A New Historicist Analysis of Bina Shah’s Novel a Season for Martyrs

This study is conducted to analyze the novel Bina Shah’ novel A Season for Martyrs, from the perspective of New Historicism. This novel presents history of Sindh blended with fiction. It highlights the main Historical events of Sindh; from the arrival of the British in 1827 and occupation of Sindh by Charles Napier till the assassination of Benazir Bhutto in present century. Shah has narrated the history to show its link with the present political and social situation of Sindh. The novel has focused social and political discourses of Sindhi society such as: Significance of love with the land and people’ faith in mystics. The novel has narrated various myths and tales about famous mystics belonging to Sindh. The novel presents story of Ali, a young media reporter, who faces identity problem because of social and psychological issues but when he realizes that his land needs his services, he becomes political activist. This study analyses historical facts and some social and political discourses presented in the novel. Effort is done to interpret the novel according to the theory. Cultural context and social environment of the author is analyzed by observing facts from her social and personal life. Social and political situation of present era are discussed to find the impact of present situation on the interpretation of the author.

Molecular Characterization of Familial Ataxic, Paraplegic and Related Movement Disorders

Movement disorders are heterogeneous neurological syndromes affecting voluntary movement, coordination, causing ataxia or some involuntary movements. Many of these disorders have a genetic cause and can have any mode of inheritance. The rate of consanguineous marriages is very high in Pakistan and therefore there is a high probability of recessively inherited rare genetic disorders, including movement disorders. The genetics of movement disorders is not very well studied in Pakistan. Next generation sequencing technology can facilitate diagnosis and identification of novel genes from affected individuals in families practicing consanguineous marriages. In this study, sixteen families with multiple affected individuals were recruited from Punjab province of Pakistan. The patients exhibited either all, or combination of symptoms including movement disability, abnormality in voluntary movements, abnormal postures, frequent falls, unusual gait with or without abnormal speech. A standard protocol was adopted for videotaping of participants. Diagnosis was made by neurologists either in Pakistan or UK. The required medical investigations and neuroimaging were performed for the probands in the families. The genetic causes of the disorder in eight families out of sixteen were identified. Most of these were in those genes which play vital roles in genome integrity, DNA repair and membrane trafficking. Novel homozygous and compound heterozygous missense variants in SETX were identified in families RDHT01, RDHT02 and RDHT10. These families were reverse phenotyped and found to suffer from ataxia with oculomotor apraxia type 2. Whole exome sequencing was performed for one or two members of all the sixteen families. Exome data was analyzed in a sequential way using appropriate filters. Variants having high frequency in public databases (>0.01) were excluded and others were prioritized based on their effect on the encoded proteins. Only homozygous and compound heterozygous variants were considered. Segregation of candidate variants was analyzed by Sanger Sequencing in all family participants. Functional assays and computational analysis were performed for selected missense variants to check their effect on protein function. ii Affected individuals in family RDHT04 were homozygous for an identified pathogenic variant in TFG and significantly extended the phenotypic spectrum of TFG related disorders. Sleep disturbances, poor intellect, undeveloped speech, obesity, and severity of the disability to bed ridden status are the important phenotypic extensions in RDHT04 patients. This report also reinforces the differential impact of same variant to cause the disease. Another family RDHT05 had a novel pathogenic homozygous variant in ALS2 in affected members. They were found to suffer from infantile onset of spastic paraplegia. The pathomechanism due to this variant is hypothesized to be a truncated protein with loss of important functional domains. This was hypothesized as mRNA was found to be expressed in blood samples of both unaffected and affected members of the family. Patients of family RDHT06 had a known pathogenic nonsense mutation in ATM which was identified for the first time in homozygous condition. The patients suffered from ataxia telangiectasia with onset at five years of age. One of their sibling was still asymptomatic at the age of six years although he also carried the variant in a homozygous form. Perhaps, he will manifest the disorder later in life or may be a modifier gene will prevent disease progression. In family RDHT08 a nonsense homozygous variant in C19orf12 was segregating with mitochondrial protein associated neurodegeneration (MPAN). The disease mechanism of this variant is hypothesized to be reduced mRNA as a result of nonsense mediated mRNA decay. The carriers for the variant exhibited no disease, which together with more than 70 unaffected C19orf12 heterozygous individuals from other reports supports the biallelic nature of neurological disorders due to C19orf12 variants. It further negates the monoallelic nature of disorder as suggested recently. In family RDHT03 a novel homozygous missense variant in DRD4 was segregating with dystonia phenotype. The variant was not conserved in zebrafish, chicken and pig, but none of the organisms had Arg>Cys substitution at this position. The segregation with dystonia in patients, absence in ethnically control chromosomes and absence of any other potential homozygous variant in affected individuals,supports the potential association of this variant with dystonia. Observation of the crystalline DRD4 at the position of the variant also supports the importance of this residue in DRD4-ligand interactions. A second homozygous novel variant in GENEA was fully conserved and segregated with iii phenotype of delayed milestones in this family. Absence of this variant in normal population and high pathogenicity scores support its disease association. Previous association of heterozygous variants in this gene with ataxia has been reported but recessive inheritance is presented for the first time, though with different phenotype. In family RDHT16, three variants were found to segregate with dopa responsive dystonia like phenotype.However, missense variant p.(Lys231Glu) in GENEB was the most likely candidate. Replication of the study is required in additional patients to establish it as bona fide gene implicated pathomechanism of neurological movement disorders if mutated. Fibroblasts of a South Asian patient who had a novel compound heterozygous variants in FGD4, associated with Charcot-Marie-Tooth disease, type 4H were collected at Institute of Neurology, University College London, UK. The fibroblasts were grown and their proliferation rates were observed to be normal. The stability and localization of the encoded protein was not affected by these pathogenic mutations which suggests that further exploration of pathomechanism of these variant is required. In a collaborative project at UCL, a novel bilallelic repeat expansion in RFC1was identified after analysis of whole genome sequencing in cerebellar atrophy, neuropathy and vestibular areflexia syndrome (CANVAS) (OMIM 614575) patients. A cohort of 304 normal individuals was screened by flanking PCR and reverse-prime PCR (RPPCR) for this newly identified expansion.The frequency of this mutant allele expansion was 0.7% in normal population with no homozygous individual for the variant. This work served as a verification that the variant is indeed rare and causes the disorder only in the homozygous condition. For five families, exome sequencing failed to identify a pathogenic variant. The genetic disorder characterization may be completed in future through whole genome sequencing.This will reveal the underlying genetic cause for the disorder and perhaps will identify some new gene involvement in these disorders. This study has benefited many families by providing the diagnosis and genetic counselling. At the same time it has revealed clinical and genetic information regarding movement disorders in Pakistani families. The results suggest that clinical and genetic diagnosis should be undertaken together to properly diagnose the disorders. Misdiagnosis undermines the possible treatment options and also negatively impacts the family in search of the right diagnosis. In future, once all genes have been identified, candidate panels could be developed for rapid identification of the involved genes and their variants.