Reporting a novel growth hormone receptor gene variant in an Iranian consanguineous pedigree with Laron syndrome: a case report.

BACKGROUND: Human growth hormone (hGH) plays a crucial role in growth by binding to growth hormone receptor (GHR) in target cells. Binding of GH molecules to their cognate receptors triggers downstream signaling pathways leading to the transcription of several genes, including insulin-like growth factor (IGF)-1. Pathogenic variants in the GHR gene can result in structural and functional defects in the GHR protein, leading to Laron Syndrome (LS) with the primary clinical manifestation of short stature. So far, around 100 GHR variants have been reported, mostly biallelic, as causing LS. CASE PRESENTATION: We report on three siblings from an Iranian consanguineous family who presented with dwarfism. Whole-exome sequencing (WES) was performed on the proband, revealing a novel homozygous missense variant in the GHR gene (NM_000163.5; c.610 T > A, p.(Trp204Arg)) classified as a likely pathogenic variant according to the recommendation of the American College of Medical Genetics (ACMG). Co-segregation analysis was investigated using Sanger sequencing. CONCLUSIONS: To date, approximately 400-500 LS cases with GHR biallelic variants, out of them 10 patients originating from Iran, have been described in the literature. Given the high rate of consanguineous marriages in the Iranian population, the frequency of LS is expected to be higher, which might be explained by undiagnosed cases. Early diagnosis of LS is very important, as treatment is available for this condition.

α-Thalassemia Mutations in Ilam Province, West Iran.

Despite several studies performed in different provinces of Iran to identify the spectrum of α-globin gene mutations, no such study has so far been carried out in Ilam Province. A total of 274 individuals, including 201 α-thalassemia (α-thal) carriers and 73 normal subjects, originating from the northern counties of Ilam Province, participated in this study. Analysis of α-globin defects was performed using multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR and direct sequencing, which revealed a total of 11 different mutations and 22 different genotypes. The -α3.7 (rightward) (NG_000006.1: g.34164_37967del3804), α-5 ntα (HBA2: c.95 + 2_95 + 6delTGAGG), and -α4.2 (leftward) deletions were the most prevalent mutations identified in our study, with frequencies of 66.23, 10.09 and 8.33%, respectively. In conclusion, the present study showed that the α-thal mutation spectrum in Ilam Province, at least in the northern part of the province, is different from that in other geographical regions of Iran. These results increase our knowledge about the spectrum and distribution of α-globin gene mutations in Iran.

Spectrum of PAH gene mutations in 1547 phenylketonuria patients from Iran: a comprehensive systematic review.

As one of the highest prevalence rates in the world, the prevalence of Phenylketonuria (PKU) in Iran has been estimated at 16.5 per 100,000 neonates. The objective of this study was to evaluate the spectrum and frequency of mutations of the phenylalanine hydroxylase (PAH) gene in Iranian PKU patients. A systematic review was carried out on previous studies on PAH gene mutations in Iranian PKU patients. A complete search was carried out on the on-line databases of Scopus, Web of Science, PubMed/Medline, ProQuest, Science Direct, Magiran, SID and the search engine Google Scholar. The keywords of Phenylketonuria, PKU, Phenylalanine Hydroxylase, PAH, and Iran, as well as their Persian equivalents, in all possible combinations were used. Finally, a total of 21 eligible articles with a sample size of 1547 Iranian PKU patients, published between 2003 and 2020, were included in our systematic review. A total of 129 different PAH gene mutations including, IVS10-11G > A (c.1066-11G > A) (19.23%), p.R261Q (c.782G > A) (7.63%), p.P281L (c.842C > T) (6.24%), IVS2 + 5G > C (c.168 + 5G > C) (5.75%), p.R243* (c.727C > T) (3.59%), IVS9 + 5G > A (c.969 + 5G > A) (2.84%), p.R176* (c.526C > T) (2.42%), p.Lys363Nfs*37 (c.1089delG) (2.13%), IVS11 + 1G > C (c.1199 + 1G > C) (2.07%) and p.L48S (c.143 T > C) (2.04%) were identified. The spectrum and frequency of mutations observed in Iran were closer to those observed in the Mediterranean countries. Our results are valuable in planning panel-based studies in provinces with incomplete data on PAH gene mutations. This study is a good reference for genetic counselors and physicians who advise couples in making decisions to maintain or terminate a pregnancy.

