Angiotensinogen, Angiotensin-Converting Enzyme, and Chymase Gene Polymorphisms as Biomarkers for Basal Cell Carcinoma Susceptibility.

INTRODUCTION: The intake of angiotensin-converting enzyme (ACE) inhibitors and specific antagonists of angiotensin II receptors, widely used as antihypertensive drugs, significantly reduces the risk of developing basal cell carcinoma (BCC), highlighting the possible tumorigenic role of angiotensin II (AngII). We present here the investigated genetic association between the development of BCC and functional DNA polymorphisms M235T, I/D, and A1903G in the genes of angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and chymase (CMA1), which mediate AngII production levels. METHODS: DNA samples of 203 unrelated Greeks were studied, including 100 patients with BCC and 103 matched healthy controls. RESULTS: The MT genotype of the AGT-M235T polymorphism was significantly more prevalent in the patient group (78.0%) versus the healthy control group (28.3%; p < 0.001). The DD genotype of the ACE-I/D polymorphism was also increased in BCC patients (72.8%) compared to controls (46.2%; p = 0.001). The heterozygous AG genotype of CMA1-A1903G was significantly more frequent in the BCC group (86%) than in the healthy controls (50.5%; p < 0.001). CONCLUSIONS: The MT, DD, and AG genotypes of the AGT- M235T, ACE-I/D, and CMA1-A1903G polymorphisms, respectively, were significantly increased in frequency within the group of cancer patients compared to the healthy controls. All three genotypes correspond to increased enzyme levels or activity and result in increased levels of AngII; therefore, they may be potentially utilized as reliable biomarkers associated with an individual's increased risk for BCC development.

Arabidopsis Coexpression Tool: a tool for gene coexpression analysis in Arabidopsis thaliana.

Gene coexpression analysis refers to the discovery of sets of genes which exhibit similar expression patterns across multiple transcriptomic data sets, such as microarray experiment data of public repositories. Arabidopsis Coexpression Tool (ACT), a gene coexpression analysis web tool for Arabidopsis thaliana, identifies genes which are correlated to a driver gene. Primary microarray data from ATH1 Affymetrix platform were processed with Single-Channel Array Normalization algorithm and combined to produce a coexpression tree which contains ∼21,000 A. thaliana genes. ACT was developed to present subclades of coexpressed genes, as well as to perform gene set enrichment analysis, being unique in revealing enriched transcription factors targeting coexpressed genes. ACT offers a simple and user-friendly interface producing working hypotheses which can be experimentally verified for the discovery of gene partnership, pathway membership, and transcriptional regulation. ACT analyses have been successful in identifying not only genes with coordinated ubiquitous expressions but also genes with tissue-specific expressions.

Phenotype and Genotype Study in a Case of Frontometaphyseal Dysplasia 1.

INTRODUCTION: Frontometaphyseal dysplasia 1 (FMD1) is a rare X-linked craniofacial syndrome belonging in the otopalatodigital spectrum of disorders. Here we present a case with severe FMD1 that was caused by a mutation in the FLNA gene located on Xq28. METHODS: A diagnosis for FMD1 was clinically set for a 22-year-old male who presented with cranial hyperostosis with marked supraorbital ridge, hypertelorism, progressive mixed hearing loss, partial anodontia, scoliosis, generalized skeletal dysplasia, and muscle atrophy. The patient's two older brothers had also severe FMD1 manifestations with generalized skeletal dysplasia, cranial hyperostosis, progressive hearing loss, and scoliosis, while their mother and maternal grandmother had some less prominent FMD1 signs. Total DNA was extracted from blood samples of the patient, his brothers, and his parents. RESULTS: DNA sequencing of all 48 exons of the FLNA gene revealed a single-point mutation (3476A>C) in exon 22. The missense mutation changes an Asp codon into an Ala codon in amino acid position 1159. The patient's two brothers had the same mutation, while their mother was a heterozygous carrier having both the mutant allele and the normal allele. CONCLUSION: The clinical diagnosis for FMD1 was confirmed by genetic analysis. It is evident that the FLNA gene product filamin A plays a critical developmental role in morphogenesis of several tissues being a cytoskeleton component, since mutations in its gene cause multiple manifestations and diverse disorders of the otopalatodigital spectrum.

Craniofacial and Neurological Phenotype in a Case of Oculodentodigital Syndrome.

