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1.  Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma 
Nature genetics  2014;46(5):482-486.
Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin POT1 gene (g.7:124493086 C>T, Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere length and elevated fragile telomeres suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two other Italian families, yielding a frequency of POT1 variants comparable to that of CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.
doi:10.1038/ng.2941
PMCID: PMC4056593  PMID: 24686846
2.  R164H and V240H Replacements by Site-Directed Mutagenesis of TEM-149 Extended-Spectrum β-Lactamase: Kinetic Analysis of TEM-149H240 and TEM-149H164-H240 Laboratory Mutants 
Two laboratory mutant forms, TEM-149H240 and TEM-149H164-H240, of the TEM-149 extended-spectrum β-lactamase enzyme were constructed by site-directed mutagenesis. TEM-149H240 and TEM-149H164-H240 were similar in kinetic behavior, except with respect to benzylpenicillin and ceftazidime. Molecular modeling of the two mutant enzymes demonstrated the role of histidine at position 240 in the reduction of the affinity of the enzyme for ceftazidime.
doi:10.1128/AAC.01268-12
PMCID: PMC3553744  PMID: 23183431
3.  MC1R variants predisposing to concomitant primary cutaneous melanoma in a monozygotic twin pair 
BMC Medical Genetics  2012;13:81.
Background
Concomitant primary cutaneous melanoma in monozygotic twins has been reported in only two pairs but in neither of them genetic analysis was performed. Two high-penetrance susceptibility genes, CDKN2A and CDK4 and one low-penetrance gene, MC1R, are well-defined genetic risk factors for melanoma. MITF has been recently identified as a novel intermediate risk melanoma-predisposing gene.
Case presentation
We describe the extraordinary occurrence of a primary cutaneous invasive melanoma in two 44-year-old identical, female twins, on the same body site within 30 days of each other and report for the first time the genetic analysis of melanoma susceptibility genes in both twins. Data on characteristics of the twins were collected through a standardized questionnaire and skin examination. Exons 1α, 1β, 2 and 3 of CDKN2A, exon 2 of CDK4, the entire open reading frame of MC1R and the recently described MITF c.952 G > A (p.Glu318Lys) variant were investigated by direct sequencing. Sequencing analysis of the high-penetrance susceptibility genes showed no changes in CDKN2A and in exon 2 of the CDK4 gene. Both patients were heterozygous for the same CDKN2A UTR c.*29C > G variant. Interestingly, the same two heterozygous variants of the MC1R were identified in both twins: the c.451C > T (p.Arg151Cys) and the c.456C > A (p.Tyr152*) variants. Neither patient showed the c.952 G > A (p.Glu318Lys) substitution in the MITF gene.
Conclusions
Identification of two high-risk MC1R variants in our identical twins in the absence of CDKN2A and CDK4 mutations highlights the contribution of low penetrance genes, such as MC1R, in melanoma susceptibility.
doi:10.1186/1471-2350-13-81
PMCID: PMC3483249  PMID: 22978401
Melanoma; Monozygotic twins; CDKN2A; CDK4; MC1R; MITF; Genetic susceptibility
4.  E240V Substitution Increases Catalytic Efficiency toward Ceftazidime in a New Natural TEM-Type Extended-Spectrum β-Lactamase, TEM-149, from Enterobacter aerogenes and Serratia marcescens Clinical Isolates▿  
The aim of this study was to characterize a novel extended-spectrum β-lactamase that belongs to the TEM family, the TEM-149 enzyme, and that was isolated from the urine of two hospitalized patients from different hospitals in southern Italy. The peculiarity of this enzyme was the finding of a valine residue at position 240. The array of amino acid substitutions found in TEM-149 was as follows: E104K, R164S, M182T, and E240V. A reversion of a threonine residue at position 182 was also performed to create a new mutant, TEM-149T182M, in order to assess the contribution of this substitution on the kinetic profile and the stability of TEM-149. The blaTEM-149 and blaTEM-149/T182M genes were cloned into pBC-SK, and the corresponding enzymes were purified from recombinant Escherichia coli HB101 by the same procedure. Both enzymes hydrolyzed all β-lactams tested, with a preference for ceftazidime, which was found to be the best substrate. By comparison of the kinetic parameters of the TEM-149 and the TEM-149T182M enzymes, a reduction of the catalytic efficiency for the TEM-149T182M mutant was observed against all substrates tested except benzylpenicillin, cefotaxime, and aztreonam. Tazobactam, clavulanic acid, and sulbactam were good inhibitors of the TEM-149 β-lactamase.
doi:10.1128/AAC.01028-07
PMCID: PMC2258539  PMID: 18160520
5.  Identification and Characterization of a New Metallo-β-Lactamase, IND-5, from a Clinical Isolate of Chryseobacterium indologenes▿  
A new natural IND-type metallo-β-lactamase variant, IND-5, was identified in a clinical isolate of Chryseobacterium indologenes. IND-5 shared 92.8% and 92.4% amino acid homology with IND-1 and IND-3, respectively. Purified enzyme (pI = 8.8, Mr = 25,000) was able to hydrolyze penicillins, some narrow- and expanded-spectrum cephalosporins, and carbapenems but not monobactams.
doi:10.1128/AAC.00083-07
PMCID: PMC1932519  PMID: 17470648

Results 1-5 (5)