Mutation analysis of the cathepsin C gene in Indian families with Papillon-Lefèvre syndrome

Background

PLS is a rare autosomal recessive disorder characterized by early onset periodontopathia and palmar plantar keratosis. PLS is caused by mutations in the cathepsin C (CTSC) gene. Dipeptidyl-peptidase I encoded by the CTSC gene removes dipeptides from the amino-terminus of protein substrates and mainly plays an immune and inflammatory role. Several mutations have been reported in this gene in patients from several ethnic groups. We report here mutation analysis of the CTSC gene in three Indian families with PLS.

Methods

Peripheral blood samples were obtained from individuals belonging to three Indian families with PLS for genomic DNA isolation. Exon-specific intronic primers were used to amplify DNA samples from individuals. PCR products were subsequently sequenced to detect mutations. PCR-SCCP and ASOH analyses were used to determine if mutations were present in normal control individuals.

Results

All patients from three families had a classic PLS phenotype, which included palmoplantar keratosis and early-onset severe periodontitis. Sequence analysis of the CTSC gene showed three novel nonsense mutations (viz., p.Q49X, p.Q69X and p.Y304X) in homozygous state in affected individuals from these Indian families.

Conclusions

This study reported three novel nonsense mutations in three Indian families. These novel nonsense mutations are predicted to produce truncated dipeptidyl-peptidase I causing PLS phenotype in these families. A review of the literature along with three novel mutations reported here showed that the total number of mutations in the CTSC gene described to date is 41 with 17 mutations being located in exon 7.

     

Early-Onset Invasive Infection Due to <Emphasis Type="Italic">Corynespora cassiicola</Emphasis> Associated with Compound Heterozygous <Emphasis Type="Italic">CARD9</Emphasis> Mutations in a Colombian Patient

Purpose

CARD9 deficiency is an inborn error of immunity that predisposes otherwise healthy humans to mucocutaneous and invasive fungal infections, mostly caused by Candida, but also by dermatophytes, Aspergillus, and other fungi. Phaeohyphomycosis are an emerging group of fungal infections caused by dematiaceous fungi (phaeohyphomycetes) and are being increasingly identified in patients with CARD9 deficiency. The Corynespora genus belongs to phaeohyphomycetes and only one adult patient with CARD9 deficiency has been reported to suffer from invasive disease caused by C. cassiicola. We identified a Colombian child with an early-onset, deep, and destructive mucocutaneous infection due to C. cassiicola and we searched for mutations in CARD9.

Methods

We reviewed the medical records and immunological findings in the patient. Microbiologic tests and biopsies were performed. Whole-exome sequencing (WES) was made and Sanger sequencing was used to confirm the CARD9 mutations in the patient and her family. Finally, CARD9 protein expression was evaluated in peripheral blood mononuclear cells (PBMC) by western blotting.

Results

The patient was affected by a large, indurated, foul-smelling, and verrucous ulcerated lesion on the left side of the face with extensive necrosis and crusting, due to a C. cassiicola infectious disease. WES led to the identification of compound heterozygous mutations in the patient consisting of the previously reported p.Q289* nonsense (c.865C > T, exon 6) mutation, and a novel deletion (c.23_29del; p.Asp8Alafs10*) leading to a frameshift and a premature stop codon in exon 2. CARD9 protein expression was absent in peripheral blood mononuclear cells from the patient.

Conclusion

We describe here compound heterozygous loss-of-expression mutations in CARD9 leading to severe deep and destructive mucocutaneous phaeohyphomycosis due to C. cassiicola in a Colombian child.

     

Liver cancer with concomitant <Emphasis Type="Italic">TP53</Emphasis> and <Emphasis Type="Italic">CTNNB1</Emphasis> mutations: a case report

Background

In the spectrum of molecular alterations found in hepatocellular carcinoma (HCC), somatic mutations in the WNT/β-catenin pathway and the p53/cell cycle control pathway are among the most frequent ones. It has been suggested that both mutations occur in a mutually exclusive manner and they are used as molecular classifiers in HCC classification proposals.

Case presentation

Here, we report the case of a treatment-naïve mixed hepatocellular/cholangiocellular carcinoma (HCC/CCC) with morphological and genetic intratumor heterogeneity. Within the predominant part of the tumor with hepatocellular differentiation, a p.D32V mutation in exon 3 of the CTNNB1 gene occurred concomitantly with a TP53 intron 7/exon 8 splice site mutation.

