Background
Progressive myoclonic epilepsy-4 with or without renal failure (EPM4) is a rare neurological autosomal recessive disorder caused by mutations in SCARB2 gene. In this study, we described ...clinical features and genetic causes of an Iranian family with two affected individuals whose clinical manifestations closely resembled progressive myoclonus epilepsy.
Methods
Our proband was a 38-year-old male with a history of tremor, generalized seizures, action myoclonus, ataxia, and dysarthria that presumptive diagnosed as progressive myoclonus epilepsy. His older sister has the same symptoms. Whole-exome sequencing of DNA sample from the proband was performed. Candidate variant and cosegregation were confirmed by direct sequencing. Functional prediction of candidate variant was performed using appropriate prediction tools.
Results
Genetic analysis identified a homozygous splicing c.423+1 G>A variant in the
SCARB2
gene of the proband and his affected sister. Segregation study identified heterozygous state in four unaffected family members (parents and two children). The variant is localized at the first nucleotide of intron 3 and was not detected among in-house healthy controls. This variant was not reported in genetic databases and predicted to potentially alter the 5’ donor splice site and disease causing using online prediction tools. It was classified as a likely pathogenic variant according to ACMG standards and guidelines.
Conclusion
This is the first report that demonstrates c.423+1 G>A variant in the
SCARB2
gene segregating with the phenotype of EPM4 in a consanguineous Iranian family.
Recent genome-wide association studies reported the association of polymorphic alleles of
PHACTR1
(rs9349379 (G)),
CDDKN2B-AS1
(rs2891168 (G)),
COL4A2
(rs11838776 (A)) and
SOD2
(rs4880 (T)) with ...increased risk of coronary artery disease (CAD). The aim of our study was to assess the association of genetic variants with risk of CAD and its severity and in Southeast Iranian population. This study was examined in 250 CAD-suspected patients (mean age 53.49 ± 6.9 years) and 250 healthy individuals (mean age 52.96 ± 5.9 years). The Taqman SNP genotyping assay was used for genotyping of rs9349379 and rs2891168 variants. Tetra-primer Amplified refractory mutation system-PCR (Tetra-primer ARMS-PCR) was employed for rs11838776 and rs4880. Multivariate logistic regression analyses indicated that the G allele of rs9349379 and rs2891168 were associated with increased risk of CAD. The GG homozygous genotype of rs9349379 and rs2891168 had also been associated with risk of CAD. Additionally, the AG genotype of rs2891168 was associated with CAD. The significance of association of rs2891168 (G, GG, AG) increases with severity of CAD; but the rs9349379 (G, GG) have shown reverse association with severity of CAD. The genetic variants of
COL4A2
(rs11838776) and
SOD2
(rs4880) reflected no association with CAD in Southeast Iranian population. The findings of this study revealed that the
PHACTR1
(rs9349379) and
CDKN2B-AS1
(rs2891168) genetic variants might serve as genetic risk factor in CAD.
Cells with non‐functional poly(ADP‐ribose) polymerase (PARP‐1) show increased levels of sister chromatid exchange, suggesting a hyper recombination phenotype in these cells. To further investigate ...the involvement of PARP‐1 in homologous recombination (HR) we investigated how PARP‐1 affects nuclear HR sites (Rad51 foci) and HR repair of an endonuclease‐induced DNA double‐strand break (DSB). Several proteins involved in HR localise to Rad51 foci and HR‐deficient cells fail to form Rad51 foci in response to DNA damage. Here, we show that PARP‐1 mainly does not localise to Rad51 foci and that Rad51 foci form in PARP‐1–/– cells, also in response to hydroxyurea. Furthermore, we show that homology directed repair following induction of a site‐specific DSB is normal in PARP‐1‐inhibited cells. In contrast, inhibition or loss of PARP‐1 increases spontaneous Rad51 foci formation, confirming a hyper recombination phenotype in these cells. Our data suggest that PARP‐1 controls DNA damage recognised by HR and that it is not involved in executing HR as such.
Background: Oral lichen planus (OLP) is a chronic inflammatory disease that affects 0.1% to 4% of the population. The disease causes lesions in the buccal mucosa, gingiva, and rarely in the palate. ...In this study, the relationship between OLP and TNFα-308 G / A and IFN-γ + 874A / T polymorphisms was investigated.Methods : In this case-control study, a sample of buccal mucosa was taken from 50 healthy individuals and 50 OLP patients referred to Kerman Faculty of Dentistry were included by easy sampling method. Then, the presence of TNFα-308 G / A and IFN-γ + 874A / T polymorphisms in the case and control groups was determined using ARM-PCR technique followed by sequencing.Results : Frequency of allele A and GA of TNF-α (-308G / A) gene was significantly higher than G and GG in OLP patients compared to control group (P-value <0.0001). Also, AA genotype of TNF-α (-308G / A) gene was not present in OLP patients. About IFN-γ + 874A / T polymorphism, the association between T allele and the risk of oral lichen planus was confirmed but it was not statistically significant (p-value: 0.068).Conclusion : There is a strong association between the A allele of TNF-α (-308G / A) and the risk of developing oral lichen planus, although this association between the IFN-γ + 874A / T genotype and Oral lichen planus was also confirmed, but it was not strong enough to be used to predict the likelihood of developing the disease.