Distribution of HBB Gene Mutations in the Kurdish Population of Ilam Province, West Iran.

ß-Thalassemia (ß-thal) is one of the most common diseases in Iran. Here, we report the spectrum of HBB gene mutations in 176 Kurdish ß-thal carriers from the northern part of Ilam Province, Iran. The amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique was used to identify common ß-globin gene mutations observed in Iran. Samples negative on ARMS-PCR were analyzed by direct sequencing of the ß-globin gene. In total, 12 different mutations were identified on the ß-globin gene. The mutations of IVS-II-1 (G>A) (HBB: c.315+1G>A), codons 8/9 (+G) (HBB: c.27_28insG), codons 36/37 (-T) (HBB: c.112delT) and IVS-I-110 (G>A) (HBB: c.93-21G>A), were the most prevalent mutations in our samples, with frequencies of 59.09, 10.80, 7.95 and 7.39%, respectively. In general, the mutation spectrum of the ß-globin gene in the northern part of Ilam Province is most similar to that in other western provinces of Iran. On the other hand, due to the high prevalence of carriers and ß-thal major (ß-TM) patients in this province, our results can be helpful in identifying carriers as well as at-risk fetuses through the prenatal diagnosis program.

Severe α-Thalassemia Due to Compound Heterozygosity for Hb Adana (α59 Gly>Asp) (HBA1: c.179G > A) and Codon 127 (A > T) (HBA2: c.382A > T) in an Iranian Family.

We describe a novel compound heterozygous genotype which consists of two point mutations named Hb Adana (HBA1: c.179G>A) and codon 127 (HBA2: c.382A>T) in a Kurdish family with two girls affected with severe α-thalassemia (α-thal). Both patients (the proband and her sister) had a history of splenectomy during childhood. Although the proband had no blood transfusion history, her affected sister has had two blood transfusions so far. In conclusion, diagnosing and reporting new genotypes on the α-globin genes will improve our knowledge about complicated genotype-phenotype correlations in α-thal disorder.

The Spectrum of α-Thalassemia Mutations in Kurdistan Province, West Iran.

In order to identify the α-thalassemia (α-thal) mutation spectrum in Kurdistan Province, West Iran, a total of 217 individuals, including 154 α-thal carriers and 63 normal subjects were investigated in this study. Molecular analysis of α1- and α2-globin genes using multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR or direct DNA sequencing, showed 11 different α-globin variants. The -α3.7 (rightward) deletion (NG_000006.1: g.34164_37967del3804) (70.32%), polyadenylation signal (polyA2) site (AATAAA>AATGAA) (αpolyA2α) (HBA2: c.*92A>G) (7.74%), -α4.2 (leftward) deletion (6.45%) and codon 59 (or Hb Adana) (G>A) (ααcodon 59) (HBA1: c.179G>A) (4.52%) were the most frequent mutations in the present study. In conclusion, the spectrum of α-thal mutations in Kurdistan Province is closest to that in western provinces of Iran (Kurdish and Laki populations). In addition, it was revealed that the codon 59 mutation is common in the Kurdish population. On the other hand, despite the same ethnic background of Kurds in Iran and Iraq, the - -MED I double gene deletion and polyA2 point mutation have different distributions in these two populations. Therefore, further studies are needed to identify the cause of these differences.

Molecular Genetic Analysis of α-Thalassemia in Hamadan Province, West Iran.

