Background: Polydactyly is a prevalent digit abnormality characterized by having extra digits/toe... more Background: Polydactyly is a prevalent digit abnormality characterized by having extra digits/toes. Mutations in eleven known genes have been associated to cause nonsyndromic polydactyly: GLI3, GLI1, ZRS regulating LMBR1, IQCE, ZNF141, PITX1, MIPOL1, FAM92A, STKLD1, KIAA0825, and DACH1.Method: A single affected family member (IV-4) was subjected to whole-exome sequencing (WES) to identify the causal gene. Bi-directional Sanger sequencing was performed to segregate the identified variant within the family. In silico analysis was performed to investigate the effect of the variant on DNA binding properties.Results: whole-exome sequencing identified a bi-allelic missense variant (c.1010C > T; p. Ser337Leu) in exon nine of GLI1 gene located on chromosome 12q13.3. With the use of Sanger sequencing, the identified variant segregated perfectly with the disease phenotype. Furthermore, in silico analysis of this DNA binding protein revealed that the variant weakened the DNA binding interac...
The V-Akt Murine Thymoma Viral Oncogene Homolog 3 (AKT3) gene is of the serine/threonine-protein ... more The V-Akt Murine Thymoma Viral Oncogene Homolog 3 (AKT3) gene is of the serine/threonine-protein kinase family and influences the production of milk fats and cholesterol by acting on the sterol administrative area restricting protein (SREBP). The AKT3 gene is highly preserved in animals, and during lactation in cattle, its expression increases. The AKT3 gene is expressed in the digestive system, mammary gland, and immune cells. A phylogenetic investigation was performed to clarify the evolutionary role of AKT3, by maximum probability. The AKT3 gene sequence data of various mammalian species was evident even with animals undergoing breeding selection. From 39 mammalian species studied, there was a signal of positive diversifying selection with Hominidae at 13Q, 16G, 23R, 24P, 121P, 294K, 327V, 376L, 397K, 445T, and 471F among other codon sites of the AKT3 gene. These sites were codes for amino acids such as arginine, proline, lysine, and leucine indicating major roles for the functio...
The purpose of this study was to evaluate associations of the CYP1A1 gene variant rs4646903 polym... more The purpose of this study was to evaluate associations of the CYP1A1 gene variant rs4646903 polymorphism with the risk of developing esophageal cancer (EC). A case-control study was carried out in Pashtun population of Khyber Pakhtunkhwa province of Pakistan in which 140 hospital based EC cases and 196 population based healthy controls exposed to similar environmental conditions were included. A specific method based on the real time polymerase chain reaction (RT-PCR) was used to detect genotypes in case and control groups and results were then analyzed with SPSS version 20. In our population, individuals with CC and TC genotypes of the CYP1A1 rs4646903 polymorphism had significantly higher risk of EC (adjusted odds (OR): 15.709, 95%CI: 6.065-40.686, OR: 3.256 95%CI: 1.902-5.574 respectively). The ‘C’ allele was strongly associated with the disease (p< 0.0001). Adjusted OR was higher (1.5 times in C/C) in case of variant alleles that show the contribution of environmental and nutritional factors towards the development of EC. Our findings suggest that presence of the ‘C’ allele of rs4646903 (T>C) may be one of the risk alleles for EC susceptibility in Pashtun population.
Hypohidrotic ectodermal dysplasia is an inherited disorder characterized by defective development... more Hypohidrotic ectodermal dysplasia is an inherited disorder characterized by defective development of teeth, hairs and sweat glands. X-linked hypohidrotic ectodermal dysplasia is caused by mutations in the EDA gene, and autosomal forms of hypohidrotic ectodermal dysplasia are caused by mutations in either the EDAR or the EDARADD genes. To study the molecular genetic cause of autosomal recessive hypohidrotic ectodermal dysplasia in three consanguineous Pakistani families (A, B and C), genotyping of 13 individuals was carried out by using polymorphic microsatellite markers that are closely linked to the EDAR gene on chromosome 2q11-q13 and the EDARADD gene on chromosome 1q42.2-q43. The results revealed linkage in the three families to the EDAR locus. Sequence analysis of the coding exons and splice junctions of the EDAR gene revealed two mutations: a novel non-sense mutation (p.E124X) in the probands of families A and B and a missense mutation (p.G382S) in the proband of family C. In addition, two synonymous single-nucleotide polymorphisms were also identified. The finding of mutations in Pakistani families extends the body of evidence that supports the importance of EDAR for the development of hypohidrotic ectodermal dysplasia.