Conclusion

Intratumor heterogeneity challenges the concept of CTNNB1 and TP53 gene mutations being mutually exclusive molecular classifiers in HCC, which has implications for HCC classification approaches.

     

<Emphasis Type="Italic">Slc11a1</Emphasis> (<Emphasis Type="Italic">Nramp</Emphasis>-<Emphasis Type="Italic">1</Emphasis>) gene modulates immune-inflammation genes in macrophages during pristane-induced arthritis in mice

Objective and design

Pristane-induced arthritis (PIA) in AIRmax mice homozygous for Slc11a1 R and S alleles was used to characterize the influence of Slc11a1 gene polymorphism on immune responses during disease manifestation. Previous reports demonstrated that the presence of the Slc11a1 S allele increased the incidence and severity of PIA in AIRmax ^SS , suggesting that this gene could interact with inflammatory loci to modulate PIA. We investigated the effects of Slc11a1 alleles on the activation of phagocytes during PIA.

Treatment

Mice were injected intraperitoneally with two doses of 0.5 mL of mineral oil pristane at 60-day intervals. Arthritis development was accompanied for 180 days.

Results

AIRmax ^SS mice showed differential peritoneal macrophage gene expression profiles during PIA, with higher expression and production of H₂O₂, NO, IL-1β, IL-6, TNF-α, and several chemokines. The presence of the Slc11a1 R allele, on the other hand, diminished the intensity of macrophage activation, restricting arthritis development.

Conclusion

Our data demonstrated the fine-tuning roles of Slc11a1 alleles modulating macrophage activation, and consequent PIA susceptibility, in those mouse lines.

     

<Emphasis Type="Italic">Helicobacter bilis</Emphasis>-Associated Suppurative Cholangitis in a Patient with X-Linked Agammaglobulinemia

?

Helicobacter bilis is a commensal bacterium causing chronic hepatitis and colitis in mice. In humans, enterohepatic Helicobacter spp. are associated with chronic hepatobiliary diseases.

Purpose

We aimed at understanding the microbial etiology in a patient with X-linked agammaglobulinemia presenting with suppurative cholangitis.

Methods

16S rDNA PCR directly performed on a liver biopsy retrieved DNA of H. bilis.

Results

Clinical outcome resulted in the normalization of clinical and biological parameters under antibiotic treatment by a combination of ceftriaxone, metronidazole, and doxycyclin followed by a 2-week treatment with moxifloxacin and a 2-month treatment with azithromycin.

Conclusion

In conclusion, these data suggest a specific clinical and microbiological approach in patients with humoral deficiency in order to detect H. bilis hepatobiliary diseases.

     

First case report of Cohen syndrome in the Tunisian population caused by <Emphasis Type="Italic">VPS13B</Emphasis> mutations

Background

Cohen syndrome is a rare autosomal recessive developmental disorder that comprises variable clinical features counting developmental delay, pigmentary retinopathy, myopia, acquired microcephaly, truncal obesity, joint hypermobility, friendly disposition and intermittent neutropenia. VPS13B (vacuolar protein sorting 13, yeast, homologue of B) gene is the only gene responsible for Cohen Syndrome, causative mutations include nonsense, missense, indel and splice-site variants. The integrity of the Golgi apparatus requires the presence of the peripheral membrane protein VPS13B that have an essential function in intracellular protein transport and vesicle-mediated sorting.

Case presentation

In this study, we performed whole exome sequencing (WES) in a Tunisian family with two young cases having developmental delay, hypotonia, autism spectrum disorder, ptosis and thick hair and eyebrows. The proposita presented also pigmentory retinopathy. Compound heterozygous mutation in VPS13B gene was detected by WES. This mutation inherited from healthy heterozygous parents, supports an unpredictable clinical diagnosis of Cohen Syndrome. The proband’s phenotype is explained by the presence of compound heterozygous mutations in the VPS13B gene. This finding refined the understanding of genotype-phenotype correlation.

Conclusions

This is the first report of a Tunisian family with Cohen syndrome mutated in the VPS13B gene.

