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1.  Two Novel Tyrosinase (TYR) Gene Mutations with Pathogenic Impact on Oculocutaneous Albinism Type 1 (OCA1) 
PLoS ONE  2014;9(9):e106656.
Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.
doi:10.1371/journal.pone.0106656
PMCID: PMC4162572  PMID: 25216246
2.  The mitochondrial DNA mutations associated with cardiac arrhythmia investigated in an LQTS family 
Objective(s):
As mitochondrial oxidative stress is probably entailed in ATP production, a candidate modifier factor for the long QT syndrome (LQTS) could be mitochondrial DNA (mtDNA). It has been notified that ion channels' activities in cardiomyocytes are sensitive to the ATP level.
Materials and Methods:
The sample of the research was an Iranian family with LQTS for mutations by PCR-SSCP and DNA sequencing. The study searched about 40% of the entire mitochondrial genome in the family.
Results:
Four novel mutations that lead to an amino acid substitution and two mutations in mitochondrial tRNA have been informed in this study. A Statistically significant correlation (r = 0.737) between QTc (ms) and the age of LQTS patients has been reported.
Conclusion:
The research data show that these mitochondrial mutations, in a family with LQTS, might be the responsible mitochondrial that defect and increase the gravity of LQTS.
PMCID: PMC4322148
Arrhythmia; Long QT syndrome; Mitochondrial DNA; Mutation, SSCP
3.  New Mutation of Pelizaeus­-Merzbacher-Like Disease; A Report from Iran 
Iranian Journal of Radiology  2014;11(2):e6913.
Pelizaeus­-Merzbacher-like disease (PMLD) is a hypomyelinating leukoencephalopathy disorder with a genetically heterogeneous pattern. Mutations in the GJA12/GJC2 gene cause one form of autosomal recessive Pelizaeus­-Merzbacher-like disease. Here, we report a new mutation in a ­10-month-old girl with nystagmus, psychomotor delay, hypotonicity, head nodding and dysmyelination from healthy second cousin parents. The genetic study showed a homozygote deletion as c902-918del in the exone 2. According to our study and recent reports from other Middle East countries, we suggest GJA12 gene mutations are common in this area, but we didnot find any previous report about this new mutation (c902-918Del).
doi:10.5812/iranjradiol.6913
PMCID: PMC4090646  PMID: 25035705
Pelizaeus­Merzbacher-Like Disease; Neurodegenerative Disease Leukodencephalopathy; Children
4.  Gene Expression Profiling of Mitochondrial Oxidative Phosphorylation (OXPHOS) Complex I in Friedreich Ataxia (FRDA) Patients 
PLoS ONE  2014;9(4):e94069.
Friedreich ataxia (FRDA) is the most frequent progressive autosomal recessive disorder associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes for the mitochondrial frataxin protein. The number of repeats correlates with disease severity, where impaired transcription of the FXN gene results in reduced expression of the frataxin protein. Gene expression studies provide insights into disease pathogenicity and identify potential biomarkers, an important goal of translational research in neurodegenerative diseases. Here, using real-time PCR (RT-PCR), the expression profiles of mitochondrial (mtDNA) and nuclear DNA (nDNA) genes that encode for the mitochondrial subunits of respiratory oxidative phosphorylation (OXPHOS) complex I in the blood panels of 21 FRDA patients and 24 healthy controls were investigated. Here, the expression pattern of mtDNA-encoded complex I subunits was distinctly different from the expression pattern of nDNA-encoded complex I subunits, where significant (p<0.05) down-regulation of the mitochondrial ND2, ND4L, and ND6 complex I genes, compared to controls, were observed. In addition, the expression pattern of one nDNA-encoded gene, NDUFA1, was significantly (p<0.05) down-regulated compared to control. These findings suggest, for the first time, that the regulation of complex I subunit expression in FRDA is complex, rather than merely being a reflection of global co-regulation, and may provide important clues toward novel therapeutic strategies for FRDA and mitochondrial complex I deficiency.
doi:10.1371/journal.pone.0094069
PMCID: PMC3976380  PMID: 24705504
5.  Three Novel Mutations in Iranian Patients with Tay-Sachs Disease 
Iranian Biomedical Journal  2014;18(2):114-119.
