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dc.contributor.authorSawal, Humaira Aziz-
dc.description.abstractInherited neurological disorders are a broad class of diseases caused by particular genetic factors. Few of them are monogenic in nature, while others are caused by a grouping of genetic risk alleles and environmental factors. The current study was designed to explore the genetic basis of particular neurological disorders in consanguineous families from Pakistan, which includes Congenital Insensitivity to Pain (CIP), Congenital Insensitivity to pain with Anhidrosis (CIPA), and Bilateral Frontoparietal Polymicrogyria (BFPP)/Intellectual Disability (ID). Congenital insensitivity to pain (CIP; MIM 243000) and congenital insensitivity to pain with anhidrosis (CIPA; MIM #256800) come under the category of hereditary sensory and autonomic neuropathies (HSAN).Mutations in SCN9A, SCN11A and PRDM12are responsible for causing CIP, while mutations in NTRK1 are known for causing CIPA. Patients are insensitive to pain, touch and sometimes heat. In some cases patients are unable to smell (anosmia). Other symptoms of the patients affected from this disease include self-harming behavior mainly related to orofacial tissues, bruises on skin, tongue biting, fractured bones and injuries on hands and feet. Additionally, early loss of teeth, many other dental abnormalities and many oral damages observed in patients affected with CIP and CIPA. Patients with CIPA however, show hyperthermia due to anhydrosis in addition to other features. Bilateral Fronto Parietal Polymicrogyria (BFPP; MIM#606854) is a heterogeneous autosomal recessive disorder of abnormal cortical lamination caused by mutations in GPR56 gene. Patients suffering from BFPP show central hypotonia during the early phase of life and symptoms of intellectual disability at later stages. Intellectual disability (ID) is a large and varied group of syndromic and non syndromic disorders. It is a common neurological disease with an inception of cognitive impairment before reaching 18 years of age. There are many genes involved in ID; some of them are AGTR2, AP1S2, ARHGEF6, ATRX, MECP2, PTCHD1 and TSPAN7. Seven autosomal recessive Pakistani families with multiple affected individuals were recruited for the present study (Families A-G). These include four families (A-D) with CIP, one family (E) with CIPA and two families (F and G) with ID and BFPP. In four families (A-D), homozygosity mapping by Illumina Human Core-Exome microarray identified a common ~10Mb homozygous haplotype on chromosome 2q24 in affected individuals. Sanger sequencing of candidate gene SCN9A within this interval revealed a novel biallelic truncating mutation chr2:167099039_167099039delG, NM_002977.3:c.3567_3567delC, which generates a premature stop codon p. Met1190*, in exon 19.This mutation completely segregated with the CIP phenotype in all four families and was absent from 100 control chromosomes. These families belong to the same ethnic group. Mutation Taster ( showed that there is premature truncation of the protein and nonsense-mediated mRNA decay (NMD). The protein structure for SCN9A was predicted by Protscale server. No signal peptide and acetylation site were present in SCN9A. Diverse specific phosphorylation sites of threonine, serine and tyrosine were anticipated in SCN9A at different positions. Kinases like PKA, PKB, PKC were involved in phosphorylation of SCN9A. This study is helpful to understand the mechanism of pathogenesis of different neurological disorders caused by mutations in SCN9A. In family E, an affected male presented with classical symptoms of CIPA. Trusight One Sequencing Panel usually covers 4813 OMIM genes, discovered a novel NTRK1 truncating mutation c.2025C>G; p. Y681X. The protein modeling of this mutation predicts the damage of the stiffness in NTRK1 tyrosine kinase domain, which resulted in the conformational changes and deleterious consequences in the function of protein. Homozygosity mapping and next generation sequencing identified two novel GPR56 mutations including a substitutional variant, chr16:57693480T>C; NM_005682.5: c.1460T>C; p. Leu487Pro (exon12) and a 13bp insertion Chr16:57689345_57689346insCCATGGAGGTGCT;NM_005682.6:c.803_804insCCATGGAGGTGCT; p.Leu269Hisfs*21, (exon7) in family F and G respectively. These mutations fully segregated with ID phenotype in respective families and were absent from 100 control chromosomes of same population. Timely clinical evaluation is necessary which helps in making the correct choice of genetic testing in families affected with rare neurogenetic syndromes. From these results, it is obvious that combination of techniques including homozygosity mapping and whole exome sequencing / targeted panel sequencing in families with multiple affected individuals is the method of choice for mutation detection. In future, functional studies of mutations in SCN9A, NTRK1 and GPR56 genes may provide novel therapeutic targetsen_US
dc.description.sponsorshipHigher Education Commission Pakistanen_US
dc.publisherNational University of Science & Technology, Islamabad.en_US
dc.subjectApplied Biosciencesen_US
dc.titleGene Mapping in Families with Complex Neurogenetic Syndromesen_US
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