Carriers Of Other Mutations Research Articles

Shift of N-MYC Oncogene Expression in AML Patients Carrying the FLT3-ITD Mutation.

Mutations in the FLT3 gene not only lead to abnormalities in its structure and function, but also affect the expression of other genes involved in leukemogenesis. This study evaluated the expression of genes that are more characteristic of neuroblastoma but less studied in leukemia. N-MYC oncogene expression was found to be more than 3-fold higher in primary AML patients carrying the FLT3-ITD mutation compared to carriers of other mutations as well as patients with normal karyotype (p = 0.03946). In contrast to the expression of several genes (C-MYC, SPT16, AURKA, AURKB) directly correlated to the allelic load of FLT3-ITD, the expression of the N-MYC oncogene is extremely weakly related or independent of it (p = 0.0405). Monitoring of N-MYC expression in some patients with high FLT3-ITD allelic load receiving therapy showed that a decrease in FLT3-ITD allelic load is not always accompanied by a decrease in N-MYC expression. On the contrary, N-MYC expression may remain elevated during the first three months after therapy, which is additional evidence of the emergence of resistance to therapy and progression of AML.

Environmental and Genetic Variables Influencing Mitochondrial Health and Parkinson's Disease Penetrance.

There is strong evidence that impairment of mitochondrial function plays a key role in the pathogenesis of PD. The two key PD genes related to mitochondrial function are Parkin (PARK2) and PINK1 (PARK6), and also mutations in several other PD genes, including SNCA, LRRK2, DJ1, CHCHD2, and POLG, have been shown to induce mitochondrial stress. Many mutations are clearly pathogenic in some patients while carriers of other mutations either do not develop the disease or show a delayed onset, a phenomenon known as reduced penetrance. Indeed, for several mutations in autosomal dominant PD genes, penetrance is markedly reduced, whereas heterozygous carriers of recessive mutations may predispose to PD in a dominant manner, although with highly reduced penetrance, if additional disease modifiers are present. The identification and validation of such modifiers leading to reduced penetrance or increased susceptibility in the case of heterozygous carriers of recessive mutations are relevant for a better understanding of mechanisms contributing to disease onset. We discuss genetic and environmental factors as well as mitochondrial DNA alterations and protein-protein interactions, all involved in mitochondrial function, as potential causes to modify penetrance of mutations in dominant PD genes and to determine manifestation of heterozygous mutations in recessive PD genes.

Variations in the 3'UTR of the CYP21A2 Gene in Heterozygous Females with Hyperandrogenaemia.

Heterozygosity for CYP21A2 mutations in females is possibly related to increased risk of developing clinical hyperandrogenism. The present study was designed to seek evidence on the phenotype-genotype correlation in female children, adolescents, and women with CYP21A2 mutations and variants in the 3′UTR region of the gene. Sixty-six patients out of the 169 were identified as carriers of CYP21A2 mutations. Higher values of stimulated 17 hydroxyprogesterone (17-OHP) levels were found in the carriers of the p.Val281Leu mutation compared to the carriers of other mutations (mean: 24.7 nmol/l versus 15.6 nmol/l). The haplotype of the ∗52C>T, ∗440C>T, and ∗443T>C in the 3′UTR was identical in all heterozygous patients with p.Val281Leu and the haplotype of the ∗12C>T and ∗52C>T was identical in all heterozygous patients with the p.Gln318∗. In conclusion, hyperandrogenaemic females are likely to bear heterozygous CYP21A2 mutations. Carriers of the mild p.Val281Leu mutation are at higher risk of developing hyperandrogenism than the carriers of more severe mutations. The identification of variants in the 3′UTR of CYP21A2 in combination with the heterozygous mutation may be associated with the mild form of nonclassic congenital adrenal hyperplasia and reveal the importance of analyzing the CYP21A2 untranslated regions for the appropriate management of this category of patients.

Comprehensive analysis of desmosomal gene mutations in Han Chinese patients with arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiomyopathy that primarily involves the right ventricle. Mutations in desmosomal genes have been associated with ARVC. But its prevalence and spectrum are much less defined in the Chinese population, especially Han Chinese, a majority ethnic group in China; also the genotype-phenotype correlation regarding left ventricular involvement is still poorly understood. The aim of this study was to elucidate the genotype in Han Chinese patients with ARVC and the phenotype regarding cardiac left ventricle involvement in mutation carriers of ARVC. 48 Han Chinese patients were recruited into the present study based on the Original International Task Force Criteria of ARVC. Clinical data were reassessed according to the modified criteria published in 2010. A total of 36 subjects were diagnosed with ARVC; 12 patients were diagnosed with suspected ARVC. Five desmosomal genes (PKP2, DSG2, DSP, DSC2 and JUP) were sequenced directly from genomic DNA. Among the 36 patients, 21 mutations, 12 of which novel, were discovered in 19 individuals (19 of 36, 53%). The distribution of the mutations was 25% in PKP2, 14% in DSP, 11% in DSG2, 6% in JUP, and 3% in DSC2. Multiple mutations were identified in 2 subjects (2 of 36, 6%); both had digenic heterozygosity. Eight mutations, of which six were novel, were located in highly conserved regions. Seven mutations introduced a stop codon prematurely, which would result in premature termination of the protein synthesis. Two-dimensional echocardiography showed that LDVd and LDVs parameters were significantly larger in nonsense mutation carriers than in carriers of other mutations. In this comprehensive desmosome genetic analysis, 21 mutations were identified in five desmosomal genes in a group of 48 local Han Chinese subjects with ARVC, 12 of which were novel. PKP2 mutations were the most common variants. Left ventricular involvement could be a sign that the patient is a carrier of a nonsense cardiac desmosomal gene mutation.