Background: Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population. Methods: In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion. Results: Molecular genetics analysis of DNA from 23 patients of TSD revealed mutations that has been previously reported, including four-base duplications c.1274_1277dupTATC in exon 11 and IVS2+1G>A, deletion TTAGGCAAGGGC in exon 10 as well as a few novel mutations, including C331G, which altered Gln>Glu in HEXB, A>G, T>C, and p.R510X in exon 14, which predicted a termination codon or nonsense mutation. Conclusion: In conclusion, with the discovery of these novel mutations, the genotypic spectrum of Iranian patients with TSD disease has been extended and could facilitate definition of disease-related mutations.
doi:10.6091/ibj.1137.2013
PMCID: PMC3933921  PMID: 24518553
Tay-Sachs disease; β- hexosaminidase A; β- hexosaminidase B
6.  The mitochondrial ATPase6 gene is more susceptible to mutation than the ATPase8 gene in breast cancer patients 
Background
Breast cancer is the most common malignancy in women throughout the world. Mitochondria play important roles in cellular energy production, free radical generation and apoptosis. Identification of mitochondrial DNA mutations and/or polymorphisms as cancer biomarkers is rapidly developing in molecular oncology research.
Methods
In this study, the DNA alterations of the mitochondrial ATPase 6 and 8 genes were investigated in 49 breast cancer patients using PCR amplification and direct DNA sequencing on mtDNA. A possible association between these variants and tumorigenesis was assessed. Furthermore, the impact of non-synonymous substitutions on the amino acid sequence was evaluated using the PolyPhen-2 software.
Results
Twenty eight distinct somatic mitochondrial DNA variants were detected in tumor tissues but not in the corresponding adjacent non-tumor tissues. Among these variants, 9 were observed for the first time in breast cancer patients. The mtDNA variants of A8384 (T7A), T8567C (I14T), G8572A (G16S), A9041G (H172R) and G9055A (A177T) showed the most significant effects probably due to damaging changes to the resulting protein. Furthermore, non-synonymous amino acid changing variants were more frequent in the ATPase6 gene compared to the ATPase8 gene.
Conclusion
Our results showed that the ATPase6 gene is more susceptible to variations in breast cancer and may play an important role in tumorigenesis by changing the energy metabolism level in cancer cells.
doi:10.1186/1475-2867-14-21
PMCID: PMC3942513  PMID: 24588805
MtDNA; ATPase6; ATPase8; Breast cancer
7.  Molecular and Clinical Investigation of Iranian Patients with Friedreich Ataxia 
Iranian Biomedical Journal  2014;18(1):28-33.
Background: Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by guanine-adenine-adenine (GAA) triplet expansions in the FXN gene. Its product, frataxin, which severely reduces in FRDA patients, leads to oxidative damage in mitochondria. The purpose of this study was to evaluate the triple nucleotide repeated expansions in Iranian FRDA patients and to elucidate distinguishable FRDA clinical differences in these patients. Methods: A number of 22 Iranian patients (8 females and 14 males) from 16 unrelated families were studied. DNA was extracted from the peripheral blood of patients. The frequency and length of (GAA)n repeats in intron 1 of the FXN gene were analyzed using long-range PCR. In this study, the clinical criteria of FRDA in our patients and the variability in their clinical signs were also demonstrated. Results: An inverse relationship was observed between GAA repeat size and the age of onset. Although some distinguishable clinical features (such as limb ataxia and lower limb areflexia) were found in our patients, 90-95% of them had extensor plantar response and dysarthria. The results showed only one positive diabetes patient and also different effects on eye movement abnormality among our patients. Conclusion: The onset age of symptoms showed a significant inverse correlation with allele size in our patients (P>0.05). Based on comparisons of the clinical data of all patients, clinical presentation of FRDA in Iranian patients did not differ significantly from other FRDA patients previously reported.
doi:10.6091/ibj.1235.2013
PMCID: PMC3892137  PMID: 24375160
Friedreich ataxia (FRDA); Frataxin; Mitochondria
8.  The mitochondrial C16069T polymorphism, not mitochondrial D310 (D-loop) mononucleotide sequence variations, is associated with bladder cancer 
Background
Bladder cancer is a relatively common and potentially life-threatening neoplasm that ranks ninth in terms of worldwide cancer incidence. The aim of this study was to determine deletions and sequence variations in the mitochondrial displacement loop (D-loop) region from the blood specimens and tumoral tissues of patients with bladder cancer, compared to adjacent non-tumoral tissues.