     

<Emphasis Type="Italic">ACTA2</Emphasis> mutation and postpartum hemorrhage: a case report

Background

ACTA2 encodes smooth muscle specific α-actin, a critical component or the contractile complex of vascular smooth muscle. Mutations in ACTA2 are the most common genetic cause of thoracic aortic aneurysm, and are also the cause of other disorders, including Moyamoya disease, coronary artery disease and stroke as well as Multisystemic Smooth Muscle Dysfunction Syndrome. We note that ACTA2 is also expressed in uterine smooth muscle, and this raises the possibility that women harboring ACTA2 mutations might exhibit uterine smooth muscle dysfunction.

Case presentation

We present a young woman whose ACTA2 mutation was ascertained during pregnancy because of her father’s history of dissecting aneurysms. She was delivered at full term by cesarean section and subsequently had severe uterine hemorrhage due to uterine atony. Although her atony was successfully treated with uterotonic medications, she required blood transfusion.

Conclusions

This case raises the possibility that women with ACTA2 mutations may be at risk of uterine muscle dysfunction and hemorrhage. Obstetricians should be alerted to and prepared for this possibility.

     

Identification of Heterozygous Single- and Multi-exon Deletions in <Emphasis Type="Italic">IL7R</Emphasis> by Whole Exome Sequencing

Purpose

We aimed to achieve a retrospective molecular diagnosis by applying state-of-the-art genomic sequencing methods to past patients with T-B+NK+ severe combined immunodeficiency (SCID). We included identification of copy number variations (CNVs) by whole exome sequencing (WES) using the CNV calling method ExomeDepth to detect gene alterations for which routine Sanger sequencing analysis is not suitable, such as large heterozygous deletions.

Methods

Of a total of 12 undiagnosed patients with T-B+NK+ SCID, we analyzed eight probands by WES, using GATK to detect single nucleotide variants (SNVs) and small insertions and deletions (INDELs) and ExomeDepth to detect CNVs.

Results

We found heterozygous single- or multi-exon deletions in IL7R, a known disease gene for autosomal recessive T-B+NK+ SCID, in four families (seven patients). In three families (five patients), these deletions coexisted with a heterozygous splice site or nonsense mutation elsewhere in the same gene, consistent with compound heterozygosity. In our cohort, about a quarter of T-B+NK+ SCID patients (26%) had such compound heterozygous IL7R deletions.

Conclusions

We show that heterozygous IL7R exon deletions are common in T-B+NK+ SCID and are detectable by WES. They should be considered if Sanger sequencing fails to detect homozygous or compound heterozygous IL7R SNVs or INDELs.

     

Mutations in Hotspot Regions of <Emphasis Type="Italic">ERG11</Emphasis> Gene in Fluconazole Resistant Isolates of <Emphasis Type="Italic">Candida albicans</Emphasis> in Guilan Province,Northern Iran

Background

Widespread use of azoles has resulted in rapid development of azole resistance in Candida albicans strains. Mutations in ERG11, a target enzyme of azoles, alter the binding ability of azoles to this enzyme and result in the development of resistant strains. In this study, we evaluated ERG11 mutations in fluconazole resistant isolates of C. albicans.

Materials and methods

In this study, 60 clinical samples were isolated from Guilan hospitals. Then differential tests were used to identify C. albicans strains. Disc diffusion and MIC tests were used to the analyze fluconazole susceptibility. Then, the resistant isolates were evaluated by PCR and sequencing methods for ERG11 mutations.

Results

Of 60 clinical samples, 40 C. albicans strains were identified through specific symptoms. Susceptibility tests showed that four C. albicans strains were resistant to high dose fluconazole (≥512 μg/mL). In all resistant isolates was found missense mutations such as K291N, C470G and Q474R and three isolates had premature nonsense mutation (Y477stop).

Discussion

Our study indicates that the level of fluconazole resistance in C. albicans strains is high in Guilan province and other drugs should be used in resistant infections. It seems that missense mutations in four isolates play role in azole resistance. However in three isolates premature stop codon may be involved in high dose resistance. And it is suggested that in fourth isolates another mechanisms introduce increase of resistance dose in combination with missense mutation in ERG11. Results of this study suggest that in patients by high dose of resistance do not use azole because of mutations that decrease azole effects.