Identifying couples who are carriers of thalassemia-causing mutations, followed by prenatal diagnosis (PND), is undoubtedly an effective way to prevent the birth of children with the disease. Our aim in this study was to report for the first time the spectrum of α-globin gene mutations in the population living in Hamadan Province, West Iran. Multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR, and direct DNA sequencing of HBA1 and HBA2 genes were used to identify the α-thalassemia (α-thal)-causing mutations in a cohort of 389 individuals including 328 α-thal carriers and 61 normal subjects. A total of 17 different mutations and 25 different genotypes were detected. The -α3.7 (rightward) deletion (NG_000006.1: g.34164_37967del3804) was the most frequent mutation, accounting for more than half of all mutations (61.04%). This study revealed that there is a variety of α-thal mutations and α-thal genotypes in Hamadan Province, West Iran. This observation is probably due to the complexity of the Hamadan Province population that is composed of Persians (Fars), Turks, Kurds, and Lurs/Laks. In conclusion, our results demonstrated the spectrum of mutations in α-globin genes in Iran and increased our understanding of their distribution in this country.

Association between activity and genotypes of paraoxonase1 L55M (rs854560) increases the disease activity of rheumatoid arthritis through oxidative stress.

Rheumatoid arthritis (RA) is considered as a long-term autoimmune disorder. Gene polymorphism and oxidative stress might be involved in the pathogenesis of the disease. We aimed to determine the association between PON-1L55M polymorphism and its effects on inflammatory markers such as anti-cytroline circulated-peptide (CCP)-antibodies, C-reactive protein (CRP), neopterin serum concentration, arylesterase (ARE) and butyrylcholinesterase (BuChE) activities and total-antioxidant-capacity (TAC) level with the activity of disease in RA patients. This case-control study consisted of 419 RA patients and 397 gender-age-matched unrelated healthy controls from the west of Iran. PON1-L55M polymorphism was detected by real-time-PCR. The TAC level, serum BuChE and ARE activities were determined spectrophotometrically. Anti-CCP-antibody and CRP were measured by ELISA and neopterin level was detected by HPLC. The PON1-M55 allele was associated with increased risk of the RA in cases with moderate or high activity (OR = 1.43, p = 0.023) and also in cases with the presence of anti-CCP antibody (OR = 1.51, p = 0.009). Synergistic effects of PON1 M55 and Q192 alleles resulted in 2.14 times (p = 0.021) increased disease activity among RA patients with moderate or high activity of the disease. RA patients carried both M (PON1 L55M) and Q alleles (PON1Q192R) had higher concentrations of neopterin (p = 0.003), anti-CCP-antibody (p < 0.001) and CRP (p = 0.026) and significantly lower TAC level (p < 0.001) and ARE (p < 0.001) activity compared to controls. The current study suggests there might be a relationship between genetic and activity of PON. Also, the PON1L55M and PON1Q192R could act in synergy to increase the risk of RA and enhance the level of oxidative stress markers.

Characterization of the IVS-II-821 (A>C) (HBB: c.316-30A>C) Mutation in a ß-Thalassemia Phenotype in Iran.

ß-Thalassemia (ß-thal) is the most frequently observed hereditary blood disorder that results from genetic defects causing deficient synthesis of hemoglobin (Hb) polypeptide chains. Detecting thalassemia mutations are necessary for prenatal diagnosis (PND) programs leading a better quality of life for the patients, as well as a reduction in the cost of their medical care. There are more than 900 different genomic mutations of the ß-globin gene described in the human hemoglobin variant (HbVar) database. In this study, we identified a mid-intronic mutation at IVS-II-821 (A>C) (HBB: c.316-30A>C) position in the HBB gene of an Iranian proband and two of her siblings that was associated with ß-thal clinical features. Direct DNA sequence analysis was performed by mutation scanning of the ß-globin gene. Based on the observed ß-thal phenotype and bioinformatics analysis results, we concluded that this ß-globin gene mutation was associated with a mild phenotype of ß-thal through activating potential splice sites by creating exonic splicing enhancers (ESEs), exon-identity element (EIE) and exonic splicing regulatory sequences (ESRs) sites.

The Spectrum of ß-Thalassemia Mutations in Hamadan Province, West Iran.

