassan et al., 2008 and Nadkarni et al., 2008). The proportions of small deletions, distribution of deletion breakpoints and the frequencies of specific deletions commonly observed in Turkish, European, North Indian and south Indian populations are not significantly different (Onengut et al., 2000) and the presence and frequency of the deletions in the two hotspot regions may be similar in the Asian populations analyzed Singapore, Japan and Vietnam (Lai et al., 2002).

Global Ethnic Characteristics:

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In families with uncharacterized mutations, carrier detection and prenatal diagnosis depend on linkage analysis using markers such as STRs, RFLPs, STR linkage analysis along with RFLP analysis, can be helpful for carrier detection Zamani et al., 2011.Studies from different ethnic groups have shown variation in the degree or distribution of polymorphism of (CA)n loci in the human DMD gene- Caucasians, Orientals, Egypt and Iran each population has logistically characterized allele frequencies.

Among the European populations, the lowest deletion rates range (35%- 45%) is reported from Czechoslovakia (Hrdlicka et al., 2001) and Spain (Kruyer et al., 1994 and Patino et al., 1995) .In Asian Countries such as China, India and Kuwait the deletion rate is between 62%-86%, and in Vietnam, Israel, Japan, Singapore and Russia it is much lower (31%- 41%). Southern (Mallikarjuna Rao et al., 2003) and Eastern Indian populations (Basak et al., 2009) show a higher deletion percentage, (73% and 74% respectively) compared to Northern (Singh et al., 1997) and Western Indian (Dastur et al., 2004) populations.

Different molecular background in populations can produce different deletion mutations as a result of population specific intronic sequences that predispose individuals to preferential deletion breakpoints (Hassan et al., 2008 and Nadkarni et al., 2008). The proportions of small deletions, distribution of deletion breakpoints and the frequencies of specific deletions commonly observed in Turkish, European, North Indian and Indian populations are not significantly different (Onengut et al., 2000) and the presence and frequency of the deletions in the two hotspot regions may be similar in the Asian populations analyzed Singapore, Japan and Vietnam (Lai et al., 2002).

Recent studies in Muscular Dystrophy:

Recent evidence demonstrates a reciprocal control between HDACs and muscle-specific microRNA (miRNAs). miRNAs are emerging as important regulators of muscle development, homeostasis and regeneration (Greco et al., 2009, Eisenberg et al., 2007). These miRNAs consists of their control by most of the same epigenetic regulators that typically control the expression of muscle genes (Rao et al., 2006, Rosenberg et al., 2006, Liu et al., 2007, Mallappa et al., 2010).The molecular rationale and the epigenetic basis of the beneficial effect of Histone Deacetylases inhibitors (HDACi) are being revealed and indicate the HDACi are strong candidates for the pharmacological treatment of DMD (Colussi et al., 2009). The potential role of epigenetic enzymes, Histone Deacetylases (HDACs), in DMD pathogenesis, the mechanism linking these enzymes to the epigenetic profile of dystrophic muscles is still unknown. (Colussi et al., 2009). However a connection between NO signaling and the altered epigenetic profile present in dystrophin deficient muscles, indicates an epigenetic contribution to the pathogenesis and progression of DMD. (Colussi et al., 2009). Recent evidence demonstrates a reciprocal control between HDACs and muscle-specific microRNA (miRNAs). miRNAs are emerging as important regulators of muscle development, homeo- stasis and regeneration (Greco et al., 2009, Eisenberg et al., 2007). These miRNAs consists of their control by most of the same epigenetic regulators that typically control the expression of muscle genes (Rao et al., 2006, Rosenberg et al., 2006, Liu et al., 2007, Mallappa et al., 2010).The molecular rationale and the epigenetic basis of the beneficial effect of Histone Deacetylases inhibitors (HDACi) are being revealed and indicate the HDACi are strong candidates for the pharmacological treatment of DMD (Colussi et al., 2009). The potential role of epigenetic enzymes, Histone Deacetylases (HDACs), in DMD pathogenesis, the mechanism linking these enzymes to the epigenetic profile of dystrophic muscles is still unknown. (Colussi et al., 2009). However a connection between NO signaling and the altered epigenetic profile present in dystrophin deficient muscles, indicates an epigenetic contribution to the pathogenesis and progression of DMD. (Colussi et al., 2009).

Multiplex Ligation Probe Amplification:

MLPA, an alternative to PCR technology, is considered as a molecular diagnostics tool for sensitive and specific detection of mutations in several disorders including neurodegenerative and movement disorders. MLPA is widely used now as a sensitive tool to identify chromosomal rearrangements like deletions and duplications [8], mRNA quantification & profiling [9], dosage analysis [10], copy number changes in genes [11]. MLPA has proven itself as a diagnostic tool to detect methylations, and single nucleotide polymorphisms.

Several different diseases are reported to be diagnosed by MLPA, some of them are Spinocerebellar ataxia [12], Fronto Temporal Disorders, Alzheimer's disease [13], Duchenne Muscular Dystrophy [14], Parkinson's disease [15], Spinal muscular atrophy[16], variants of Motor Neuron Disease(MND) [17], Autism [18], Cancers [19], Alpha-Thalassemia [19], X linked Mental Retardation [20], Micro-deletion syndromes [21] etc. Methylation specific MLPA kits have proven to be an effective tool in molecular diagnostics [22]. Reverse transcriptase MLPA can be used for mRNA profiling.

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Amplification of probe instead of template DNA strand is the basis of MLPA as per standardized instructions by MRC-Holland. Pre determined ratios are used to differentiate between normal and diseased individual.

Sequencing:

Muscular Dystrophies are genetically heterogeneous disorder and must be diagnosed in a single platform to make it cost effective and specific [23]. Deletions and duplications can be screened by multiplex ligation probe amplification but point mutations and novel genetic mutations need screening by means of sequencing. Genetic screening of North Indian population will give insight to the pattern of mutations to design a diagnostic strategy for muscular dystrophies. Identification of single nucleotide variants from the sequencing data using bioinformatics alignment tools and NCBI reference sequences is useful for such studies.

Importance:

Higher prevalence rate of muscular dystrophies in INDIA is suggestive of exon wise screening and copy no. analysis including deletions and duplications which can be accomplished by multiplex ligation probe amplification. Further sequencing will reveal possible diagnostic and therapeutic outcomes in North Indian population contributing in the efforts of genetic counseling. Patients screened after established inclusion criteria and those negatively diagnosed for DYSF, LMNA, CAV3, SMN1, SMN2 genes through MLPA, will be further analyzed for screening for novel mutations.