Methods
The DNA from blood, tumoral tissues and adjacent non-tumoral tissues of twenty-six patients with bladder cancer and DNA from blood of 504 healthy controls from different ethnicities were investigated to determine sequence variation in the mitochondrial D-loop region using multiplex polymerase chain reaction (PCR), DNA sequencing and southern blotting analysis.
Results
From a total of 110 variations, 48 were reported as new mutations. No deletions were detected in tumoral tissues, adjacent non-tumoral tissues and blood samples from patients. Although the polymorphisms at loci 16189, 16261 and 16311 were not significantly correlated with bladder cancer, the C16069T variation was significantly present in patient samples compared to control samples (p < 0.05). Interestingly, there was no significant difference (p > 0.05) of C variations, including C7TC6, C8TC6, C9TC6 and C10TC6, in D310 mitochondrial DNA between patients and control samples.
Conclusion
Our study suggests that 16069 mitochondrial DNA D-Loop mutations may play a significant role in the etiology of bladder cancer and facilitate the definition of carcinogenesis-related mutations in human cancer.
doi:10.1186/1475-2867-13-120
PMCID: PMC3930351  PMID: 24308421
Mitochondrial DNA displacement loop; 16069 D-Loop mutation; Urinary bladder neoplasm
9.  Distinguishing the co-ancestries of haplogroup G Y-chromosomes in the populations of Europe and the Caucasus 
European Journal of Human Genetics  2012;20(12):1275-1282.
Haplogroup G, together with J2 clades, has been associated with the spread of agriculture, especially in the European context. However, interpretations based on simple haplogroup frequency clines do not recognize underlying patterns of genetic diversification. Although progress has been recently made in resolving the haplogroup G phylogeny, a comprehensive survey of the geographic distribution patterns of the significant sub-clades of this haplogroup has not been conducted yet. Here we present the haplogroup frequency distribution and STR variation of 16 informative G sub-clades by evaluating 1472 haplogroup G chromosomes belonging to 98 populations ranging from Europe to Pakistan. Although no basal G-M201* chromosomes were detected in our data set, the homeland of this haplogroup has been estimated to be somewhere nearby eastern Anatolia, Armenia or western Iran, the only areas characterized by the co-presence of deep basal branches as well as the occurrence of high sub-haplogroup diversity. The P303 SNP defines the most frequent and widespread G sub-haplogroup. However, its sub-clades have more localized distribution with the U1-defined branch largely restricted to Near/Middle Eastern and the Caucasus, whereas L497 lineages essentially occur in Europe where they likely originated. In contrast, the only U1 representative in Europe is the G-M527 lineage whose distribution pattern is consistent with regions of Greek colonization. No clinal patterns were detected suggesting that the distributions are rather indicative of isolation by distance and demographic complexities.
doi:10.1038/ejhg.2012.86
PMCID: PMC3499744  PMID: 22588667
Y-chromosome; haplogroup G; human evolution; population genetics
11.  Association of fibroblast growth factor (FGF-21) as a biomarker with primary mitochondrial disorders, but not with secondary mitochondrial disorders (Friedreich Ataxia) 
Molecular Biology Reports  2013;40(11):6495-6499.
