Mohsen Fathzadeh

All Publications

• CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation. Nature genetics Esteghamat, F., Broughton, J. S., Smith, E., Cardone, R., Tyagi, T., Guerra, M., Szabó, A., Ugwu, N., Mani, M. V., Azari, B., Kayingo, G., Chung, S., Fathzadeh, M., Weiss, E., Bender, J., Mane, S., Lifton, R. P., Adeniran, A., Nathanson, M. H., Gorelick, F. S., Hwa, J., Sahin-Tóth, M., Belfort-DeAguiar, R., Kibbey, R. G., Mani, A. 2019; 51 (8): 1233–43

  Abstract

  Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.

  View details for DOI 10.1038/s41588-019-0470-3

  View details for PubMedID 31358993

  View details for PubMedCentralID PMC6675645

• The human arylamine N-acetyltransferase type 2 gene: Genomics and Cardiometabolic Risk Chapter book in: Arylamine N-acetyltransferases in Health and Disease. Edited by Edith Sim and Nicola Laurieri. World Scientific Publishing Group. In press. Fathzadeh, M., Hein, D. W., Knowles, J. . 2018
• Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus. American journal of human genetics Li, N., Subrahmanyan, L., Smith, E., Yu, X., Zaidi, S., Choi, M., Mane, S., Nelson-Williams, C., Behjati, M., Kazemi, M., Hashemi, M., Fathzadeh, M., Narayanan, A., Tian, L., Montazeri, F., Mani, M., Begleiter, M. L., Coon, B. G., Lynch, H. T., Olson, E. N., Zhao, H., Ruland, J., Lifton, R. P., Mani, A. 2016; 99 (4): 1000-?

  View details for DOI 10.1016/j.ajhg.2016.09.003

  View details for PubMedID 27716515

• Nat1 Deficiency Is Associated with Mitochondrial Dysfunction and Exercise Intolerance in Mice CELL REPORTS Chennamsetty, I., Coronado, M., Contrepois, K., Keller, M. P., Carcamo-Orive, I., Sandin, J., Fajardo, G., Whittle, A. J., Fathzadeh, M., Snyder, M., Reaven, G., Attie, A. D., Bernstein, D., Quertermous, T., Knowles, J. W. 2016; 17 (2): 527-540

  Abstract

  We recently identified human N-acetyltransferase 2 (NAT2) as an insulin resistance (IR) gene. Here, we examine the cellular mechanism linking NAT2 to IR and find that Nat1 (mouse ortholog of NAT2) is co-regulated with key mitochondrial genes. RNAi-mediated silencing of Nat1 led to mitochondrial dysfunction characterized by increased intracellular reactive oxygen species and mitochondrial fragmentation as well as decreased mitochondrial membrane potential, biogenesis, mass, cellular respiration, and ATP generation. These effects were consistent in 3T3-L1 adipocytes, C2C12 myoblasts, and in tissues from Nat1-deficient mice, including white adipose tissue, heart, and skeletal muscle. Nat1-deficient mice had changes in plasma metabolites and lipids consistent with a decreased ability to utilize fats for energy and a decrease in basal metabolic rate and exercise capacity without altered thermogenesis. Collectively, our results suggest that Nat1 deficiency results in mitochondrial dysfunction, which may constitute a mechanistic link between this gene and IR.

  View details for DOI 10.1016/j.celrep.2016.09.005

  View details for Web of Science ID 000385850700019

  View details for PubMedID 27705799

  View details for PubMedCentralID PMC5097870

• The Protective Effect of Transcription Factor 7-Like 2 Risk Allele rs7903146 against Elevated Fasting Plasma Triglyceride in Type 2 Diabetes: A Meta-Analysis JOURNAL OF DIABETES RESEARCH Wang, S., Song, K., Srivastava, R., Fathzadeh, M., Li, N., Mani, A. 2015

  Abstract

  The results from published studies regarding association of transcription factor 7-like 2 (TCF7L2) variant rs7903146 with dyslipidemia have been conflicting and inconclusive.We carried out a meta-analysis that aimed to investigate the association of the rs7903146 variant with plasma lipid levels using electronic database and published studies. Data was extracted by a standard algorithm. Dominant, recessive, homozygote, and heterozygote comparison models were utilized.24 studies incorporating 52,785 subjects were included in this meta-analysis. Overall, the minor allele (T) was associated with lower risk for hypertriglyceridemia in subjects with type 2 diabetes (dominant model: SMD = -0.04, 95% CI (-0.08, 0.00), P = 0.048, P heterogeneity = 0.47; recessive model: SMD = -0.10, 95% CI (-0.18, -0.02), P = 0.01, P heterogeneity = 0.56). No association was found between minor (T) allele and plasma TC, LDL-c, or HDL-c levels in subjects with type 2 diabetes or metabolic syndrome (MetS) and no association was found between minor (T) allele and plasma TG levels in nondiabetic subjects.Our meta-analysis indicated the association between TCF7L2 rs7903146 polymorphism and low plasma triglyceride (TG) level in subjects with type 2 diabetes. No association was found between rs7903146 variant and plasma lipids in nondiabetic subjects.

