Abdul Khaliq Naveed

Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families.

Background  Autosomal recessive hypotrichosis is a rare genetic irreversible hair loss characterized by sparse scalp hair, sparse to absent eyebrows and eyelashes, and sparse axillary and body hair. Affected male individuals have normal beard hair.

Breast and Ovarian Cancer Risk due to Prevalence of BRCA1 and BRCA2 Variants in Pakistani Population: A Pakistani Database Report

Introduction. Pakistani population has a very rich anthrogeneological background with waves of migration from neighboring regions. Incidence rates of breast and ovarian cancer in Pakistan are on such a rapid rise that it is necessary to check the contributory factors, genetic and nongenetic. An insight into the prevalence data emphasizes the formulation of a BRCA1 and BRCA2 database for the Pakistani population. Method. In this study conducted by authors, data from diagnosed cases of both sporadic and inherited female breast and ovarian cancer cases was gathered after performing molecular genetic analysis by screening for alterations in the coding sequence of the BRCA gene. The region of interest was analyzed by the aid of various molecular biology tools such as automated DNA sequencer. Bioinformatics software was used to interpret the results, and database was prepared. Results. Mutational screening of the exons in all the samples of our study group did not reveal any pathogenic mutation. These results along with the results of the previous Pakistani studies for both BRCA1 and BRCA2 genes were summed up to prepare a Pakistani database. Percentage involvement of these genes was estimated. Nine percent of these cancers show alterations in BRCA1 gene while 3 percent have shown BRCA2 variants. The remaining 88 percent of breast and ovarian cancers can be attributed to the involvement of other genes.

Recurrent mutations in functionally-related EDA and EDAR genes underlie X-linked isolated hypodontia and autosomal recessive hypohidrotic ectodermal dysplasia

Mutations in three functionally related genes EDA, EDAR and EDARDD have been reported to cause hypohidrotic ectodermal dysplasia (HED), which is characterized by sparse hair, reduced ability to sweat, and hypodontia. In few cases mutations in the EDA gene have been found to result in X-linked recessive isolated hypodontia. In the study, presented here, we have ascertained two large Pakistani families (A and B) with autosomal recessive form of hypohidrotic ectodermal dysplasia and X-linked recessive isolated hypodontia. Genetic mapping showed linkage of family A to EDAR gene on chromosome 2q11-q13 and family B to EDA gene on chromosome Xq12-q13.1. Subsequently, DNA sequencing of the coding regions of EDAR and EDA genes revealed previously described mutations. Sequence analysis identified a four base-pair splice-junction deletion mutation (c.718_721delAAAG) in EDAR gene in family A and a missense mutation (c.T1091C; p.M364T) in EDA gene in family B. Recurrence of mutations in EDAR and EDA genes in unrelated families is evocative of the dispersion of ancestral chromosome in different locality groups through common ancestors.

A novel deletion mutation in the phospholipase H (LIPH) gene in a consanguineous Pakistani family with autosomal recessive hypotrichosis (LAH2)

To date, seven isolated forms of hair loss have been reported and mapped on different human chromosomes. These include congenital atrichia at 8q12, hypotrichosis simplex at 6p21.3, Marie Unna hereditary hypotrichosis at 8p21, three similar forms of localized hereditary hypotrichosis, LAH1 at 18q12.1, LAH2 at 3q26.33 and LAH3 at 13q14.11-q21.32, and autosomal recessive hypotrichosis simplex at 13q14.11-q21.33. All these conditions have been described at the molecular level and causative genes including hairless (HR, MIM 602302) for congenital atrichia, corneodesmosin (CDSN, MIM 602593) for hypotrichosis simplex, desmoglein 4 (DSG4, MIM 607892) for LAH1, LIPH (MIM 607365) for LAH2 and P2RY5 (MIM 609239) for autosomal recessive hypotrichosis simplex have been identified. The LIPH gene contains 10 exons and is expressed in several tissues including prostate, testis, ovary, colon, pancreas, kidney, lung, spleen, brain, heart and hair follicle. To date only three mutations (all deletions) in the LIPH gene have been reported. The first deletion mutation encompassing exon 4 and the flanking intronic sequences of the LIPH gene was reported by Kazantseva et al. in a large number of affected individuals in two populations from the Volga-Ural region of Russia. Our group previously reported two novel deletion mutations, c.346-350delATATA and c.659-660delTA in exon 2 and 5 of the LIPH gene, respectively. In this study we have identified the fourth novel deletion mutation of a single base pair (c.682delT) in exon 5 of the LIPH gene in a consanguineous Pakistani family, which showed linkage to the LAH2 locus on chromosome 3q26.33. Approval for the study was obtained from the Institutional Review Board of Quaid-i-Azam University, Islamabad, Pakistan. Informed consent was obtained from all participating subjects of the family.