ß-Thalassemia (ß-thal) is one of the most common hemoglobinopathies worldwide and is caused by mutations on the ß-globin (HBB) gene. The aim of the present study was to determine the mutation spectrum of the ß-globin gene in ß-thal carriers who were originally from Hamadan Province, Western Iran. Two hundred and eighty-two ß-thal carriers participated in the study. Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and direct sequencing were used for detection of different mutations. A total of 25 different mutations, including 21 ß-thal mutations and four other hemoglobin (Hb) variants, in 280 ß-thal carriers (99.3%) were detected in the present study. Three types of mutations including IVS-II-1 (G>A) (HBB: c.315+1G>A) (26.24%), codons 8/9 (+G) (HBB: c.27_28insG) (14.54%) and codons 36/37 (-T) (HBB: c.112delT) (12.76%) accounted for more than 50.0% of the identified mutations. Moreover, IVS-I-110 (G>A) (HBB: c.93-21G>A), codon 44 (-C) (HBB: c.135delC) and IVS-I (25 bp deletion) (HBB: c.93-21_del), had frequencies of 7.09, 7.09 and 5.67%, respectively. Allele frequencies of the remaining 19 mutations were less than 5.0%. This study is the first comprehensive study on a large sample size in Hamadan Province, Iran. In conclusion, the present study significantly increased the spectrum of HBB gene mutations in Hamadan Province compared with previous studies. Therefore, these results can be helpful in identifying ß-thal carriers and at-risk fetuses through prenatal diagnosis (PND).

The Spectrum of α-Thalassemia Mutations in the Lak Population of Iran.

α-Thalassemia (α-thal) is one of the most common genetic disorders worldwide. The aim of this study was to investigate for the first time the α-thal mutation spectrum in the Lak population living in Lorestan Province, Iran. One hundred and seventy-six α-thal carriers participated in the study. Multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR and direct sequencing were used for the detection of different mutations on the α-globin (HBA1 and HBA2) genes. A total of 11 different mutations was identified. The -α3.7 (rightward; NG_000006.1: g.34164_37967del3804) deletion was observed most frequently (56.35%), followed by α-5 ntα (HBA2: c.95+2_95+6delTGAGG), αpolyA2α (HBA2: c.*92A>G) and - -MED I (NG_000006.1: g.24664_41064del16401), with frequencies of 15.47, 9.39, and 6.08%, respectively. These four mutations accounted for more than 87.0% of the total mutated alleles. Moreover, 19 different genotypes were identified. The types and distribution pattern of the mutations identified in this study, in comparison with other studies conducted in Iran, was most similar to the Kurdish population of Kermanshah Province, Iran. Due to the lack of information on α-thal in Lorestan Province, it was not possible to compare the mutation spectrum in the Lur and Lak populations. In conclusion, our results may help in setting up a strategy for an α-thal screening program and genetic counseling in the Lak people.

The status of PAH gene-VNTR alleles and mini-haplotypes associations with PAH gene mutations in Iranian Kurdish PKU patients.

Background: The analysis of haplotypes/mini-haplotypes in the PAH gene has been used as an informative tool in several genetic anthropology studies. Considering the notion that Iranian population is one of the most heterogeneous i the world, this study was conducted to evaluate the association of VNTR-STR mini-haplotypes with the PAH gene mutations in PKU patients in Kermanshah province. Methods: A total of 24 unrelated Kurdish PKU patients with the known PAH gene causing mutations and 72 healthy controls were selected. The DNA fragments containing VNTR and STR systems were amplified by polymerase chain reaction (PCR). For VNTR system, PCR products were separated using electrophoresis on 2.5% agarose gel. For STR system, the samples were analyzed using DNA sequencing analysis version 5.2 software. Results: Overall, 5 PAH-VNTR-alleles, including VNTR3, 7, 8, 9, 12, and 3 PAH-STR-alleles, including STR238, 242, and 250, were detected in this study. VNTR3 and 8 alleles had the most frequency among healthy controls. Also, 6 different mini-haplotype alleles were found to be associated with PKU chromosomes. The 2 most prevalent mutations in Kermanshah province, IVS2+5G>C and IVS9+5G>A, were strongly linked to mini-haplotypes 9/242 and 8/238, respectively. Conclusion: The distributions and frequencies of VNTR alleles in Kurdish population have the most similarity to alleles previously described in European Caucasian families. Moreover, since the most common mutations in Kermanshah PKU chromosomes are rare and this was the first study on mini-haplotypes VNTR/STR among Iranian Kurdish PKU patients, given that this study was the first of its kind, it was not possible to compare its results with that of other studies on Iranian and non-Iranian populations.