Acanthosis nigricans (AN) is characterized by non-inflamed, thick, brown-black pigmentation of th... more Acanthosis nigricans (AN) is characterized by non-inflamed, thick, brown-black pigmentation of the epidermis of the neck, dorsal hands and feet, axilla, umbilicus, knees, and elbows. It has been reported in both inherited as well as acquired forms (e.g., as a paraneoplastic syndrome). Most cases of AN have been described in association with insulin resistance syndromes and fibroblast growth factor receptor (FGFR) mutations. However, it also occurs as a symptom of diverse syndromes, including leprechaunism, Rabson-Mendenhall syndrome, and thanatophoric dysplasia
Background: Polydactyly is a prevalent digit abnormality characterized by having extra digits/toe... more Background: Polydactyly is a prevalent digit abnormality characterized by having extra digits/toes. Mutations in eleven known genes have been associated to cause nonsyndromic polydactyly: GLI3, GLI1, ZRS regulating LMBR1, IQCE, ZNF141, PITX1, MIPOL1, FAM92A, STKLD1, KIAA0825, and DACH1.Method: A single affected family member (IV-4) was subjected to whole-exome sequencing (WES) to identify the causal gene. Bi-directional Sanger sequencing was performed to segregate the identified variant within the family. In silico analysis was performed to investigate the effect of the variant on DNA binding properties.Results: whole-exome sequencing identified a bi-allelic missense variant (c.1010C > T; p. Ser337Leu) in exon nine of GLI1 gene located on chromosome 12q13.3. With the use of Sanger sequencing, the identified variant segregated perfectly with the disease phenotype. Furthermore, in silico analysis of this DNA binding protein revealed that the variant weakened the DNA binding interac...
The V-Akt Murine Thymoma Viral Oncogene Homolog 3 (AKT3) gene is of the serine/threonine-protein ... more The V-Akt Murine Thymoma Viral Oncogene Homolog 3 (AKT3) gene is of the serine/threonine-protein kinase family and influences the production of milk fats and cholesterol by acting on the sterol administrative area restricting protein (SREBP). The AKT3 gene is highly preserved in animals, and during lactation in cattle, its expression increases. The AKT3 gene is expressed in the digestive system, mammary gland, and immune cells. A phylogenetic investigation was performed to clarify the evolutionary role of AKT3, by maximum probability. The AKT3 gene sequence data of various mammalian species was evident even with animals undergoing breeding selection. From 39 mammalian species studied, there was a signal of positive diversifying selection with Hominidae at 13Q, 16G, 23R, 24P, 121P, 294K, 327V, 376L, 397K, 445T, and 471F among other codon sites of the AKT3 gene. These sites were codes for amino acids such as arginine, proline, lysine, and leucine indicating major roles for the functio...
The purpose of this study was to evaluate associations of the CYP1A1 gene variant rs4646903 polym... more The purpose of this study was to evaluate associations of the CYP1A1 gene variant rs4646903 polymorphism with the risk of developing esophageal cancer (EC). A case-control study was carried out in Pashtun population of Khyber Pakhtunkhwa province of Pakistan in which 140 hospital based EC cases and 196 population based healthy controls exposed to similar environmental conditions were included. A specific method based on the real time polymerase chain reaction (RT-PCR) was used to detect genotypes in case and control groups and results were then analyzed with SPSS version 20. In our population, individuals with CC and TC genotypes of the CYP1A1 rs4646903 polymorphism had significantly higher risk of EC (adjusted odds (OR): 15.709, 95%CI: 6.065-40.686, OR: 3.256 95%CI: 1.902-5.574 respectively). The ‘C’ allele was strongly associated with the disease (p< 0.0001). Adjusted OR was higher (1.5 times in C/C) in case of variant alleles that show the contribution of environmental and nutritional factors towards the development of EC. Our findings suggest that presence of the ‘C’ allele of rs4646903 (T>C) may be one of the risk alleles for EC susceptibility in Pashtun population.
Hypohidrotic ectodermal dysplasia is an inherited disorder characterized by defective development... more Hypohidrotic ectodermal dysplasia is an inherited disorder characterized by defective development of teeth, hairs and sweat glands. X-linked hypohidrotic ectodermal dysplasia is caused by mutations in the EDA gene, and autosomal forms of hypohidrotic ectodermal dysplasia are caused by mutations in either the EDAR or the EDARADD genes. To study the molecular genetic cause of autosomal recessive hypohidrotic ectodermal dysplasia in three consanguineous Pakistani families (A, B and C), genotyping of 13 individuals was carried out by using polymorphic microsatellite markers that are closely linked to the EDAR gene on chromosome 2q11-q13 and the EDARADD gene on chromosome 1q42.2-q43. The results revealed linkage in the three families to the EDAR locus. Sequence analysis of the coding exons and splice junctions of the EDAR gene revealed two mutations: a novel non-sense mutation (p.E124X) in the probands of families A and B and a missense mutation (p.G382S) in the proband of family C. In addition, two synonymous single-nucleotide polymorphisms were also identified. The finding of mutations in Pakistani families extends the body of evidence that supports the importance of EDAR for the development of hypohidrotic ectodermal dysplasia.
Acanthosis nigricans (AN) is characterized by non-inflamed, thick, brown-black pigmentation of th... more Acanthosis nigricans (AN) is characterized by non-inflamed, thick, brown-black pigmentation of the epidermis of the neck, dorsal hands and feet, axilla, umbilicus, knees, and elbows. It has been reported in both inherited as well as acquired forms (e.g., as a paraneoplastic syndrome). Most cases of AN have been described in association with insulin resistance syndromes and fibroblast growth factor receptor (FGFR) mutations. However, it also occurs as a symptom of diverse syndromes, including leprechaunism, Rabson-Mendenhall syndrome, and thanatophoric dysplasia
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