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1.
E. A. Bliznetz V. A. Galkina G. N. Matyushchenko A. G. Kisina T. G. Markova A. V. Polyakov 《Russian Journal of Genetics》2012,48(1):101-112
Molecular testing for mutations in the connexin 26 gene (GJB2) is a routine diagnostic analysis for subjects with hereditary hearing loss worldwide. However, till now there is no assessment
of the diagnostic significance of this analysis for Russian patients, and there are difficulties in interpretation of the
results of DNA diagnostics. In the present study, a sample of 705 patients with nonsyndromic autosomal recessive hearing loss
from different regions of Russian Federation was investigated. A portion of DFNB1 hearing loss caused by mutations in the
GJB2 gene among the sample was 46%. The frequency of DFNB1 hearing loss was 1:1000, that is, the frequency of isolated autosomal
recessive hearing loss 1:500 in the population. It was found that each sixteenth individual in Russia is a heterozygous carrier
of the mutation in the GJB2 gene. Totally, 20 pathological GJB2 alleles were detected; among them, a c.35delG mutation with the allelic frequency 81% prevails. Six most frequent mutations
(c.35delG, c.313_326del14, c.23+1G>A (IVS1+1G>A), c.235delC, c.167delT, and p.Glu120del), which account for 95% of pathological
GJB2 alleles, were detected. Mutations previously not described in the GJB2 gene (c.129delG, p.Gly200Arg, and c[Arg127His, Gly160Ser]) were found. An optimal algorithm of molecular testing of Russian
patients which detects up to 100% of mutations in the GJB2 gene was suggested. Data concerning a clinical significance of p.Met34Thr and p.Val37Ile mutations are confirmed in the study.
Eight polymorphic substitutions in the GJB2 gene which do not have clinical significance (p.Val27Ile, c.*3C>A, p.Val153Ile, p.Gly160Ser, c.Arg127His, p.Glu114Gly (c.341A>G),
c.-45C>A, and p.Ala149Thr) were also detected. 相似文献
2.
Mutations in the MECP2 gene are known to cause Rett syndrome (RTT)—a neurodevelopmental disorder, one of the most common causes of intellectual disability in females, with an incidence of 1 in 10000–15000. We have investigated exons 3 and 4 of the MECP2 gene, that coding MBD and TRD domains of the MeCP2 protein, in 21 RTT patients from Ukraine by PCR-DGGE analysis followed by Sanger sequencing of PCR fragments with abnormal migration profiles. In 13 of 21 (61.9%) patients 7 different mutations were identified one nonsense mutation—c. NC_000023.11:g.154031326G>A (MECP2:c.502C>T) and 4 missense mutation NC_000023.11:g.154031409G>T (MECP2:c.419C>T), NC_000023.11:g.154031355G>A (MECP2:c.473C>T), NC_000023.11:g.154031354A>C (MECP2:c.472A>C), NC_000023.11:g.154031431G>A (MECP2:c.397C>T) located in exon 4, a rare RTT-causing splice site mutation NC_000023.10:g.153296903T>G (MECP2:c.378-2A>C) in intron 3 and deletion NC_000023.10:g.1532 96079_153296122del44 in exon 4. The novel mutation MECP2:c.472A>C identified in our study in patients withclassic RTT phenotype leds to T158P substitution. It is one more confirmation of crucial role that 158 codon in MECP2 protein function. 相似文献
3.
Oculocutaneous Albinism Type 3 (OCA3): Analysis of Two Novel Mutations in <Emphasis Type="Italic">TYRP1</Emphasis> Gene in Two Chinese Patients 总被引:1,自引:0,他引:1
Oculocutaneous albinism (OCA) is a genetic disease characterized by the reduction or deficiency of melanin in eyes, skin,
and hair. OCA exhibits genetic heterogeneity. Presently, there are four types of OCA named as OCA1, OCA2, OCA3, and OCA4.
OCA3 is more common in African born blacks but rarely found in other ethnic populations. Our recent genotyping of patients
with OCA of Chinese descent has identified two patients who were not OCA1, OCA2, or OCA4. Examination and analysis of the
TYRP1 gene identified them to be having OCA3. PCR and DNA sequencing analysis found that the mutant TYPR1 alleles were present in each of the two patients, c.780-791del/c.1067G>A (p.R356Q) and c.625G>TT (p.G209LfsX1)/c.643C>T (p.H215Y).
