Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive inte... more Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering and in silico analysis identified three known mutations in ASPM, a MC...
Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present wi... more Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay. We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein a...
ABSTRACT Aims: Medicago is known as the Queen of forage with potential economic importance to our... more ABSTRACT Aims: Medicago is known as the Queen of forage with potential economic importance to our society. The present study aimed at the use of RAPD-PCR DNA marker to identify the genetic fingerprints affinities of six species of Alfalfa. Place and Duration of Study: The study was conducted at the Department of Genetics, Garden Campus, Hazara University, Mansehra Pakistan during February, 2011 to August, 2013. Methodology: In this study, six species of Medicago namely TWAL (Tetraploid Wisconsin Alfalfa Line), Medicago arborea, Medicago falcata, Medicago sativa, Medicago lupulina and Medicago polymorpha were used to explore the diversity of alfalfa. Seven out of 120 decamers produced 34 polymorphic loci with 100% polymorphism to identify the different species of Medicago crop. Therange of polymorphic loci was observed from 300 to 700 bp. Eleven species specific loci were generated by seven decamers. Primer B-18 generated single specific locus 700 bp against genomic DNA of M. lupulina and it is important to identify particular species of Alfalfa. The bivariate data were recorded as the presence of locus 1 and absence 0 and then this data was transferred into A and C respectively to make it suitable for DNAMAN software (version 5.2.2.0; Applied Biostatistics Inc). Moreover, cluster analysis was performed using sequence alignment and divergence function of the DNAMAN against the bivariate data collected from the products of decamers. All members clustered in a unique pattern except M. falcata and M. lupulina those shared 86% homology. Three distinct groups were observed during UPGMA (Unweighted pair Group Method with Arithmetic Mean). During the phylogenetic study, TWAL was observed to have genetic diversity from other five species of Alfalfa. Conclusion: So, the present study is enabling us to discriminate different species of Alfalfa and it could be useful to identify and authenticate different species of the same genus of medicinal important plant from the Flora of Pakistan.
The Journal of clinical investigation, Jan 4, 2018
Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disea... more Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, ...
Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of ... more Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of intellectual disability. It is a heterogeneous genetic disorder with 28 associated genes reported so far. Most of these genes encode centrosomal proteins. Recently, AKNA was recognized as a novel centrosomal protein that regulates neurogenesis via microtubule organization, making AKNA a likely candidate gene for MCPH. Using linkage analysis and whole-exome sequencing, we found a frameshift variant in exon 12 of AKNA (NM_030767.4: c.2737delG) that cosegregates with microcephaly, mild intellectual disability and speech impairment in a consanguineous family from Pakistan. This variant is predicted to result in a protein with a truncated C-terminus (p.(Glu913Argfs*42)), which has been shown to be indispensable to AKNA’s localization to the centrosome and a normal brain development. Moreover, the amino acid sequence is altered from the beginning of the second of the two PEST domains, which ar...
Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive inte... more Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering and in silico analysis identified three known mutations in ASPM, a MC...
Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present wi... more Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay. We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein a...
ABSTRACT Aims: Medicago is known as the Queen of forage with potential economic importance to our... more ABSTRACT Aims: Medicago is known as the Queen of forage with potential economic importance to our society. The present study aimed at the use of RAPD-PCR DNA marker to identify the genetic fingerprints affinities of six species of Alfalfa. Place and Duration of Study: The study was conducted at the Department of Genetics, Garden Campus, Hazara University, Mansehra Pakistan during February, 2011 to August, 2013. Methodology: In this study, six species of Medicago namely TWAL (Tetraploid Wisconsin Alfalfa Line), Medicago arborea, Medicago falcata, Medicago sativa, Medicago lupulina and Medicago polymorpha were used to explore the diversity of alfalfa. Seven out of 120 decamers produced 34 polymorphic loci with 100% polymorphism to identify the different species of Medicago crop. Therange of polymorphic loci was observed from 300 to 700 bp. Eleven species specific loci were generated by seven decamers. Primer B-18 generated single specific locus 700 bp against genomic DNA of M. lupulina and it is important to identify particular species of Alfalfa. The bivariate data were recorded as the presence of locus 1 and absence 0 and then this data was transferred into A and C respectively to make it suitable for DNAMAN software (version 5.2.2.0; Applied Biostatistics Inc). Moreover, cluster analysis was performed using sequence alignment and divergence function of the DNAMAN against the bivariate data collected from the products of decamers. All members clustered in a unique pattern except M. falcata and M. lupulina those shared 86% homology. Three distinct groups were observed during UPGMA (Unweighted pair Group Method with Arithmetic Mean). During the phylogenetic study, TWAL was observed to have genetic diversity from other five species of Alfalfa. Conclusion: So, the present study is enabling us to discriminate different species of Alfalfa and it could be useful to identify and authenticate different species of the same genus of medicinal important plant from the Flora of Pakistan.
The Journal of clinical investigation, Jan 4, 2018
Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disea... more Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, ...
Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of ... more Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of intellectual disability. It is a heterogeneous genetic disorder with 28 associated genes reported so far. Most of these genes encode centrosomal proteins. Recently, AKNA was recognized as a novel centrosomal protein that regulates neurogenesis via microtubule organization, making AKNA a likely candidate gene for MCPH. Using linkage analysis and whole-exome sequencing, we found a frameshift variant in exon 12 of AKNA (NM_030767.4: c.2737delG) that cosegregates with microcephaly, mild intellectual disability and speech impairment in a consanguineous family from Pakistan. This variant is predicted to result in a protein with a truncated C-terminus (p.(Glu913Argfs*42)), which has been shown to be indispensable to AKNA’s localization to the centrosome and a normal brain development. Moreover, the amino acid sequence is altered from the beginning of the second of the two PEST domains, which ar...
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