Mitochondrial respiratory chain deficiencies are a group of more than 100 disorders of adults and children, with highly variable phenotypes. The high prevalence of mitochondrial disorders (MIDs) urges the clinician to diagnose these disorders accurately, which is difficult in the light of highly variable and overlapping phenotypes, transmission patterns and molecular backgrounds. Fibroblast growth factor 21 (FGF-21) is an important endocrine and paracrine regulator of metabolic homeostasis. The FGF-21 transcript is reported to be abundantly expressed in liver, but little is known about the regulation of FGF-21 expression in other tissues. FGF-21 could play a role in the metabolic alterations that are often associated with mitochondrial diseases. The aim of this study was to show the association of the FGF-21 biomarker with human primary MIDs and secondary MIDs in suspected patients in Iran. Serum FGF-21 levels were determined using ELISA in 47 mitochondrial patients, including 32 with primary MIDs, 15 patients with Friedreich ataxia as a secondary MID and 30 control subjects. Serum FGF-21 levels were significantly higher in subjects with the primary MIDs (p < 0.05), compared to subjects without MIDs. However, serum FGF-21 levels did not show significant increase in subjects with FA as a secondary MID. There is an association between increasing concentrations of FGF-21 with mitochondrial diseases, suggesting FGF-21 as a biomarker for diagnosis of primary MIDs in humans. However, this biomarker is not appropriate for the diagnosis of FA.
doi:10.1007/s11033-013-2767-0
PMCID: PMC3824290  PMID: 24078096
Fibroblast growth factor 21 (FGF-21); Respiratory chain deficiency (RCD); Mitochondrial disorders (MIDs); Friedreich ataxia (FA); OXPHOS
12.  Alexander Disease: Report of Two Unrelated Infantile Form Cases, Identified by GFAP Mutation Analysis and Review of Literature; The First Report from Iran 
Iranian Journal of Pediatrics  2013;23(4):481-484.
Background
Alexander disease (AD) is a sporadic leukodystrophy that predominantly affects infants and children and usually results in death within ten years after onset. The infantile form comprises the most of affected individuals. It presents in the first two years of life, typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly and frontal bossing, seizures, pyramidal signs and ataxia. The diagnosis is based on magnetic resonance imaging (MRI) findings and confirmed by GFAP gene molecular testing. GFAP gene encodes glial fibrillary acidic protein, is the only gene in which mutation is currently known to cause AD which is inherited in autosomal dominant manner.
Case Presentation
In this article we report the first two Iranian cases of infantile AD and their clinical, brain MRI and molecular findings. We report two novel mutations too in the GFAP gene that are associated with infantile form of AD.
Conclusion
GFAP gene mutations are a reliable marker for infantile AD diagnosed according to clinical and MRI defined criteria. A genotype-phenotype correlation had been discerned for the two most frequently reported GFAP gene mutations in infantile type of AD (R79 and R239), with the phenotype of the R79 mutations appearing much less severe than that of the R239 mutations. Our findings confirm this theory.
PMCID: PMC3883381  PMID: 24427505
Alexander Disease; Leukoencephalopathy; Alexander's leukodystrophy; Megalencephaly; Macrocephaly
14.  Beta-Thalassemia in Iran: New Insight into the Role of Genetic Admixture and Migration 
The Scientific World Journal  2012;2012:635183.
Iran with an area of 1.648 million km2 is located between the Caspian Sea and the Persian Gulf. The Iranian population consists of multiethnic groups that have been influenced by various invasions and migration throughout history. Studies have revealed the presence of more than 47 different β-globin gene mutations responsible for β-Thalassemia in Iran. This paper is an attempt to study the origin of β-Thalassemia mutations in different parts of Iran. Distribution of β-Thalassemia mutations in Iran shows different patterns in different areas. β-Thalassemia mutations have been a reflection of people and area in correlation with migration and origin of ancestors. We compared the frequencies of β-globin mutations in different regions of Iran with those derived from neighboring countries. The analysis provided evidence of complementary information about the genetic admixture and migration of some mutations, as well as the remarkable genetic classification of the Iranian people and ethnic groups.
doi:10.1100/2012/635183
PMCID: PMC3539370  PMID: 23319887
15.  Establishment and characterization of two human breast carcinoma cell lines by spontaneous immortalization: Discordance between Estrogen, Progesterone and HER2/neu receptors of breast carcinoma tissues with derived cell lines 
Background
Breast cancer is one of the most common cancers among women throughout the world. Therefore, established cell lines are widely used as in vitro experimental models in cancer research.