The c.780-791del and c.1067G>A mutations have been already reported. However, the c.625G>TT and c.643C>T mutations have not
been previously reported and were found to be maternal and paternal mutations, respectively. Moreover, population screening
and bioinformatic analysis were carried out to determine the effects of these two mutations which revealed that both the mutation
were pathogenic. Based on the similar mild phenotype of these two patients, we suggest that OCA3 might be prevalent within
the Chinese population. 相似文献
4.
Jiajie Sun Qijiang Jin Chunlei Zhang Xingtang Fang Chuanwen Gu Chuzhao Lei Juqiang Wang Hong Chen 《Molecular biology reports》2011,38(5):3153-3160
Transgenically expressed Syndecan-1 was found in the hypothalamic nuclei that control energy balance, and was associated with
maturity-onset obesity, while ghrelin has been shown to play important roles in the control of food intake, gastric acid secretion,
energy homeostasis, and glucose and lipid metabolism. However, the roles of genetic variations of Syndecan-1 and ghrelin on
growth trait have few been reported in cattle. Herein, five Chinese cattle breeds were analyzed by PCR–SSCP and DNA sequencing
methods. The bovine ghrelin gene showed eleven SNPs g.[267G>A, 271G>A, 290C>T, 326A>G, 327T>C, 420C>A, 569A>G, 945C>T, 993C>T,
4491A>G, 4644G>A] and three SNPs g.[420C>A, 569 A>G, 945C>T] were firstly detected in cattle. The bovine Syndecan-1 gene showed
two SNPs. One SNP showed a transition C>G at position 21514, resulting in a synonymous mutation p.G(GGC)169G(GGG) and another
showed a transversion C>T at position 22591, resulting in a synonymous mutation p.D(GAC)283D(GAT). In ghrelin gene, no significant
associations were revealed between any variant sites and body weight, average daily gain, body sizes for different growth
periods (6, 12, 18, and 24 months old), as well as for the milk yield at 305 days, milk protein rate and milk fat percentage.
However, the polymorphism of Syndecan-1 gene was significantly associated with bovine birth weight and body length. Hence,
we first suggested that Syndecan-1 gene could be regarded as molecular marker for superior birth weight and body length. 相似文献
5.
Schnitzler F Brand S Staudinger T Pfennig S Hofbauer K Seiderer J Tillack C Göke B Ochsenkühn T Lohse P 《Immunogenetics》2006,58(2-3):99-106
We performed a limited DNA sequence analysis of the CARD15 gene in 89 patients with Crohn’s disease (CD), 19 patients with ulcerative colitis (UC), and three patients with indeterminate colitis (IC), who were heterozygous carriers of one of the common CARD15 mutations [c.2104C>T (p.R702W), c.2722G>C (p.G908R), or c.3019_3020insC (p.Leu1007fsX1008)], the c.2462+10A>C variant, or of a new amino acid substitution in the 3′-end of exon 4. CARD15 exons 4, 5, 6, 8, and 11 were amplified by PCR and completely sequenced, thereby theoretically covering 73.9% of the described CARD15 variants and 96.6% of the mutated alleles. Using this approach, eight novel amino acid substitutions [c.1171C>T (p.R391C), c.1387C>G (p.P463A), c.2138G>A (p.R713H), c.2278C>T (p.R760C), c.2368C>T (p.R790W), c.2371C>T (p.R791W), c.2475C>G (p.N825K), and c.2546C>T (p.A849V)] were detected in six CD and two IC patients, and one UC patient. A severe disease phenotype was observed especially in patients who are compound-heterozygous for a common and a novel CARD15 mutation.Schnitzler and Brand contributed equally 相似文献
6.