Spectrum of Phenylalanine Hydroxylase Gene Mutations in Hamadan and Lorestan Provinces of Iran and Their Associations with Variable Number of Tandem Repeat Alleles.

Phenylketonuria (PKU) is one of the most common known inherited metabolic diseases. The present study aimed to investigate the status of molecular defects in phenylalanine hydroxylase (PAH) gene in western Iranian PKU patients (predominantly from Kermanshah, Hamadan, and Lorestan provinces) during 2014-2016. Additionally, the results were compared with similar studies in Iran. Nucleotide sequence analysis of all 13 exons and their flanking intronic regions of the PAH gene was performed in 18 western Iranian PKU patients. Moreover, a variable number of tandem repeat (VNTR) located in the PAH gene was studied. The results revealed a mutational spectrum encompassing 11 distinct mutations distributed along the PAH gene sequence on 34 of the 36 mutant alleles (diagnostic efficiency of 94.4%). Also, four PAH VNTR alleles (with repeats of 3, 7, 8 and 9) were detected. The three most frequent mutations were IVS9+5G>A, IVS7-5T>C, and p.P281L with the frequency of 27.8%, 11%, and 11%, respectively. The results showed that there is not only a consanguineous relation, but also a difference in PAH characters of mutations between Kermanshah and the other two parts of western Iran (Hamadan and Lorestan). Also, it seems that the spectrum of mutations in western Iran is relatively distinct from other parts of the country, suggesting that this region might be a special PAH gene distribution region. Moreover, our findings can be useful in the identification of genotype to phenotype relationship in patients, and provide future abilities for confirmatory diagnostic testing, prognosis, and predict the severity of PKU patients.

IVS-II-648/649 (-T) (HBB: c.316-202del) Triggers a Novel ß-Thalassemia Phenotype.

Thalassemia is the most common inherited disorder in Iran. There are approximately 800 different genomic alterations of the ß-globin gene described in the HbVar database. In this study, we identified a novel mutation in a 21-year-old woman [IVS-II-648/649 (-T); HBB: c.316-202del)] and describe its clinical implications. Two other members of this family, all with hematological and clinical features associated with ß-thalassemia (ß-thal), also carried this mutation. The molecular diagnosis of the ß-globin gene mutation was performed by direct sequencing. Based on the observed ß-thal phenotype and in silico analysis results, we concluded that this novel ß-globin gene mutation was associated with the mild phenotype of ß-thal.

The Spectrum of α-Thalassemia Mutations in Kermanshah Province, West Iran.

Thalassemia is a hereditary blood disorder that results from genetic defects causing deficient synthesis of hemoglobin (Hb) polypeptide chains. Although thalassemia mostly affects developing countries, there is limited knowledge of its accurate frequency and distribution in these regions. Knowing the prevalence of thalassemia and the frequency of responsible mutations is therefore an important step in the prevention and control program as well as treatment strategies. α-Thalassemia (α-thal) is prevalent in Middle East Asian populations, including Iran. In this study, 678 unrelated α-thal carriers, attending the Kermanshah Medical Genetics Laboratory, Kermanshah, Iran, were investigated for α-globin gene mutations by multiplex polymerase chain reaction (PCR) and direct sequencing. The most common mutation among our patients was -α(3.7) (rightward) (60.9%) deletion, which is also known to occur in high frequencies in other parts of Iran, in Southeast Asia and Mediterranean countries. Other prevalent α-thal mutations were α(-5 nt) (10.6%), α(polyA4) (9.9%), α(polyA6) (3.7%), - -(MED) (3.2%), -α(4.2) (leftward) (3.1%) deletion and codon 59 (Hb Adana; HBA1: c.179 G > A) (2.5%). These comprehensive new data are useful for establishing a screening strategy for the effective control of α-thal in Kermanshah Province.