Ataxia telangiectasia (AT) is a rare autosomal recessive disorder caused by mutation in the Ataxia telangiectasia mutated (ATM) gene. This disorder is characterized by progressive cerebellar ataxia, ...telangiectasia, immunodeficiency and a predisposition to leukemia/lymphoma. In this study, we investigated a family with a new mutation in ATM, confirmed by molecular genetic test.
Four members of a family including a symptomatic AT patient, his parents and sibling were examined for ATM gene defects at Kerman University Hospital, Kerman, Iran in 2016. DNA was extracted from peripheral leukocytes and the coding regions and exon-intron boundaries of ATM gene were amplified by next-generation sequencing technique. The identified mutation was tested in all members of the family.
Molecular analyses identified a homozygous T to G substitution in c.7308-6 position resulting in a novel acceptor splice site in intron 49 of the ATM gene in the index patient. Parents and sibling of the proband were heterozygous for the same mutation.
The variant c.7308-6T>G is predicted to be pathogenic due to impaired splice site causing exon skipping. This newly found frameshift mutation cosegregated as an autosomal recessive trait as expected for Ataxia telangiectasia syndrome.
Background: β-thalassemia is characterized by reduced synthesis of the hemoglobin beta chain that results in microcytic hypochromic anemia and reduced amounts of hemoglobin A (HbA) on hemoglobin ...analysis. β-thalassemias are caused by mutations in the β-globin gene, inherited in an autosomal recessive manner. Determining molecular defects in couples carrying β-thalassemia is a prerequisite for prenatal diagnosis of the disease. In this regards, database of β-globin gene haplotypes facilitates mutation detection of the gene and helps genetic counselors to reach the goals of β-thalassemia prevention program.Methods: In this cross-sectional study, 255 couples attended genetic counseling between December 2017 and January 2019 in Afzalipour Hospital, Kerman University of Medical Scinces, Kerman, Iran as suspicious of β-thalassemia carriers. Furthermore, they were investigated using amplification refractory mutations system-polymerase chain reaction and restriction fragment length polymorphism methods for mutation screening and haplotype analysis of polymorphic sites in β-globin gene cluster, respectively.Results: We identified 20 different types of β-globin gene mutation in 449 β-thalassemia carriers. Analysis of the pattern of Hind III/Gγ, Hinf I/5′β, Hinc II/3′Ψβ, Rsa I/5′β, AvaII/β and Hind III/Aγ polymorphic sites in 257 alleles of informative families revealed 17 different haplotypes. Haplotype 1 (77.24%) showed strong linkage with the most common mutation IVSI-5 while haplotype 5 (66.67%) was associated with the second frequent mutation IVSII-1.Conclusion: To our knowledge, these β-globin haplotypes are reported for the first time which are different with those found in other parts of Iran. The current haplotypes pattern data makes the counseling of β-thalassemia carriers more straightforward and the process of mutation screening faster and more accurate.
The aim of this study was to identify the genetic basis of a chorioretinal dystrophy with high myopia of unknown origin in a child of a consanguineous marriage. The proband and ten family members of ...Iranian ancestry participated in this study. Linkage analysis was carried out with DNA samples of the proband and her parents by using the Human SNP Array 6.0. Whole exome sequencing (WES) was performed with the patients' DNA. Specific sequence alterations within the homozygous regions identified by whole exome sequencing were verified by Sanger sequencing. Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient. Both parents were heterozygous for this sequence variation. Mutations in COL18A1 are known to cause Knobloch syndrome (KS). Retrospective analysis of clinical records of the patient revealed surgical removal of a meningocele present at birth. The clinical features shown by our patient were typical of KS with the exception of chorioretinal degeneration which is a rare manifestation. This is the first case of KS reported in a family of Iranian ancestry. We identified a novel disease-causing (deletion) mutation in the COL18A1 gene leading to a frameshift and premature stop codon in the last exon. The mutation was not present in SNP databases and was also not found in 192 control individuals. Its localization within the endostatin domain implicates a functional relevance of endostatin in KS. A combined approach of linkage analysis and WES led to a rapid identification of the disease-causing mutation even though the clinical description was not completely clear at the beginning.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The BRCA2 tumour suppressor protein is involved in maintaining genetic stability through its role in homologous recombination (HR), where it mediates RAD51-dependent strand invasion. Here, we show ...that BRCA2-defective cells are not completely impaired in HR by strand invasion although the spontaneous HR rate is 10-fold lower than that in wild-type cells. Furthermore, a DNA double-strand break (DSB) triggers HR repair by strand invasion also in BRCA2-defective cells, but less efficiently. Thus, either the strand invasion pathway(s) in which BRCA2 operates is still operative in the absence of a functional BRCA2, albeit at a reduced frequency, or there is a separate pathway for strand invasion still functional in BRCA2-deficient cells. Consistent with the latter hypothesis, we show that HR events occurring in BRCA2-defective cells differ from HR events in wild-type cells. These data suggest that BRCA2-defective hamster cells are impaired in short tract gene conversion but maintain proficiency in sister chromatid exchange.
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