Bing Han Wei Liu Chun-Lin Zuo Hui Zhu Lu Li Chao Xu Xia-Juan Wang Bing-Li Liu Chun-Ming Pan Ying-Li Lu Wan-Ling Wu Ming-Dao Chen Huai-Dong Song Kai-Xiang Cheng Jie Qiao 《Gene》2013
Mutations of CYP17A1 gene could cause complete or partial, combined or isolated 17α-hydroxylase/17,20-lyase enzyme deficiencies (17OHD). We intended to investigate the CYP17A1 mutation in five unrelated patients and analyze its possible influence on phenotype of an atypical 17OHD patient presented with micropenis, hypertension and intermittent hypokalemia. Steroid hormones were assayed in these patients. A novel missense mutation (c.1169C>G, p. Thr390Arg) located in exon 7 was detected in one of the patients. Homozygous c. 985_987delinsAA, p. Tyr329fs mutation was found in two patients, while compound heterozygous mutations (c. 985_987delinsAA, p. Tyr329fs/c. 932–939 del, p. Val311fs and c. 287G>A, p. Arg96Gln/c. 985_987delinsAA, p. Tyr329fs) were found in two other patients, respectively. Then, steric model analysis of CYP17A1 showed that the novel mutation T390R changed the local structure as well as the electrostatic potential of the nearby beta sheet. Finally, site-directed mutagenesis and in vitro expression were used to analyze the activity of novel mutant CYP17A1. It indicated the T390R mutant retained part of enzyme activity, which was consistent to the clinical features. In conclusion, we identified a novel missense mutation of CYP17A1 gene from a patient with micropenis, hypertension and intermittent hypokalemia, which varied from other four patients. It also expanded our understanding of genotype–phenotype correlation of the disease. 相似文献
7.
Raquel L.F. Teixeira Floriano P. Silva Aline R. Silveira Pedro H. Cabello Leila Mendonça-Lima Marcelo F. Rabahi Afrânio L. Kritski Fernanda C.Q. Mello Philip N. Suffys Antonio B. de Miranda Adalberto R. Santos 《Mutation research》2010,683(1-2):43-49
N-Acetyltransferase 2 (NAT2) metabolizes a variety of xenobiotics that includes many drugs, chemicals and carcinogens. This enzyme is genetically variable in human populations and polymorphisms in the NAT2 gene have been associated with drug toxicity and efficacy as well as cancer susceptibility. Here, we have focused on the identification of NAT2 variants in Brazilian individuals from two different regions, Rio de Janeiro and Goiás, by direct sequencing, and on the characterization of new haplotypes after cloning and re-sequencing. Upon analysis of DNA samples from 404 individuals, six new SNPs (c.29T>C, c.152G>T, c.203G>A, c.228C>T, c.458C>T and c.600A>G) and seven new NAT2 alleles were identified with different frequencies in Rio de Janeiro and Goiás. All new SNPs were found as singletons (observed only once in 808 genes) and were confirmed by three independent technical replicates. Molecular modeling and structural analysis suggested that p.Gly51Val variant may have an important effect on substrate recognition by NAT2. We also observed that amino acid change p.Cys68Tyr would affect acetylating activity due to the resulting geometric restrictions and incompatibility of the functional group in the Tyr side chain with the admitted chemical mechanism for catalysis by NATs. Moreover, other variants, such like p.Thr153Ile, p.Thr193Met, p.Pro228Leu and p.Val280Met, may lead to the presence of hydrophobic residues on NAT2 surface involved in protein aggregation and/or targeted degradation. Finally, the new alleles NAT2*6H and NAT2*5N, which showed the highest frequency in the Brazilian populations considered in this study, may code for a slow activity. Functional studies are needed to clarify the mechanisms by which new SNPs interfere with acetylation. 相似文献
8.
I. M. Khidiyatova I. A. Skachkova E. V. Saifullina R. V. Magzhanov O. A. Schagina R. A. Zinchenko A. N. Petrin E. K. Khusnutdinova 《Russian Journal of Genetics》2013,49(7):771-777
Hereditary motor and sensory neuropathy (HMSN) type IIA is caused by mutations in the mitofusin type-2 (MFN2) gene and represents one of the most common axonal forms of HMSN. We determined the spectrum and frequency of MFN2 gene mutations in patients from the Bashkortostan Republic (BR). Four different mutations were revealed in 5 out of 170 unrelated patients, i.e., c.2113G>A (p.Val705Ile) (1.2% among all types of HMSN in the total sample of patients and 2% among patients of Tatar ethnicity). This mutation was described previously; c.775C>T (p.Arg259Cys) (0.6%, in the total sample of patients and 2% among the patients of Tatar ethnicity); c.776G>A (p.Arg259His) (0.6% in the total sample of patients and 1.5% among the patients of Russians ethnicity); and c.2171T>C (p.Leu724Pro) (1.2% in the total sample of patients and 7.4% among the patients of Bashkirs ethnicity). These are new mutations that were not observed among healthy family members and in control samples of healthy subjects. Five identified nucleotide substitutions represent single nucleotide polymorphisms of the gene, including c.892G>A (p.Gly298Arg), c.957C>T (Gly319Gly), and c1039-222t>c, which were described previously, while c.175+28c>t and c.2204+15t>c represent new nucleotide substitutions in the intron regions of the gene. 相似文献
9.