Lipoprotein (a) is associated with basal insulin levels in patients with type 2 Diabetes Mellitus

FUNDAMENTO: Ainda nao foi claramente estabelecido se a resistencia/deficiencia insulinica leva diretamente a aterogenese ou atraves de sua associacao com outros fatores de risco como os niveis de lipoproteina (a)[Lp(a)]. OBJETIVO: O objetivo do estudo foi estabelecer a relacao entre os niveis basais de insulina, lipides e lipoproteina (a) em pacientes com diabetes mellitus (DM) tipo 2. METODOS: Amostras de sangue foram colhidas em jejum e os niveis de insulina, lipoproteina (a), colesterol total (CT), triglicerides (TG), lipoproteina de baixa densidade (LDL-C), lipoproteina de alta densidade (LDL-C), glicose e hemoglobina glicada (HbA1c) foram medidos em 60 pacientes com DM tipo 2 e 28 individuos saudaveis. Nos dividimos os pacientes em dois grupos baseados nos niveis basais de insulina: > 10 µIU/ml e 10 µIU/ml comparados com aqueles que apresentavam insulina basal < 10 µIU/ml (p < 0.05). A analise de regressao mostrou uma relacao significante da Lp(a) com os niveis de insulina (r = 0,262, p < 0,05) e razao Insulina/Glicose(r = 0,257, p < 0,05). CONCLUSAO: Os niveis de Lp(a) se correlacionam inversamente com os niveis de insulina em pacientes com DM tipo 2. Os niveis de Lp(a) podem ser um dos fatores de risco cardiovascular em pacientes com DM tipo 2 com maior duracao da doenca. (Arq Bras Cardiol 2009;93(1):28-33)BACKGROUND It has not been clearly established whether insulin resistance/deficiency leads directly to atherogenesis or through its association with other risk factors such as lipoprotein(a) [Lp(a)]. OBJECTIVE This project aimed at studying the association between basal insulin, lipids and lipoprotein(a) levels in patients with type 2 diabetes mellitus. METHODS Fasting blood samples were analyzed for Insulin, Lipoprotein(a), total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), glucose and glycosylated hemoglobin (HbA1c) levels in 60 patients with type 2 Diabetes Mellitus (DM) and 28 healthy subjects. We divided patients into two groups based on basal insulin levels: > or = 10 microIU/ml and < 10 microIU/ml. RESULTS Insulin levels were higher in diabetic versus control individuals [p < 0.05]. TC (p< 0.01), LDL-C (p< 0.05), TC/HDL ratio (p< 0.01) and TG levels (p< 0.05) were higher and HDL- C levels were significantly lower (p < 0.001) in both diabetic groups as compared to control. Lp(a) levels were significantly higher in both diabetic groups, when compared to the control group. Lp(a) levels were significantly lower in diabetics with basal insulin > or =10 microIU/ml when compared to those with basal insulin < 10 microIU/ml (p < 0.05). Regression analysis revealed a significant relationship of Lp(a) with insulin levels (r = 0.262, p < 0.05) and Insulin Glucose ratio (r = 0.257, p < 0.05). CONCLUSION Lp(a) levels correlate inversely with insulin levels in Type 2 diabetic patients. Lp(a) may be one of the cardiovascular risk factor in type 2 diabetic patients with longer duration of DM.

Gene-gene, gene-environment, gene-nutrient interactions and single nucleotide polymorphisms of inflammatory cytokines.

Inflammation plays a significant role in the etiology of type 2 diabetes mellitus (T2DM). The rise in the pro-inflammatory cytokines is the essential step in glucotoxicity and lipotoxicity induced mitochondrial injury, oxidative stress and beta cell apoptosis in T2DM. Among the recognized markers are interleukin (IL)-6, IL-1, IL-10, IL-18, tissue necrosis factor-alpha (TNF-α), C-reactive protein, resistin, adiponectin, tissue plasminogen activator, fibrinogen and heptoglobins. Diabetes mellitus has firm genetic and very strong environmental influence; exhibiting a polygenic mode of inheritance. Many single nucleotide polymorphisms (SNPs) in various genes including those of pro and anti-inflammatory cytokines have been reported as a risk for T2DM. Not all the SNPs have been confirmed by unifying results in different studies and wide variations have been reported in various ethnic groups. The inter-ethnic variations can be explained by the fact that gene expression may be regulated by gene-gene, gene-environment and gene-nutrient interactions. This review highlights the impact of these interactions on determining the role of single nucleotide polymorphism of IL-6, TNF-α, resistin and adiponectin in pathogenesis of T2DM.

Analysis of clinical and biochemical spectrum of Wilson disease patients.