INTRODUCTION: Oculodentodigital syndrome (ODDS) is a rare genetic disorder caused by mutations in the gap junction GJA1 gene encoding connexin-43 (chromosome 6q22). A typical ODDS case is presented. MATERIAL AND METHODS: A 40-year-old male patient was examined neurologically and genetically. He had a history of recent parieto-occipital leukodystrophy, some episodes of temporary hearing loss, and characteristic facial features of ODDS. Sequencing of the GJA1 gene was performed in patient's total genomic DNA sample isolated from peripheral blood cells. RESULTS: A novel heterozygous missense mutation (443G>A) was identified in the GJA1 gene, resulting in coding for a different amino acid (Arg148Gln). CONCLUSION: The molecular genetic analysis confirmed the diagnosis of ODDS. The novel mutation, located within a calmodulin binding region of connexin-43, probably affects proper channel function.

Clinical and Molecular Study of Common Thrombophilia Mutation Prothrombin G20210A.

BACKGROUND: One of the most common genetic causes associated with thrombophilia is mutation G20210A of the coagulation factor II (F2) gene. MATERIALS AND METHODS: Data collected from 355 unrelated Greeks examined for the mutation G20210A over a period of two decades were anonymously analyzed. RESULTS: The statistical analysis confirmed the importance of F2 G20210A in thrombosis and the significance of a positive family history of thrombosis. An interesting finding was the increased prevalence of G20210A in men with thrombotic events aged >40 years. CONCLUSIONS: This study highlighted the great value of a positive family history of thrombosis and the importance of testing for this common mutation as a putative prevention strategy and a future biomarker for thrombophilia.

Craniofacial and Neurological Phenotype in a Patient with De Novo 18q Microdeletion and 18p Microduplication.

INTRODUCTION: Chromosome 18q deletion syndrome (18q-) is a rare chromosomal disorder with phenotypic variability, including mental deficiency, short stature, hypotonia, cleft palate, and hearing impairment. We present a case with features of 18q- syndrome who had combined 18q partial monosomy and 18p partial trisomy. MATERIAL AND METHODS: A 50-year-old female patient was examined during the genetic counseling of her brother. She had a history of congenital cleft palate and developmental deficiency with hypotonia, hearing loss, and epilepsy until adulthood. Her family history was free of related cases. Karyotype analysis and comparative genomic hybridization array (aCGH) were performed in patient's blood samples. RESULTS: Clinical examination showed features of 18q- syndrome including hypotonia and tremor. Neuropsychological deficiency of moderate cognitive disorder was noticed. The patient's karyotype was normal. The aCGH analysis revealed 8 Mb deletion (del18q22.3q23) and 7.2 Mb duplication (dup18p11.32p11.23). CONCLUSION: Almost all patients' clinical features were associated with 18q- syndrome. There are very few reported cases with similar genotype possibly caused by a de novo unequal recombination mechanism.

Genetic Counseling for Adult-Onset Spinal and Bulbar Muscular Atrophy (Kennedy Syndrome): Multiple Cases of Prenatal Testing in a Family.

X-linked spinal and bulbar muscular atrophy (SBMA), also known as Kennedy syndrome, is an adult-onset neurodegenerative disorder characterized by slowly progressive muscle atrophy and other severe symptoms gradually leading to reduced mobility and ultimately to death due to respiratory failure. Two decades ago we reported the first prenatal diagnosis of SBMA worldwide. Here we present a Greek family in which we have performed seven prenatal DNA tests for SBMA mutation after extensive genetic counseling. Since there is not yet a cure for SBMA, prenatal testing may be a good choice for couples at risk for prevention of this neurodegenerative disorder in their offspring. The issues addressed during genetic counseling for such a disabling disorder of adult onset are discussed as a paradigm for other conditions with similar characteristics.

Association of Polymorphisms in the Genes of Angiotensinogen and Angiotensin Receptors With Risk for Basal Cell Carcinoma.

BACKGROUND/AIM: Basal cell carcinoma (BCC) has been genetically associated with an increased expression of angiotensin-converting enzyme (ACE), an important factor of the renin-angiotensin system which produces vasoconstrictor angiotensin II. Other factors of this system include angiotensinogen (AGT) and angiotensin receptors AGTR1, AGTR2. We investigated the possible association of BCC with genetic variability in the AGT, AGTR1 and AGTR2 genes. MATERIALS AND METHODS: DNA samples of 190 Greeks were studied, including 91 patients with BCC and 99 matched healthy controls. Molecular genotyping of patients and controls was performed for the polymorphisms AGT M235T, AGTR1 A1166C and AGTR2 G1675A. RESULTS: The mutant T allele that increases AGT gene expression was detected in two-fold increased frequency in BCC patients in comparison to healthy controls (p <0.001). On the contrary, no significant difference was observed in AGTR1 and AGTR2 variants between patients and controls. CONCLUSION: Increased expression of AGT may be associated with BCC.