Myocilin (MYOC) gene is expressed in many ocular tissues, including the trabecular meshwork, a specialized eye tissue essential
in regulating intraocular pressure. Many mutations in MYOC have been detected in primary open-angle glaucoma (POAG). We investigated whether MYOC mutations contributed to the susceptibility to POAG in a Chinese family. In a four-generation family affected with POAG,
ocular examinations were performed on all members of the pedigree to determine their disease status, and 200 healthy matched
controls were recruited. PCR–restriction fragment length polymorphism (PCR–RFLP) analysis and DNA sequencing were used to
determine the mutations in MYOC. Biological software was used to analyze the corresponding proteins for missense mutations. The c.1084G>− was found, for
the first time, in four of eight affected patients and in one of two patients with suspected POAG. The c.1006C>T mutation
was found in two of eight patients and in one of 19 subjects who were asymptomatic. The frequencies of c.1084G>− and c.1006C>T
were 12.82 and 7.69%, respectively, in patients but not in the controls. These data provide additional clues to the pathogenesis
of POAG because no other mutation was detected in either group. Our results suggest that the MYOC c.1084G>− may contribute to a genetic predisposition to POAG. 相似文献
10.
Polycystic kidney disease (PKD) is a systemic disorder which adds majority of renal patients to end stage renal disease. Autosomal dominant polycystic kidney disease (ADPKD) is more prevalent and leading cause of dialysis and kidney transplant. Linkage analysis revealed some closely linked loci, two of which are identified as PKD1, PKD2 and an unidentified locus to ADPKD. This study was performed using PCR and automated DNA sequencing in 84 cases and 80 controls to test potential candidature of PKD2 as underlying cause of PKD by in silico and statistical analyses. Two associated symptoms, hypertension (19%) and liver cyst (31%) have major contribution to PKD. Gender-based analysis revealed that familial female patients (27%) and familial male patients (33%) are more hypertensive. Liver cyst, the second major contributing symptom presented by large percentage of sporadic males (46%). Genetic screening of all 15 exons of PKD2 revealed eight pathogenic (c.854_854delG, c.915C>A, c.973C>T, c.1050_1050delC, c.1604_1604delT, c.1790T>C, c.2182_2183delAG, c.2224C>T) and eight likely pathogenic (g.11732A>G, c.646T>C, c.1354A>G, g.39212G>C, c.1789C>A, c.1849C>A, c.2164G>T, c.2494A>G) DNA sequence variants. In our study, 27.38% (23/84) cases shown pathogenic / likely pathogenic variants in PKD2 gene. Some regions of PKD2 prone for genetic variation suggested to be linked with disease pathogenesis. This noticeable hot spot regions hold higher frequency (50%) of pathogenic / likely pathogenic genetic variants constituting single nucleotide variants than large deletion and insertion that actually represents only 41.08% of coding sequence of PKD2. Statistically significant association for IVS3-22AA genotype was observed with PKD, while association of IVS4+62C>T was found insignificant. 相似文献
11.
P. L. C. Walker Adele Corrigan Monica Arenas Emilia Escuredo Lynette Fairbanks Anthony Marinaki 《Nucleosides, nucleotides & nucleic acids》2013,32(12):1243-1247
Purine nucleoside phosphorylase (PNPase) deficiency is an autosomal recessive disorder affecting purine degradation and salvage pathways. Clinically, patients typically present with severe immunodeficiency, neurological dysfunction, and autoimmunity. Biochemically, PNPase deficiency may be suspected in the presence of hypouricemia. We report biochemical and genetic data on a cohort of seven patients from six families identified as PNPase deficient. In all patients, inosine, deoxyinosine, guanosine, and deoxyguanosine were elevated in urine, and mutation analysis revealed seven different mutations of which three were novel. The mutation c.770A>G resulted in the substitution p.His257Arg. A second novel mutation c.257A>G (p.His86Arg) was identified in two siblings and a third novel mutation, c.199C>T (p.Arg67X), was found in a 2-year-old female with delayed motor milestones and recurrent respiratory infections. A review of the literature identified 67 cases of PNPase deficiency from 49 families, including the cases from our own laboratory. PNPase deficiency was confirmed in 30 patients by genotyping and 24 disease causing mutations, including the three novel mutations described in this paper, have been reported to date. In five of the seven patients, plasma uric acid was found to be within the pediatric normal range, suggesting that PNPase deficiency should not be ruled out in the absence of hypouricemia. 相似文献
12.