BACKGROUND AND AIMS Wilson disease (WD) is autosomal recessive disorder of copper metabolism. Wilson disease patients usually suffer from hepatic or neuropsychiatric complications. The symptoms appear between ages five to 35 but it can vary from two years to 72 years. MATERIALS AND METHODS Study was carried out from June 2008 to November 2010. This study included nine families with eleven cases of WD to determine clinical presentation, diagnostic findings (including laboratory results) and liver histology. It included 11 patients who presented with hepatic manifestations and/or Neuropsychiatric manifestations and/or family history suggesting features of WD. Patients with hepatitis B and C and those with history of taking antipsychotic drugs were excluded from the study. Patients data was included in a well designed performa. Liver function test, serum ceruloplasmin, serum copper, 24 hour urinary copper, blood complete picture were analyzed. Quantitative data such as age, hemoglobin etc were expressed as mean with ± SD and quantitative variables such as sex, movement disorders, hepatic involvement etc were expressed as frequency and percentage. RESULTS There were five male and six female patients with evidence of various manifestations here (i) hepatic in which they had only liver dysfunction (ii) hepatic and neurological (iii) neurological. The mean age of presentation was 8.7±3.92 years (range 4-19 years) and 45% were male patients. Decreased serum ceruloplasmin, enhanced 24-h urinary copper excretion and signs of chronic liver damage were confirmed in all patients and Kayser-Fleischer rings (KF rings) in 72% of patients. In severe WD patients, serum prothrombin activity was less than 50%, serum ceruloplasmin were low and serum copper levels were high than those in non-severe WD patients. High degree of suspicion leads to early treatment with good outcome. CONCLUSIONS The WD is rare but important cause of chronic liver disease. Clinical and biochemical analysis in cases of patients with unexplained liver disease with high degree of suspicion can lead to early treatment with good outcome.

Examination of CK2α and NF-κB p65 expression in human benign prostatic hyperplasia and prostate cancer tissues.

Protein kinase CK2 plays a critical role in cell growth, proliferation, and suppression of cell death. CK2 is overexpressed, especially in the nuclear compartment, in the majority of cancers, including prostate cancer (PCa). CK2-mediated activation of transcription factor nuclear factor kappa B (NF-κB) p65 is a key step in cellular proliferation, resulting in translocation of NF-κB p65 from the cytoplasm to the nucleus. As CK2 expression and activity are also elevated in benign prostatic hyperplasia (BPH), we sought to increase the knowledge of CK2 function in benign and malignant prostate by examination of the relationships between nuclear CK2 and nuclear NF-κB p65 protein expression. The expression level and localization of CK2α and NF-κB p65 proteins in PCa and BPH tissue specimens was determined. Nuclear CK2α and NF-κB p65 protein levels are significantly higher in PCa compared with BPH, and these proteins are positively correlated with each other in both diseases. Nuclear NF-κB p65 levels correlated with Ki-67 or with cytoplasmic NF-κB p65 expression in BPH, but not in PCa. The findings provide information that combined analysis of CK2α and NF-κB p65 expression in prostate specimens relates to the disease status. Increased nuclear NF-κB p65 expression levels in PCa specifically related to nuclear CK2α levels, indicating a possible CK2-dependent relationship in malignancy. In contrast, nuclear NF-κB p65 protein levels related to both Ki-67 and cytoplasmic NF-κB p65 levels exclusively in BPH, suggesting a potential separate impact for NF-κB p65 function in proliferation for benign disease as opposed to malignant disease.

Variations in association of Interleukin 6 -G174C single nucleotide polymorphism with type 2 diabetes mellitus—a review

Inflammation plays a role in the etiology of type 2 diabetes mellitus (DM). Interleukin-6 is one of the inflammatory markers which play role in the pathogenesis of diabetes mellitus DM. Single nucleotide polymorphism (SNP); -G174C in interleukin −6 (IL-6) gene promoter area has been reported to be associated with type 2 DM (T2DM). The frequency of polymorphism is found to be variable in various ethnic groups and also within an ethnic group. Many studies reported a positive association between T2DM and IL-6 SNP although quite a number of other studies failed to find such association. IL-6 polymorphism has been found to be associated with higher serum IL-6 levels, insulin resistance and BMI, although these findings are also challenged by many studies. There is no single explanation for such highly variable results in different studies. Presence of yet unidentified gene polymorphism in linkage disequilibrium with IL-6 SNP could be responsible. The different results can also be attributed to the study groups differing as age, gender distribution, age of onset of disease, life style, degree of obesity and glucose tolerance. This review highlights the varying results reported in association of IL 6 –G174C SNP with risk of T2DM, serum IL-6 levels, BMI and insulin resistance.

Correlation Between Serum Amyloid A-low Density Lipoprotein And Genotoxicity In Smokers

OBJECTIVE To investigate the relation between serum amyloid A-low density lipoprotein (SAA-LDL) and genotoxicity in smokers. STUDY DESIGN An experimental study. PLACE AND DURATION OF STUDY Army Medical College, Rawalpindi and National Institute of Health (NIH), Islamabad, from June 2014 to February 2015. METHODOLOGY Seventy healthy Sprague Dawley rats were purchased from NIH and exposed to cigarette smoke in smoke chamber for three months. Blood samples were drawn from each rat at the end of the study period. SAA-LDL was determined by enzyme-linked immunosorbent assay (ELISA). Genotoxicity was assessed by cytokinesis block micronucleus (CBMN) assay. Pearson correlation was used to find correlation between SAA-LDL and genotoxicity. RESULTS Strong positive correlation was found between SAA-LDL and micronuclei frequency in smoke-exposed rats (r=0.799, N=70, p <0.01). CONCLUSION Statistically significant strong positive correlation between SAA-LDL and genotoxicity in smoke-exposed rats shows that changes in one is associated with changes in other and vice versa.