     

Comparison of targeted next-generation sequencing and Sanger sequencing for the detection of <Emphasis Type="Italic">PIK3CA</Emphasis> mutations in breast cancer

Background

Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PIK3CA, is one of the most frequently mutated genes in breast cancer, and the mutation status of PIK3CA has clinical relevance related to response to therapy.The aim of our study was to investigate the mutation status of PIK3CA gene and to evaluate the concordance between NGS and SGS for the most important hotspot regions in exon 9 and 20, to investigate additional hotspots outside of these exons using NGS, and to correlate the PIK3CA mutation status with the clinicopathological characteristics of the cohort.

Methods

In the current study, next-generation sequencing (NGS) and Sanger Sequencing (SGS) was used for the mutational analysis of PIK3CA in 186 breast carcinomas.

Results

Altogether, 64 tumors had PIK3CA mutations, 55 of these mutations occurred in exons 9 and 20. Out of these 55 mutations, 52 could also be detected by Sanger sequencing resulting in a concordance of 98.4 % between the two sequencing methods. The three mutations missed by SGS had low variant frequencies below 10 %. Additionally, 4.8 % of the tumors had mutations in exons 1, 4, 7, and 13 of PIK3CA that were not detected by SGS. PIK3CA mutation status was significantly associated with hormone receptor-positivity, HER2-negativity, tumor grade, and lymph node involvement. However, there was no statistically significant association between the PIK3CA mutation status and overall survival.

Conclusions

Based on our study, NGS is recommended as follows: 1) for correctly assessing the mutation status of PIK3CA in breast cancer, especially for cases with low tumor content, 2) for the detection of subclonal mutations, and 3) for simultaneous mutation detection in multiple exons.

     

Role of topoisomerase mutations,plasmid mediated resistance (<Emphasis Type="Italic">qnr</Emphasis>) and acrAB efflux pump in fluoroquinolone resistant clinical isolates of avian <Emphasis Type="Italic">Escherichia coli</Emphasis>

Introduction

We investigated the role of topoisomerase mutations, increased level of the multidrug efflux pump AcrAB, and the plasmid-borne genes (qnr) in the fluoroquinolone (FQ) resistant avian Escherichia coli simultaneously.

Material and method

Here, we used four FQs (ciprofloxacin, enrofloxacin, ofloxacin and pefloxacin) and eight clinical isolates of E. coli containing six fluoroquinolone-resistant and two fluoroquinolone- susceptible. PCR and direct sequencing methods were used to detect the role of regulator/ repressor gene (acrR).

Objective

The objective of this study was to determine the relationship of these resistance mechanisms for fluoroquinolone resistance.

Result

The results showed that (i) all four fluoroquinolone- resistant isolates have topoisomerase mutation and plasmid borne genes qnrS and aac(6')-Ib; (ii) three FQ (enrofloxacin, ofloxacin and pefloxacin) resistant isolates harboring qnrS genes; (iii) two FQ (ciprofloxacin and pefloxacin) resistant isolates had topoisomerase mutation and plasmid borne gene qnrS; (iv) all fluoroquinolone susceptible were not harboring qnrS gene and topoisomerase mutation (v) All isolates were negative for qnrA and qnrB.

Conclusion

We found that FQs resistance combination was correlated with synergistically contribution of these resistance mechanisms. Plasmid mediated resistance by qnrS was correlated to pefloxacin resistance but did not correlate to ofloxacin, enrofloxacin and ciprofloxacin. This mechanism might be account for the pefloxacin resistance in avian E. coli.

     

Inflammatory protein response in <Emphasis Type="Italic">CDKL5</Emphasis>-Rett syndrome: evidence of a subclinical smouldering inflammation

Background

Mutations in the cyclin-dependent kinase-like 5 gene cause a clinical variant of Rett syndrome (CDKL5-RTT). A role for the acute-phase response (APR) is emerging in typical RTT caused by methyl-CpG-binding protein 2 gene mutations (MECP2-RTT). No information is, to date, available on the inflammatory protein response in CDKL5-RTT. We evaluated, for the first time, the APR protein response in CDKL5-RTT.

Methods

Protein patterns in albumin- and IgG-depleted plasma proteome from CDKL5-RTT patients were evaluated by two-dimensional gel electrophoresis/mass spectrometry. The resulting data were related to circulating cytokines and compared to healthy controls or MECP2-RTT patients. The effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) were evaluated.