Methods
Two continuous human breast cell lines, designated MBC1 and MBC2, were successfully established and characterized from invasive ductal breast carcinoma tissues of Malaysian patients. MBC1 and MBC2 have been characterized in terms of morphology analysis, population doubling time, clonogenic formation, wound healing assay, invasion assay, cell cycle, DNA profiling, fluorescence immunocytochemistry, Western blotting and karyotyping.
Results
MBC1 and MBC2 exhibited adherent monolayer epithelial morphology at a passage number of 150. Receptor status of MBC1 and MBC2 show (ER+, PR+, HER2+) and (ER+, PR-, HER2+), respectively. These results are in discordance with histopathological studies of the tumoral tissues, which were triple negative and (ER-, PR-, HER2+) for MBC1 and MBC2, respectively. Both cell lines were capable of growing in soft agar culture, which suggests their metastatic potential. The MBC1 and MBC2 metaphase spreads showed an abnormal karyotype, including hyperdiploidy and complex rearrangements with modes of 52–58 chromosomes per cell.
Conclusions
Loss or gain in secondary properties, deregulation and specific genetic changes possibly conferred receptor changes during the culturing of tumoral cells. Thus, we hypothesize that, among heterogenous tumoral cells, only a small minority of ER+/PR+/HER2+ and ER+/PR-/HER2+ cells with lower energy metabolism might survive and adjust easily to in vitro conditions. These cell lines will pave the way for new perspectives in genetic and biological investigations, drug resistance and chemotherapy studies, and would serve as prototype models in Malaysian breast carcinogenesis investigations.
doi:10.1186/1475-2867-12-43
PMCID: PMC3527183  PMID: 23106969
Malaysian breast cell lines; Estrogen (ER); Progesterone (PR) and HER2/neu; Clonogenic assay; Invasive ductal breast carcinoma tissues; DNA profiling
16.  A Novel Mutation in the Aprataxin (APTX) Gene in an Iranian Individual Suffering Early-Onset Ataxia with Oculomotor Apraxia Type 1(AOA1) Disease 
Iranian Biomedical Journal  2012;16(4):223-225.
Background
Ataxia with oculomotor apraxia type 1 (AOA1) shows early onset with autosomal recessive inheritance and is caused by a mutation in the aprataxin (APTX) gene encoding for the APTX protein.
Methods
In this study, a 7-year-old girl born of a first-cousin consanguineous marriage was described with early-onset progressive ataxia and AOA, with increased cholesterol concentration and decreased albumin concentration in serum. PCR and direct DNA sequencing was performed after DNA extraction.
Results
Sequencing analysis revealed a novel homozygous deletion in c.643 and A>T single nucleotide polymorphism in c.641 in exon 6 of the APTX gene [ENST00000379825].
Conclusion
It seems that this region of exon 6 is probably a hot spot; however, no deletions have been reported in exon 6 yet.
doi:10.6091/ibj.1077.2012
PMCID: PMC3600965  PMID: 23183622
Ataxia oculomotor apraxia 1 (AOA1); aprataxin (APTX); Iranian
17.  Specific-mutational patterns of p53 gene in bladder transitional cell carcinoma among a group of Iraqi patients exposed to war environmental hazards 
BMC Research Notes  2012;5:466.
Background
To unfold specific-mutational patterns in TP53 gene due to exposures to war environmental hazards and to detect the association of TP53 gene alteration with the depth of bladder cancer.
Methods
Twenty-nine bladder carcinomas were analyzed for TP53 alterations. PCR-single strand conformational polymorphism analysis, DNA sequencing and immunohistochemical analysis using monoclonal mouse anti-human p53 antibody (Clone DO-7) were employed.
Results
TP53 gene mutations occurred in 37.9% of the cases while TP53 overexpression occurred in 58.6%. Both of them were associated with deep invasive-tumors. Single mutations were seen in 63.6%, whereas only 27.3% have shown double mutations. Four mutations were frameshifted (30.8%); two of them showed insertion A after codon 244. There was no significant association between TP53 mutations and protein overexpression (P>0.05), while a significant association was observed between TP53 alterations and tumors progression (P ≤ 0.01).
