The dopaminergic pathways control neural signals that modulate mood and behaviour along and have ... more The dopaminergic pathways control neural signals that modulate mood and behaviour along and have a vital role in the aetiology of major depression (MDD), schizophrenia (SHZ) and bipolar disorder (BD). Genome-wide association studies (GWAS) have reported several dopaminergic pathway’s and other genetic loci’s association with these disorders, therefore, the present study was conducted to analyse the GWAS and candidate gene loci of the dopaminergic and cognitive system genes in MDD, SHZ, and BD, in the Pakistani population. A total of 1237 subjects [MDD n = 479; BD n = 222; SHZ n = 146; and controls n = 390], were screened for eleven genetic variants through polymerase chain reaction (PCR) techniques. Univariant followed by multivariant logistic regression analysis were applied to determine the genetic association. Significant risk associations were observed for rs4532 and rs1799732 with MDD; and rs1006737 and rs2238056 with BD. However, after applying multiple test corrections rs4532...
Psoriasis is chronic inflammatory skin disease characterized by scaly skin, which affects 24% pop... more Psoriasis is chronic inflammatory skin disease characterized by scaly skin, which affects 24% population globally. Role of different SNPs among ACE (angiotensin converting enzyme), eNOS (Endothelial nitric oxide synthase) and MTHFR (Methyltetrahydrofolate reductase) has been established in different genetic disorders, till date there is very limited data available which quadrate the role of these important genes in the pathogenesis of Psoriasis. The present study was conducted to determine the association of ACE, eNOS and MTHFR polymorphisms with psoriasis in the Pakistani population. A total of 240 psoriatic patients and 264 healthy controls were genotyped by polymerase chain reaction (PCR) for rs464699 Insertion/Deletion (ID) polymorphism in intron 16 of ACE, rs869109213 VNTR (a/b) polymorphism in intron 4 of eNOS and by restriction fragment length polymorphism (RFLP) for rs2274976 G1793A, rs1801133 C677T and rs1801131 A1298C of MTHFR. In order to statistically analyze the genotyp...
The American Journal of Human Genetics, Jun 1, 2019
Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, an... more Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: {"type":"entrez-nucleotide","attrs":{"text":"NM_001378.2","term_id":"422398870","term_text":"NM_001378.2"}}NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290∗) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.
A complex microcephaly syndrome in a Pakistani family associated with a novel missense mutation i... more A complex microcephaly syndrome in a Pakistani family associated with a novel missense mutation in RBBP8 and a heterozygous deleti… Highlights An RBBP8 mutation is causative for intellectual disability and microcephaly The phenotype resembles both the Seckel and as Jawad syndrome A heterozygous deletion in NRXN1 may aggravate the phenotype Abstract We report on a consanguineous Pakistani family with a severe congenital microcephaly syndrome resembling the Seckel syndrome and Jawad syndrome. The affected individuals in this family were born to consanguineous parents of whom the mother presented with mild intellectual disability (ID), epilepsy and diabetes mellitus. The two living affected brothers presented with microcephaly, white matter disease of the brain, hyponychia, dysmorphic facial features with synophrys, epilepsy, diabetes mellitus and ID. Genotyping with a 250K SNP array in both affected brothers revealed an 18 MB homozygous region on chromosome 18p11.21-q12.1 encompassing the SCKL2 locus of the Seckel and Jawad syndromes. Sequencing of the
The dopaminergic pathways control neural signals that modulate mood and behaviour along and have ... more The dopaminergic pathways control neural signals that modulate mood and behaviour along and have a vital role in the aetiology of major depression (MDD), schizophrenia (SHZ) and bipolar disorder (BD). Genome-wide association studies (GWAS) have reported several dopaminergic pathway’s and other genetic loci’s association with these disorders, therefore, the present study was conducted to analyse the GWAS and candidate gene loci of the dopaminergic and cognitive system genes in MDD, SHZ, and BD, in the Pakistani population. A total of 1237 subjects [MDD n = 479; BD n = 222; SHZ n = 146; and controls n = 390], were screened for eleven genetic variants through polymerase chain reaction (PCR) techniques. Univariant followed by multivariant logistic regression analysis were applied to determine the genetic association. Significant risk associations were observed for rs4532 and rs1799732 with MDD; and rs1006737 and rs2238056 with BD. However, after applying multiple test corrections rs4532...
Psoriasis is chronic inflammatory skin disease characterized by scaly skin, which affects 24% pop... more Psoriasis is chronic inflammatory skin disease characterized by scaly skin, which affects 24% population globally. Role of different SNPs among ACE (angiotensin converting enzyme), eNOS (Endothelial nitric oxide synthase) and MTHFR (Methyltetrahydrofolate reductase) has been established in different genetic disorders, till date there is very limited data available which quadrate the role of these important genes in the pathogenesis of Psoriasis. The present study was conducted to determine the association of ACE, eNOS and MTHFR polymorphisms with psoriasis in the Pakistani population. A total of 240 psoriatic patients and 264 healthy controls were genotyped by polymerase chain reaction (PCR) for rs464699 Insertion/Deletion (ID) polymorphism in intron 16 of ACE, rs869109213 VNTR (a/b) polymorphism in intron 4 of eNOS and by restriction fragment length polymorphism (RFLP) for rs2274976 G1793A, rs1801133 C677T and rs1801131 A1298C of MTHFR. In order to statistically analyze the genotyp...
The American Journal of Human Genetics, Jun 1, 2019
Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, an... more Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: {"type":"entrez-nucleotide","attrs":{"text":"NM_001378.2","term_id":"422398870","term_text":"NM_001378.2"}}NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290∗) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.
A complex microcephaly syndrome in a Pakistani family associated with a novel missense mutation i... more A complex microcephaly syndrome in a Pakistani family associated with a novel missense mutation in RBBP8 and a heterozygous deleti… Highlights An RBBP8 mutation is causative for intellectual disability and microcephaly The phenotype resembles both the Seckel and as Jawad syndrome A heterozygous deletion in NRXN1 may aggravate the phenotype Abstract We report on a consanguineous Pakistani family with a severe congenital microcephaly syndrome resembling the Seckel syndrome and Jawad syndrome. The affected individuals in this family were born to consanguineous parents of whom the mother presented with mild intellectual disability (ID), epilepsy and diabetes mellitus. The two living affected brothers presented with microcephaly, white matter disease of the brain, hyponychia, dysmorphic facial features with synophrys, epilepsy, diabetes mellitus and ID. Genotyping with a 250K SNP array in both affected brothers revealed an 18 MB homozygous region on chromosome 18p11.21-q12.1 encompassing the SCKL2 locus of the Seckel and Jawad syndromes. Sequencing of the
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