Mike Gerards Bianca van den Bosch Chantal Calis Kees Schoonderwoerd Klaartje van Engelen Marina Tijssen René de Coo Anneke van der Kooi Hubert Smeets 《Mitochondrion》2010,10(5):510-515
Hereditary ataxias are genetic disorders characterized by uncoordinated gait and often poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. Many ataxias are autosomal dominant, but autosomal recessive (AR) disease occurs as well. Homozygosity mapping in a consanguineous family with three affected children with progressive cerebellar ataxia and atrophy revealed a candidate locus on chromosome 1, containing the CABC1/ADCK3 (the chaperone, ABC1 activity of bc1 complex homologue) gene. CABC1/ADCK3 is the homologue of the yeast Coq8 gene, which is involved in the ubiquinone biosynthesis pathway. Mutation analysis of this gene showed a homozygous nonsense mutation (c.1042C > T, p.R348X). Eight additional patients with AR cerebellar ataxia and atrophy were screened for mutations in the CABC1/ADCK3 gene. One patient was compound heterozygous for the same c.1042C > T mutation and a second nonsense mutation (c.1136T > A, p.L379X). Both mutations created a premature stop codon, triggering nonsense mediated mRNA decay as the pathogenic mechanism. We found no evidence of a Dutch founder for the c.1042C > T mutation in AR ataxia. We report here the first nonsense mutations in CABC1 that most likely lead to complete absence of a functional CABC1 protein. Our results indicate that CABC1 is an important candidate for mutation analysis in progressive cerebellar ataxia and atrophy on MRI to identify those patients, who may benefit from CoQ10 treatment. 相似文献
13.
A. E. Motushchuk T. Yu. Komarova N. A. Grudinina V. V. Rakhmanov M. Yu. Mandelshtam Yu. S. Astakhov V. B. Vasilyev 《Russian Journal of Genetics》2009,45(12):1467-1474
In 32 unrelated patients with primary congenital glaucoma (PCG), a search for mutations in the myocilin (MYOC), cytochrome P450B1 (CYP1B1), and WDR36 genes was performed. The Q368X mutation in myocilin gene, typical of the patients with adult-onset primary open-angle glaucoma
(POAG), was not detected in the PCG patients. Screening of the CYP1B1 introns 2 and 3 for the presence of mutations in PCG patients revealed only six DNA polymorphisms, including IVS1-12ntT>C
(g.3793 T>C), A119S (g.4160 G>T; GCC>TCC), G188G (g.4369 C>A; GGC>GGA), L432V (g.8131 C>G; CTG>GTG), D449D (g.8184 C>T; GAC>GAT),
and N453S (g.8195 A>G; AAC>AGC) (nucleotide numbering is given in accordance with the GenBank sequence U56438). In the groups
of PCG patients and donors without eye diseases, the frequencies of these variants were not statistically significantly different,
pointing to the neutrality of these polymorphisms. Furthermore, the CYP1B1 polymorphism L432V, considered to be associated with POAG in some world populations, was not associated with this disease
in the patients from St. Petersburg. DNA collections obtained from the POAG and PCG patients and from the control group were
tested for the carriage of the worldwide distributed mutations of the WRD36 gene, D658G, R529Q, A449T, and N355S. D658G variant was found with equally low frequencies in the groups of POAG and PCG
patients, as well as in the control group. Mutations A449T and R529Q were found only once each, while mutation N355S was not
detected in any of the groups examined. Our results indicate that the WDR36 variants make no substantial contribution to the development of POAG and PCG in the patients from St. Petersburg and represent
normal DNA polymorphism. It is likely that in most of the PCG patients from the population examined the disease is not associated
with the CYP1B1 gene defects. 相似文献
14.