Conclusion
The infrequent TP53mutations, especially insertion A and 196 hotspot codon, may represent the specific-mutational patterns in bladder carcinoma among the Iraqi patients who were exposed to war environmental hazards. TP53 alteration associated with bladder cancer progression should be analyzed by both mutational and protein expression analysis.
doi:10.1186/1756-0500-5-466
PMCID: PMC3439300  PMID: 22929185
Bladder cancer; TP53 alteration; Specific mutation; Immunohistochemistry
18.  Ancient Migratory Events in the Middle East: New Clues from the Y-Chromosome Variation of Modern Iranians 
PLoS ONE  2012;7(7):e41252.
Knowledge of high resolution Y-chromosome haplogroup diversification within Iran provides important geographic context regarding the spread and compartmentalization of male lineages in the Middle East and southwestern Asia. At present, the Iranian population is characterized by an extraordinary mix of different ethnic groups speaking a variety of Indo-Iranian, Semitic and Turkic languages. Despite these features, only few studies have investigated the multiethnic components of the Iranian gene pool. In this survey 938 Iranian male DNAs belonging to 15 ethnic groups from 14 Iranian provinces were analyzed for 84 Y-chromosome biallelic markers and 10 STRs. The results show an autochthonous but non-homogeneous ancient background mainly composed by J2a sub-clades with different external contributions. The phylogeography of the main haplogroups allowed identifying post-glacial and Neolithic expansions toward western Eurasia but also recent movements towards the Iranian region from western Eurasia (R1b-L23), Central Asia (Q-M25), Asia Minor (J2a-M92) and southern Mesopotamia (J1-Page08). In spite of the presence of important geographic barriers (Zagros and Alborz mountain ranges, and the Dasht-e Kavir and Dash-e Lut deserts) which may have limited gene flow, AMOVA analysis revealed that language, in addition to geography, has played an important role in shaping the nowadays Iranian gene pool. Overall, this study provides a portrait of the Y-chromosomal variation in Iran, useful for depicting a more comprehensive history of the peoples of this area as well as for reconstructing ancient migration routes. In addition, our results evidence the important role of the Iranian plateau as source and recipient of gene flow between culturally and genetically distinct populations.
doi:10.1371/journal.pone.0041252
PMCID: PMC3399854  PMID: 22815981
19.  Investigation of the Mitochondrial ATPase 6/8 and tRNALys Genes Mutations in Autism 
Cell Journal (Yakhteh)  2012;14(2):98-101.
Objective:
Autism results from developmental factors that affect many or all functional brain systems. Brain is one of tissues which are crucially in need of adenosine triphosphate (ATP). Autism is noticeably affected by mitochondrial dysfunction which impairs energy metabolism. Considering mutations within ATPase 6, ATPase 8 and tRNALys genes, associated with different neural diseases, and the main role of ATPase 6/8 in energy generation, we decided to investigate mutations on these mtDNA-encoded genes to reveal their roles in autism pathogenesis.
Materials and Methods:
In this experimental study, mutation analysis for the mentioned genes were performed in a cohort of 24 unrelated patients with idiopathic autism by employing amplicon sequencing of mtDNA fragments.
Results:
In this study, 12 patients (50%) showed point mutations that represent a significant correlation between autism and mtDNA variations. Most of the identified substitutions (55.55%) were observed on MT-ATP6, altering some conserved amino acids to other ones which could potentially affect ATPase 6 function. Mutations causing amino acid replacement denote involvement of mtDNA genes, especially ATPase 6 in autism pathogenesis.
Conclusion:
MtDNA mutations in relation with autism could be remarkable to realize an understandable mechanism of pathogenesis in order to achieve therapeutic solutions.
PMCID: PMC3584428  PMID: 23508290
Autism; Mitochondria; Mutation; ATP ase6/8; tRNALys
20.  No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss 
Purpose
Repeated pregnancy loss (RPL) occurs in 1 out of 300 couples, and the cause of about 50% of them remains idiopathic. Mitochondria have an important role in human development through ATP production and their involvement in apoptosis.