Mutation analysis of PAH gene in patients with PKU in western Iran and its association with polymorphisms: identification of four novel mutations.

Phenylketonuria (PKU) is an autosomal recessive disorder characterized by a mutation in the phenylalanine hydroxylase (PAH) gene. Untreated PKU can lead to mental retardation, seizures, and other serious medical problems. This study was designed to investigate the status of molecular defects in the PAH gene and their association with polymorphisms in Kurdish patients with PKU in the Kermanshah province, western Iran. The study was conducted on 27 unrelated patients with PKU over a 2-year period (from 2010 to 2012). All 13 exons plus exon-intron boundaries of the PAH gene were analyzed and we identified 15 different mutations, including two novel mutations, in 51 of the 54 mutant alleles (diagnostic efficiency of 94.4 %). IVS4 + 1G > C (c.441 + 1G > C) and IVS7 - 5 T > C (c.843 - 5 T > C) are novel mutations that have not been reported in the academic literature or the PAH locus database ( http://www.pahdb.mcgill.ca ); therefore, they may be specific to the Kurdish population. IVS2 + 5G > C and IVS9 + 5G > A were the two most prevalent mutations in our sample, with frequencies of 26 % and 17 %, respectively. The second most common mutations were p.R261X, IVS10 - 11G > A, p.K363 > Nfs and IVS7 - 5 T > C, with each showing a relative frequency of 7.4 %. All other detected mutations, including p.F55 > Lfs, p.R176X, p.R243Q, p.V230I, p.R243X, p.R261Q, IVS8 - 7A > G and p.E390G had frequencies of less than 4 %. The present study showed that there is a distinct difference in the characteristics of PAH mutations between the Kermanshah province and other parts of Iran, suggesting that Kermanshah may have a unique population distribution of PAH gene mutations. Iran lies on the route of major ancient movements of the Caucasian people toward the Mediterranean basin, and Kermanshah has previously been called the gateway to Asia. Most of the mutations identified in this study are common in the Mediterranean region. Therefore, our findings are consistent with the historical and geographical links between the Iranian population and the populations of Mediterranean region.

Contribution of chromosomal aberrations to the pathogenesis of primary and secondary amenorrhea: A study from Western Iran.

Objective: Amenorrhea is an abnormal condition characterized by the absence of menstruation in women of reproductive age. According to the World Health Organization, amenorrhea ranks as the sixth leading cause of female infertility. Approximately 2% to 5% of women of reproductive age experience amenorrhea, which can be classified as primary amenorrhea (PA) or secondary amenorrhea (SA). Several studies have named chromosomal abnormalities among the main causes of amenorrhea, though the prevalence of these abnormalities may differ across populations. The objective of this study was to ascertain the frequency and types of chromosomal abnormalities in women with amenorrhea in Kermanshah Province, Iran. Methods: This retrospective study included patients with PA and SA who underwent standard cytogenetic analysis. We also conducted a review of the literature on chromosomal abnormalities and their prevalence in SA. Results: Among the 137 cases of PA in this study, 22% exhibited chromosomal abnormalities. Numerical changes were the most common finding (46.6%) in this group, including 45,X, mosaic, and 47,XXX karyotypes. These were followed by the 46,XY karyotype (40%). Of the 51 cases of SA that received chromosomal analysis, abnormalities were identified in only one case. Additionally, our review of the literature revealed that chromosomal aberrations are responsible for 7% of SA cases globally. Conclusion: In this study, we successfully characterized the cytogenetic causes of PA and SA in a substantial population from Kermanshah Province, Iran.

The influence of Nrf2 gene promoter methylation on gene expression and oxidative stress parameters in preeclampsia.