Pauline Gaignard Jérôme Fagart Natalia Niemir Jean-Philippe Puech Emilie Azouguene Jeanne Dussau Catherine Caillaud 《Gene》2013
Sandhoff disease (SD) is an autosomal recessive lysosomal storage disease caused by mutations in the HEXB gene encoding the beta subunit of hexosaminidases A and B, two enzymes involved in GM2 ganglioside degradation. Eleven French Sandhoff patients with infantile or juvenile forms of the disease were completely characterized using sequencing of the HEXB gene. A specific procedure was developed to facilitate the detection of the common 5′-end 16 kb deletion which was frequent (36% of the alleles) in our study. Eleven other disease-causing mutations were found, among which four have previously been reported (c.850C>T, c.793T>G, c.115del and c.800_817del). Seven mutations were completely novel and were analyzed using molecular modelling. Two deletions (c.176del and c.1058_1060del), a duplication (c.1485_1487dup) and a nonsense mutation (c.552T>G) were predicted to strongly alter the enzyme spatial organization. The splice mutation c.558+5G>A affecting the intron 4 consensus splice site led to a skipping of exon 4 and to a truncated protein (p.191X). Two missense mutations were found among the patients studied. The c.448A>C mutation was probably a severe mutation as it was present in association with the known c.793T>G in an infantile form of Sandhoff disease and as it significantly modified the N-terminal domain structure of the protein. The c.171G>C mutation resulting in a p.W57C amino acid substitution in the N-terminal region is probably less drastic than the other abnormalities as it was present in a juvenile patient in association with the c.176del. Finally, this study reports a rapid detection of the Sandhoff disease-causing alleles facilitating genetic counselling and prenatal diagnosis in at-risk families. 相似文献
15.
Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary renal cystic disease involving multiple organs, mainly the kidney and liver. Parents who had an affected child with ARPKD are in strong demand for an early and reliable prenatal diagnosis to guide the future pregnancies. Here we provide an example of prenatal diagnosis of an ARPKD family where traditional antenatal ultrasound examinations failed to produce conclusive results till 26th week of gestation. Compound heterozygous mutations c.274C>T (p.Arg92Trp) and c.9059T>C (p.Leu3020Pro) were identified using targeted exome sequencing in the patient and confirmed by Sanger sequencing. Further, the mother and father were revealed to be carriers of heterozygous c.274C>T and c.9059T>C mutations, respectively. Molecular prenatal diagnosis was performed for the current pregnancy by direct sequencing plus linkage analysis. Two mutations identified in the patient were both found in the fetus. In conclusion, compound heterozygous PKHD1 mutations were elucidated to be the molecular basis of the patient with ARPKD. The newly identified c.9059T>C mutation in the patient expands mutation spectrum in PKHD1 gene. For those ultrasound failed to provide clear diagnosis, we propose the new prenatal diagnosis procedure: first, screening underlying mutations in PKHD1 gene in the proband by targeted exome sequencing; then detecting causative mutations by direct sequencing in the fetal DNA and confirming results by linkage analysis. 相似文献
16.
Katarzyna Kiwerska Małgorzata Rydzanicz Andrzej Kram Martyna Pastok Agata Antkowiak Wenancjusz Domagała Krzysztof Szyfter 《Molecular biology reports》2010,37(1):325-332
CDKN2A gene belongs to the genes involved in cell cycle regulation. When is absent or inactivated by mutation or promoter hypermethylation
a cell may undertake an uncontrolled proliferation. Inactivation of CDKN2A gene is observed in many human malignancies, including larynx cancer. In this study we investigated mutations in exon 1 and
exon 2 of CDKN2A gene in a large group of 390 laryngeal cancers. We found 40 different alterations (17%) and nearly half of them was not described
previously. Out of these alterations two transversions in codon 108: c.322G>C (Asp108His) and c.322G>T (Asp108Tyr) as well
as a G>A transition in codon 110 (Trp110X) were found more frequently (altogether: 7 cases in codon 108 and 10 cases in codon
110). This result, concerning the location of these codons in the ankyrin repeat structures, may suggest that these two codons
may be critical hot-spots in larynx carcinogenesis. 相似文献
17.