Methods
96 RPL and 96 control females were used to investigate the frequency of deletions and point mutations in the displacement loop (D-loop) on mitochondria. Multiplex PCR and DNA sequencing methods were used to detect possible variations in the mitochondrial DNA (mtDNA).
Results
No deletions but a high frequency of point mutations were found in RPL females; among 129 variations observed in RPL, 22 mutations were significant (P < 0.05) and the insertion of C in nucleotide 114 was novel.
Conclusion
High rate of mutations in D-loop of mtDNA was observed in maternal blood, a fact that may have a direct or indirect role in inducing RPL. The results can be used in the assessment of RPL and designing possible treatments for improving assisted reproduction.
doi:10.1007/s10815-010-9435-2
PMCID: PMC2995430  PMID: 20499271
Mitochondrial DNA; Deletion; Mutation; Repeated pregnancy loss
21.  Comprehensive study of mtDNA among Southwest Asian dogs contradicts independent domestication of wolf, but implies dog–wolf hybridization 
Ecology and Evolution  2011;1(3):373-385.
Studies of mitochondrial DNA (mtDNA) diversity indicate explicitly that dogs were domesticated, probably exclusively, in southern East Asia. However, Southwest Asia (SwAsia) has had poor representation and geographical coverage in these studies. Other studies based on archaeological and genome-wide SNP data have suggested an origin of dogs in SwAsia. Hence, it has been suspected that mtDNA evidence for this scenario may have remained undetected. In the first comprehensive investigation of genetic diversity among SwAsian dogs, we analyzed 582 bp of mtDNA for 345 indigenous dogs from across SwAsia, and compared with 1556 dogs across the Old World. We show that 97.4% of SwAsian dogs carry haplotypes belonging to a universal mtDNA gene pool, but that only a subset of this pool, five of the 10 principal haplogroups, is represented in SwAsia. A high frequency of haplogroup B, potentially signifying a local origin, was not paralleled with the high genetic diversity expected for a center of origin. Meanwhile, 2.6% of the SwAsian dogs carried the rare non-universal haplogroup d2. Thus, mtDNA data give no indication that dogs originated in SwAsia through independent domestication of wolf, but dog–wolf hybridization may have formed the local haplogroup d2 within this region. Southern East Asia remains the only region with virtually full extent of genetic variation, strongly indicating it to be the primary and probably sole center of wolf domestication. An origin of dogs in southern East Asia may have been overlooked by other studies due to a substantial lack of samples from this region.
doi:10.1002/ece3.35
PMCID: PMC3287314  PMID: 22393507
Canis familiaris; domestication; fertile crescent; hybridization; mitochondrial DNA
22.  Investigation of tRNALys/Leu and ATPase 6/8 gene mutations in Iranian ataxia telangiectasia patients 
Introduction
Ataxia telangiectasia (AT) is a rare human neurodegenerative autosomal recessive multisystem disease. AT is the result of mutations in the AT-mutated (ATM) gene. ATM protein is required for radiation-induced apoptosis and acts before mitochondrial collapse. The tRNA genes are considered one of the hot spots for mutations causing mitochondrial disorders. Due to the important role of ATM in apoptosis and its effect on the cell cycle it might be possible that it has a central role in mtDNA mutations. On the other hand, the tRNALys/Leu gene and also ATPase6 and ATPase8 genes are important for many mitochondrial diseases and many causative mutations have been reported from these genes.
Material and methods
In the present research, we performed mutation screening for these genes in 20 patients who were diagnosed with ataxia telangiectasia by a PCR sequencing method.
Results
The results showed a significant level of mtDNA variations in AT patients. Among 20 patients in this study, 12 patients (60%) were detected with point mutations, among which 8 mutations (40%) belonged to the MT-ATP6 gene. There was probably a second effect of mtDNA mutations in AT disease and mtDNA plays a main role in establishment of AT.