BACKGROUND AND AIMS: Preeclampsia (PE) is a serious medical condition that usually causes high blood pressure and affects multiple organs. Considering the adverse effect of oxidative stress on the process of PE in pregnant women and regarding the role of the Nrf2 gene in placental oxidative pathways, this study was conducted to investigate the DNA methylation status of Nrf2 in PE and healthy pregnant women. MATERIALS AND METHODS: The present case-control study consisted of 70 PE and 70 healthy pregnant women. Blood and placenta samples were taken from all subjects, and the percentage of the Nrf2 gene methylation in the samples was assessed by the Methyl Light PCR method. Also, the Nrf2 gene expression was evaluated by real-time PCR. The total antioxidant capacity (TAC) and total oxidative status (TOS) were measured by the colorimetric method. RESULTS: In PE women, there was a significant increase in blood pressure, term of pregnancy, and BMI. In addition, there were enhanced Nrf2 DNA methylation percentage in placenta tissue and increased TOS levels in placenta tissue and blood compared to healthy pregnant women (P < 0.05). Also, in the PE group, there was a significant decrease in Nrf2 gene expression and TAC level in placenta tissue compared to the control group (P < 0.05). CONCLUSION: The Nrf2 gene undergoes epigenetic modifications of DNA hypermethylation in the PE placenta. Decreased expression of this gene and the changes in the level of oxidative parameters (TAC, TOS) confirm it.

The spectrum of ß-thalassemia mutations in Kermanshah Province in West Iran and its association with hematological parameters.

ß-Thalassemia (ß-thal) is a hereditary autosomal disorder with decreased or absent ß-globin chain synthesis. Two hundred and one unrelated ß-thal carriers, attending the Kermanshah Medical Genetics Laboratory, Kermanshah, Iran, were investigated for ß-globin gene mutations by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and direct sequencing. Eighteen different mutations were identified in these subjects. Four of the mutations accounted for about 75.0% of the studied cases. IVS-II-1 (G>A) was the most frequent (45.8%) followed by codons 8/9 (+G) (15.9%), IVS-I-110 (G>A) (8.0%), IVS-I-6 (T>C) (5.5%), IVS-I-1 (G>A) (3.5%) and codon 44 (-C) (3.5%); the remaining 12 mutations were present with a frequency less than 3.0%. The mean corpuscular volume (MCV) values for males and females were 63.7 ± 3.7 and 63.2 ± 3.2 fL, respectively, while these values were 19.3 ± 1.6 and 19.3 ± 1.4 pg for mean corpuscular hemoglobin (Hb) (MCH). The mean Hb A2 values for males and females were 4.4 ± 0.5 and 4.1 ± 0.6%, respectively. This study provides a distribution guide for ß-thal mutations in Kermanshah Province, West Iran.

The proportion of tetrahydrobiopterin deficiency and PAH gene deficiency variants among cases with hyperphenyalaninemia in Western Iran.

BACKGROUND: Defects either in phenylalanine hydroxylase (PheOH) or in the production and recycling of its cofactor (tetrahydrobiopterin [BH4]) are the causes of primary hyperphenylalaninemia (HPA). The aim of our study was to investigate the current status of different variants of HPA Kurdish patients in Kermanshah province, Iran. MATERIALS AND METHODS: From 33 cases enrolled in our study, 32 were identified as HPA patients. Reassessing of pre-treatment phenylalanine concentrations and the analysis of urinary pterins was done by high-performance liquid chromatography method. RESULTS: A total of 30 patients showed PAH deficiency and two patients were diagnosed with BH4 deficiency (BH4/HPA ratio = 6.25%). Both of these two BH4-deficient patients were assigned to severe variant of dihydropteridine reductase (DHPR) deficiency. More than 75% of patients with PAH deficiency classified as classic phenylketonuria (PKU) according their levels of pre-treatment phenylalanine concentrations. CONCLUSION: Based on the performed study, we think that the frequency of milder forms of PKU is higher than those was estimated before and/or our findings here. Furthermore, the frequency of DHPR deficiency seems to be relatively high in our province. Since the clinical symptoms of DHPR deficiency are confusingly similar to that of classic PKU and its prognosis are much worse than classical PKU and cannot be solely treated with the PKU regime, our pilot study support that it is crucial to set up screening for BH4 deficiency, along with PAH deficiency, among all HPA patients diagnosed with HPA.