Lili Hao Shanshan Li Duan Ma Shiyu Chen Bowen Zhang Deyong Xiao Jin Zhang Nan Jiang Shayi Jiang Jing Ma 《Journal of cellular and molecular medicine》2019,23(6):4454-4463
Hereditary spherocytosis (HS) is the most common inherited haemolytic anaemia disorder. ANK1 mutations account for most HS cases, but pathogenicity analysis and functional research have not been widely performed for these mutations. In this study, in order to confirm diagnosis, gene mutation was screened in two unrelated Chinese families with HS by a next‐generation sequencing (NGS) panel and then confirmed by Sanger sequencing. Two novel heterozygous mutations (c.C841T, p.R281X and c.T290G, p.L97R) of the ANK1 gene were identified in the two families respectively. Then, the pathogenicity of the two new mutations and two previously reported ANK1 mutations (c.C648G, p.Y216X and c.G424T, p.E142X) were studied by in vitro experiments. The four mutations increased the osmotic fragility of cells, reduced the stabilities of ANK1 proteins and prevented the protein from localizing to the plasma membrane and interacting with SPTB and SLC4A1. We classified these four mutations into disease‐causing mutations for HS. Thus, conducting the same mutation test and providing genetic counselling for the two families were meaningful and significant. Moreover, the identification of two novel mutations enriches the ANK1 mutation database, especially in China. 相似文献
18.
Chartier-Harlin MC Dachsel JC Vilariño-Güell C Lincoln SJ Leprêtre F Hulihan MM Kachergus J Milnerwood AJ Tapia L Song MS Le Rhun E Mutez E Larvor L Duflot A Vanbesien-Mailliot C Kreisler A Ross OA Nishioka K Soto-Ortolaza AI Cobb SA Melrose HL Behrouz B Keeling BH Bacon JA Hentati E Williams L Yanagiya A Sonenberg N Lockhart PJ Zubair AC Uitti RJ Aasly JO Krygowska-Wajs A Opala G Wszolek ZK Frigerio R Maraganore DM Gosal D Lynch T Hutchinson M Bentivoglio AR Valente EM Nichols WC Pankratz N 《American journal of human genetics》2011,(3):140-406
Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease. 相似文献
19.
Pompe disease is a clinically and genetically heterogeneous autosomal recessive disorder caused by lysosomal acid α-glucosidase (GAA) deficiency. We report on two affected members of a non-consanguineous Caucasian family, including a classical infantile-onset patient with severe cardiomyopathy (IO) and his paternal grandmother with the adult-onset (AO) form. Two compound heterozygous sequence variants of the GAA gene were identified in each patient by mutation analyses (IO = c.1211A > G and c.1798C > T; AO = c.1211A > G and c.692 + 5G > T). For this study, the biochemical phenotype resulting from the missense mutation c.1211A > G in exon 8, which converts a highly conserved aspartate to glycine (p.Asp404Gly), was of specific interest because it had not been reported previously. Western blotting revealed a robust expression of all GAA isoforms in quadriceps muscle of both patients (fully CRIM positive), while enzymatic activity was 3.6% (IO) and 6.6% (AO) of normal controls. To further validate these findings, the c.1211A > G sequence variant was introduced in wild type GAA cDNA and over-expressed in HEK293T cells. Site-directed mutagenesis analyses confirmed that the mutation does not affect processing or expression of GAA protein, but rather impairs enzyme function. Similar results were reported for c.1798C > T (p.Arg600Cys), which further supports the biochemical phenotype observed in IO. The third mutation (c.692 + 5G > T, in intron 3) was predicted to affect normal splicing of the GAA mRNA, and qPCR indeed verified a 4-fold lower mRNA expression in AO. It is concluded that the novel sequence variant c.1211A > G results in full CRIM but significantly lower GAA activity, which in combination with c.1798C > T leads to infantile-onset Pompe disease. We surmise that the difference in disease severity between the two family members in this study is due to a milder effect of the intronic mutation c.692 + 5G > T (vs. c.1798C > T) on phenotype, partially preserving GAA activity and delaying onset in the proband (paternal grandmother). 相似文献
20.
Jiandong Zhao Yongyi Yuan Shasha Huang Bangqing Huang Jing Cheng Dongyang Kang Guojian Wang Dongyi Han Pu Dai 《PloS one》2014,9(11)