Descriptive profile of β-thalassemia mutations in West Bengal population: a hospital-based study

The present study was based in a hospital at which 660 individuals have been screened for thalassemia in the past 4 years. The main purposes of the study were to identify different types of beta mutations prevailing among these patients, and to establish a genotype-phenotypic correlation. Complete blood count, high-performance liquid chromatography, and amplification refractory mutation system-based polymerase chain reaction were performed on peripheral blood samples to detect beta mutations. Of the 660 subjects studied, 380 (57.6 %) were male and 280 (42.4 %) were female. These included 258 (39.09 %) normal individuals, 176 (26.67 %) β-thalassemia carriers, 44 (6.67 %) β-thalassemia major, 6 (0.91 %) cases of sickle β-thalassemia, 6 (0.91 %) carriers of sickle cell anemia, 102 (15.45 %) Hb Eβ-thalassemia, 42 (6.36 %) HbE carriers, 16 (2.42 %) HbE homozygous, and 10 (1.52 %) carriers of other mutations. Genotypic study of beta mutations revealed the prevalence of IVS1-5 mutation among the studied beta carriers to be 46.6 %, and codon 26 (G>A) mutation to be 31.54 %. Other prevailing mutations among the screened individuals include codon 30 (7.53 %), codon 15 (5.01 %), codon 41/42 (3.58 %), and codon 8/9 (1.07 %). Genotype-phenotype correlation revealed that the phenotype of the above-mentioned mutations is associated with mild, moderate, and severe forms of thalassemia.

Familial Mediterranean Fever: A Retrospective Clinical and Molecular Study in the East of Anatolia Region of Turkey

Familial Mediterranean Fever (FMF) is an autoinflammatory periodic disorder. We aim to identify the distribution and the frequency of the Mediterranean Fever (MEFV) gene mutations in the east of Anatolia in Turkey and perform a genotype/phenotype correlation in the patients’ cohort. The study was carried out on 415 clinically diagnosed Turkish FMF patients and 103 healthy controls. The tested individuals were screened for the most common twelve MEFV mutations. The most important features were the predominance of the M694V and E148Q mutations in patient group and the earlier of onset of the disease in M694V mutation carriers compared with the carriers of other mutations (P=0.00). We discuss the high frequency of E148Q mutations in patient group compared with controls, genetic counseling in intermarriage families and the variations in mutation frequency according to regions of Turkey.

Hyperandrogenism in carriers of CYP21 mutations: the role of genotype

It has been hypothesized that carriers of CYP21 mutations are at increased risk of developing clinically evident hyperandrogenism. In the present study, we assessed the risk for symptoms of androgen excess in carriers of CYP21 gene mutations and the effect of different mutations on phenotype. All subjects underwent clinical evaluation, ACTH stimulation testing, and molecular analysis of the CYP21 gene. One hundred and eighty-seven subjects were included in the study. Five groups were defined according to genotype: A, 38 patients with classical-congenital adrenal hyperplasia (CAH); B, 16 patients with non classical CAH; C, 66 family member carriers; D, 24 children and adolescents with symptoms suggestive of hyperandrogenism who were found to be heterozygous and E, 43 subjects with androgen excess symptoms who had normal genotype. Cortisol and 17-hydroxyprogesterone (17OHP) were measured basally and 60 min after ACTH stimulation. Analysis of seven common mutations of the CYP21 gene, which collectively cover 95% of the mutations in the Israeli population, was performed. The hormonal results were correlated with the genotype. The symptomatic carriers had a significantly higher rate of the mild mutation V281L compared with the family members (58% vs. 22%) and significantly higher levels of ACTH-stimulated 17OHP (mean 37.2 and 21 nmol/l, respectively; P = 0.025). Higher values of peak 17OHP levels were found in the carriers of the V281L mutation compared with carriers of other mutations (P = 0.025). Stimulated 17OHP levels were significantly higher in carriers compared with normal genotype subjects (P < 0.0001). Our findings are the first to show that there is increased risk of androgen excess in carriers of CYP21 mutations and that the risk is related to genotype. Carriers for the mild, V281L mutation, are at higher risk of symptoms of androgen excess than carriers of the severe mutations. It appears that the variable phenotypes can be at least partially attributed to the degree of impairment of enzyme activity in different mutations. The severe consequences of hyperandrogenism in some of the carrier subjects indicate the need for long-term follow-up in these patients.