Conclusions
MtDNA mutations might be responsible for the decline of mitochondrial function in AT patients. Mitochondrial investigation can help to understand the mechanism of damage in AT disease.
doi:10.5114/aoms.2011.23424
PMCID: PMC3258747  PMID: 22295039
ataxia telangiectasia; mitochondrial tRNA gene; ATPase 6/8 genes
23.  Is 8860 variation a rare polymorphism or associated as a secondary effect in HCM disease? 
Introduction
mtDNA defects, both deletions and point mutations, have been associated with hypertrophic cardiomyopathies. The aim of this study was to establish a spectrum for mtDNA mutations in Iranian hypertrophic cardiomyopathy (HCM) patients.
Material and methods
The control group was chosen among the special medical centre visitors who did not have hypertrophic cardiomyopathy or any related heart disease. Hypertrophic cardiomyopathy (HCM) is widely accepted as a pluricausal or multifactorial disease. Because of the linkage between energy metabolism in the mitochondria and cardiac muscle contraction, it is reasonable to assume that mitochondrial abnormalities may be responsible for some forms of HCM. Point mutations and deletions in the two hot spot regions of mtDNA were investigated by PCR and sequencing methods.
Results
Some unreported point mutations have been found in this study but no deletion was detected. Meanwhile some of these point mutations have been investigated among HCM patients for the first time.
Conclusions
A8860G transition was detected in a high proportion, raising the question whether this rare polymorphism is associated as a secondary effect in HCM disease.
doi:10.5114/aoms.2011.22074
PMCID: PMC3258716  PMID: 22291763
hypertrophic cardiomyopathy; mtDNA mutation disease
24.  BAX pro-apoptotic gene alterations in repeated pregnancy loss  
Introduction
Recurrent pregnancy loss (RPL) is a critical medical problem in about 0.5-2% of women. The molecular genetic background for spontaneous abortion is being increasingly understood, and some polymorphisms associated with it have been reported. This study investigates alterations of the Bax gene as a pro-apoptotic gene in women with idiopathic RPL.
Material and methods
The frequency of mutations in the Bax gene of 67 idiopathic RPL women was studied in comparison to a sample of 70 healthy women. The promoter and the entire coding regions (exons 1-7) were amplified using polymerase chain reaction (PCR). The purity of the PCR product was first verified by electrophoresis on a 2% agarose gel. The amplified fragment was then sequenced by automated DNA sequencing.
Results
A statistically significant difference was observed between patients and the control group regarding the frequency of alleles A(-179)G in the Bax promoter region (p= 0.013). Also among patients, G90C and G95A transitions were found in the coding region of exon 1 that change amino acid glutamine (Q) to histidine (H) and arginine (R) to lysine (K), respectively. A statistically significant association was observed between H allele (p = 0.0001) and K allele (p< 0.0001) and the occurrence of RPL.
Conclusions
Our results indicate an association between A(-179)G mutation in the Bax promoter and RPL. Moreover, two polymorphisms, G90C and G95A in exon 1, found among our patients, could be considered as genetic factors making people susceptible to miscarriages. According to our findings, the Bax gene has an important role in pregnancy loss and the variations of this gene could help in the assessment of RPL.
doi:10.5114/aoms.2011.20614
PMCID: PMC3258677  PMID: 22291743
BAX; repeated pregnancy loss; polymorphism; apoptosis
25.  MTHFR polymorphisms and breast cancer risk 
Introduction
Two functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumour cells.
Material and methods
We evaluated these two common polymorphisms and breast cancer risk association in an Iranian sporadic breast cancer population-based case-control study of 294 breast cancer cases and 306 controls using a PCR-RFLP-based assay.
Results
Analyses of affected and controls show that homozygote genotype MTHFR 677CC has the highest frequency in both groups (28.3% in patients and 25.3% in control group). Genotype MTHFR 677CT and genotype MTHFR 1298AC were found to be statistically significant risk factors in our population (odds ratio: 1.6, 95% CI: 1.019-2.513, p = 0.041; and odds ratio: 2.575, 95% CI: 1.590-4.158, p = 0.001 respectively).
Conclusions
We can conclude based on the results of our study that a significant association between breast cancer and C677T and A1298C polymorphism might exist.
doi:10.5114/aoms.2011.20618
PMCID: PMC3258688  PMID: 22291746
MTHFR gene; polymorphism; breast cancer; PCR-RFLP; susceptibility factor

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