Results

CDKL5-RTT mutations resulted in a subclinical attenuated inflammation, specifically characterized by an overexpression of the complement component C3 and CD5 antigen-like, both strictly related to the inflammatory response. Cytokine dysregulation featuring a bulk increase of anti-inflammatory cytokines, predominantly IL-10, could explain the unchanged erythrocyte sedimentation rate and atypical features of inflammation in CDKL5-RTT. Omega-3 PUFAs were able to counterbalance the pro-inflammatory status.

Conclusion

For the first time, we revealed a subclinical smouldering inflammation pattern in CDKL5-RTT consisting in the coexistence of an atypical APR coupled with a dysregulated cytokine response.

     

Association of Uncoupling Protein 1 (<Emphasis Type="Italic">UCP1</Emphasis>) gene polymorphism with obesity: a case-control study

Background

Obesity is one of the main causes of morbidity and mortality worldwide. More than 120 genes have been shown to be associated with obesity related phenotypes. The aim of this study was to determine the effect of selected genetic polymorphisms in Uncoupling protein 1 (UCP1) and Niemann-Pick C1 (NPC1) genes in an obese population in Saudi Arabia.

Methods

The genotypes of rs1800592, rs10011540 and rs3811791 (UCP1 gene) and rs1805081 and rs1805082 (NPC1 gene) were determined in a total of 492 subjects using TaqMan chemistry by Real-time PCR. In addition, capillary sequencing assay was performed to identify two specific polymorphisms viz., rs45539933 (exon 2) and rs2270565 (exon 5) of UCP1 gene.

Results

A significant association of UCP1 polymorphisms rs1800592 [OR, 1.52 (1.10–2.08); p?=?0.009] was observed in the obese cohort after adjusting with age, sex and type 2 diabetes. Further BMI based stratification revealed that this association was inconsistent with both moderate and extreme obese cohort. A significant association of UCP1 polymorphisms rs3811791 was observed only in the moderate-obese cohort [OR?=?2.89 (1.33–6.25); p?=?0.007] but not in the extreme-obese cohort indicating an overlying genetic complexity between moderate-obesity and extreme-obesity. The risk allele frequencies, which were higher in moderate-obese cohort, had abnormal HDL, LDL and triglyceride levels.

Conclusion

The rs1800592 and rs3811791 of UCP1 gene are associated with obesity in general and in the moderate-obese group in particular. The associated UCP1 polymorphisms in the moderate-obese group may regulate the impaired energy metabolism which plays a significant role in the initial stages of obesity.

     

Genotype-phenotype correlations among <Emphasis Type="Italic">BRCA1</Emphasis>4153delA and 5382insC mutation carriers from Latvia

Background

Mutations in the high penetrance breast and ovarian cancer susceptibility gene BRCA1 account for a significant percentage of hereditary breast and ovarian cancer cases. Genotype-phenotype correlations of BRCA1 mutations located in different parts of the BRCA1 gene have been described previously; however, phenotypic differences of specific BRCA1 mutations have not yet been fully investigated. In our study, based on the analysis of a population-based series of unselected breast and ovarian cancer cases in Latvia, we show some aspects of the genotype-phenotype correlation among the BRCA1 c.4034delA (4153delA) and c.5266dupC (5382insC) founder mutation carriers.

Methods

We investigated the prevalence of the BRCA1 founder mutations c.4034delA and c.5266dupC in a population-based series of unselected breast (n = 2546) and ovarian (n = 795) cancer cases. Among the BRCA1 mutation carriers identified in this analysis we compared the overall survival, age at diagnosis and family histories of breast and ovarian cancers.

Results

We have found that the prevalence of breast and ovarian cancer cases (breast: ovarian cancer ratio) differs significantly among the carriers of the c.5266dupC and c.4034delA founder mutations (OR = 2.98, 95%CI = 1.58 to 5.62, P < 0.001). We have also found a difference in the prevalence of breast and ovarian cancer cases among the 1^st and 2^nd degree relatives of the c.4034delA and c.5266dupC mutation carriers. In addition, among the breast cancer cases the c.4034delA mutation has been associated with a later age of onset and worse clinical outcomes in comparison with the c.5266dupC mutation.

Conclusions

Our data suggest that the carriers of the c.4034delA and c.5266dupC founder mutations have different risks of breast and ovarian cancer development, different age of onset and prognosis of breast cancer.