  View details for DOI 10.1155/2015/468627

  View details for Web of Science ID 000364845900001

  View details for PubMedID 26576435

• The metabolic syndrome and DYRK1B. New England journal of medicine Keramati, A. R., Fathzadeh, M., Mani, A. 2014; 371 (8): 785-786

  View details for DOI 10.1056/NEJMc1408235

  View details for PubMedID 25140972

• A Form of the Metabolic Syndrome Associated with Mutations in DYRK1B NEW ENGLAND JOURNAL OF MEDICINE Keramati, A. R., Fathzadeh, M., Go, G., Singh, R., Choi, M., Faramarzi, S., Mane, S., Kasaei, M., Sarajzadeh-Fard, K., Hwa, J., Kidd, K. K., Bigi, M. A., Malekzadeh, R., Hosseinian, A., Babaei, M., Lifton, R. P., Mani, A. 2014; 370 (20): 1909-1919

  Abstract

  Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome.We identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene.A founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-of-function activities by potentiating these effects. A second mutation, substituting proline for histidine 90, was found to cosegregate with a similar clinical syndrome in an ethnically distinct family.These findings indicate a role for DYRK1B in adipogenesis and glucose homeostasis and associate its altered function with an inherited form of the metabolic syndrome. (Funded by the National Institutes of Health.).

  View details for DOI 10.1056/NEJMoa1301824

  View details for Web of Science ID 000336123600007

  View details for PubMedID 24827035

• Rare Nonconservative LRP6 Mutations Are Associated with Metabolic Syndrome HUMAN MUTATION Singh, R., Smith, E., Fathzadeh, M., Liu, W., Go, G., Subrahmanyan, L., Faramarzi, S., McKenna, W., Mani, A. 2013; 34 (9): 1221-1225

  Abstract

  A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation.

  View details for DOI 10.1002/humu.22360

  View details for Web of Science ID 000323109200007

  View details for PubMedID 23703864

• Apolipoprotein E polymorphism in Southern Iran: E4 allele in the lowest reported amounts MOLECULAR BIOLOGY REPORTS Bazrgar, M., Karimi, M., Fathzadeh, M., Senemar, S., Peiravian, F., Shojaee, A., Saadat, M. 2008; 35 (4): 495-499

  Abstract

  Apolipoprotein E (apoE) with three major alleles E2, E3 and E4 is one of the critical genes in lipid metabolism. Common apoE alleles are in association with an increase in risk for central nervous and cardiovascular diseases such as Alzheimer's disease, dementia, multiple sclerosis, atherosclerosis, coronary heart disease, hyperlipoproteinemia and stroke. ApoE3 is known as the most frequent allele in all populations, while association of apoE gene polymorphism with reported diseases have mostly been related to other two major alleles especially apoE4.To determine of apoE alleles frequencies in Southern Iran and comparison of those frequencies with other populations.DNA was extracted from the whole blood of 198 healthy unrelated candidates from population of Fars Province, Southern Iran, for apoE genotyping who were checked up by a physician. The frequencies of apoE alleles were compared with other populations by chi(2) test.The frequencies of E2, E3 and E4 were 0.063, 0.886 and 0.051 respectively. These values were similar to those reported from populations of Kuwait, Oman, Lebanon, India, Turkey, Greece, Spain, Sardinia Islands of Italy and two Iranian populations but were different from South of Italy and Caucasians in other Europe regions, American, American-Indian, African, East Asian and Saudi populations (P < 0.05).The frequency of E4 allele as a genetic risk factor for some multifactorial diseases in the population of Southern Iran is in the lowest reported amounts in the world. Iranian population has Caucasoid origin but differs from some Caucasian populations in Europe and America. The results of present study are in agreement with the historical evidences which show admixture of Iranian population with other populations and some studies based on genetic polymorphisms in the population of Southern Iran.

  View details for DOI 10.1007/s11033-007-9113-3

  View details for Web of Science ID 000261424100002

  View details for PubMedID 17594534

• Genetic counseling in southern Iran: consanguinity and reason for referral. Journal of genetic counseling Fathzadeh, M., Babaie Bigi, M. A., Bazrgar, M., Yavarian, M., Tabatabaee, H. R., Akrami, S. M. 2008; 17 (5): 472-479

  Abstract

  Population based genetic counseling that promotes public health goals is an appropriate health care service. The genetic counseling center in Shiraz, southern Iran serves most of the clients in the region. During a 4-year period, 2,686 couples presented for genetic counseling. Data files revealed that 85% had consanguineous relationships (1.5% double first cousin, 74% first cousin, 8% second cousin, 1.5% beyond second cousin). Most prevalent reasons for referral were premarital counseling (80%), with 89% consanguinity, followed by preconception (12%), postnatal (7%), and prenatal counseling (1%). The most common abnormalities in probands or relatives were intellectual and developmental disabilities, hearing loss/impairment, and neuromuscular dystrophies. Family history of medical problem(s) and/or consanguinity was the main indication for referral in nearly every family. Premarital consanguinity poses unique challenges and opportunities. There is considerable opportunity for genetic counseling and education for couples in this population. The tradition of consanguinity, which is likely to persist in Iran, requires multidisciplinary agreement regarding the appropriate process of genetic counseling. Effective genetic counseling in Iran hinges on inclusion of data from genetic counseling services in national genomic and epidemiologic research programs.

  View details for DOI 10.1007/s10897-008-9163-2

  View details for PubMedID 18551360

• Apolipoprotein E gene polymorphism and left ventricular function in Iranian patients with thalassemia major HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Bazrgar, M., Karimi, M., Peiravian, F., Fathzadeh, M. 2007; 92 (2): 256-257

  Abstract

  Left ventricular (LV) failure is the main cause of death in thalassemia. Iron overload in patients with thalassemia leads to the formation of oxygen free radicals. Of the various apolipoprotein E (apoE) alleles, apoE4 is the least efficient in conditions of oxidative stress in comparison with apoE2 and apoE3. Our results showed that apoE4 is a genetic risk factor for LV dysfunction in thalassemia.

  View details for Web of Science ID 000244233600020

  View details for PubMedID 17296580