     

Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder <Emphasis Type="Italic">IL12B</Emphasis> Mutation in Saudi Arabia

Purpose

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30).

Methods

Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain.

Results

Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect.

Conclusions

This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.

     

Exonic duplication of the <Emphasis Type="Italic">OTC</Emphasis> gene by a complex rearrangement that likely occurred via a replication-based mechanism: a case report

Background

Ornithine transcarbamylase deficiency (OTCD) is an X-linked recessive disorder involving a defect in the urea cycle caused by OTC gene mutations. Although a total of 417 disease-causing mutations in OTC have been reported, structural abnormalities in this gene are rare. We here describe a female OTCD case caused by an exonic duplication of the OTC gene (exons 1–6).

Case presentation

A 23-year-old woman with late-onset OTCD diagnosed by biochemical testing was subjected to subsequent genetic testing. Sanger sequencing revealed no pathogenic mutation throughout the coding exons of the OTC gene, but multiplex ligation-dependent probe amplification (MLPA) revealed duplication of exons 1–6. Further genetic analyses revealed an inversion of duplicated exon 1 and a tandem duplication of exons 2–6. Each of the junctions of the inversion harbored a microhomology and non-templated microinsertion, respectively, suggesting a replication-based mechanism. The duplication was also of de novo origin but segregation analysis indicated that it took place in the paternal chromosome.

Conclusion

We report the first OTCD case harboring an exonic duplication in the OTC gene. The functional defects caused by this anomaly were determined via structural analysis of its complex rearrangements.

     

New Mutations in Ciprofloxacin Resistant Strains of <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> Isolated from Guilan Province,Northern Iran

Introduction

Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative bacterium that continues to be a major cause of opportunistic nosocomial infections. In P. aeruginosa, several fluoroquinolones resistance mechanisms have been proposed such as mutations in the target enzymes GyrA and ParC and upregulation of efflux pump MexAB-OprM. Fluoroquinolones inhibit the target enzymes DNA gyrase and topoisomerase IV, each comprised of two subunits: GyrA and GyrB, and ParC and ParE, respectively. In addition, fluoroquinolones were blocked by overexpression of MexAB-OprM induced through mutations in the regulatory genes mexR and nalC.

Materials and methods

In this study, 44 P. aeruginosa strains were isolated from different clinical samples of burn and infection from patients in some hospitals and laboratories in Guilan, which were identified by biochemical tests. The antibiotic resistance and susceptibility of strains was determined by Kirby Bauer method and microdilution method, and then PCR-sequencing was carried out to assess mutation in several genes involved in ciprofloxacin resistance.

Results

Of 44 isolates, 14 isolates were fluoroquinolone resistant. All 14 strains were nalidixic acid resistant with MIC = 1024 μg/mL. While ciprofloxacin resistance was showed in resistant isolates with MIC to be 32–1024 μg/mL. PCR-sequencing analysis showed that all 14 fluoroquinolone resistant isolates had one or two mutations in gyrA mutation. Mutations in parC, mexR and nalC were shown in some ciprofloxacin resistant isolates. Moreover, three strains had new mutation in mexR gene (111InsC and 262-263delAG).

Conclusions

It seems that high resistance to ciprofloxacin can simultaneously be the result of mutation in several genes such as topoisomerase enzymes and negative regulatory genes implicated in the expression of efflux pump systems in Guilan Province.

     

A novel mutation in the <Emphasis Type="Italic">VHL</Emphasis> gene in a Chinese family with von Hippel-Lindau disease

Background

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer syndrome, and VHL is identified as a tumor suppressor gene. The main objective of this study was to identify disease-causing mutations in a Chinese family affected with VHL disease.

Methods

Genomic DNA was extracted from peripheral blood from a Chinese family with VHL. A predicted pathogenic variant was identified by targeted exome capture technology and next-generation sequencing.

Results

A novel heterozygous mutation (c.349?T?>?A, p.W117R) was detected in affected family members. No mutation was detected in unaffected family members or in the 150 normal controls. The mutation segregated with the disease phenotype throughout three generations. Histopathological examination revealed the characteristics of hemangioblastoma.

Conclusions

A novel W117R was detected in the VHL gene that caused retinal hemangioblastomas in affected members of a Chinese family.