@article {554, title = {Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.}, journal = {Br J Dermatol}, volume = {181}, year = {2019}, month = {2019 09}, pages = {512-522}, abstract = {

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.

OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.

METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.

RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in~situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.

CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What{\textquoteright}s already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

}, keywords = {Adolescent, Adult, Biopsy, Blister, Case-Control Studies, Cells, Cultured, Child, Child, Preschool, Epidermolysis Bullosa, Epidermolysis Bullosa Dystrophica, Extracellular Matrix, Extracellular Matrix Proteins, Female, Fibroblasts, Fibrosis, Gene Expression Regulation, Healthy Volunteers, Humans, Infant, Infant, Newborn, Male, Middle Aged, mutation, Periodontal Diseases, Photosensitivity Disorders, Primary Cell Culture, RNA-seq, Skin, Xeroderma Pigmentosum, Young Adult}, issn = {1365-2133}, doi = {10.1111/bjd.17698}, author = {Chac{\'o}n-Solano, E and Le{\'o}n, C and D{\'\i}az, F and Garc{\'\i}a-Garc{\'\i}a, F and Garc{\'\i}a, M and Esc{\'a}mez, M J and Guerrero-Aspizua, S and Conti, C J and Menc{\'\i}a, {\'A} and Mart{\'\i}nez-Santamar{\'\i}a, L and Llames, S and P{\'e}vida, M and Carbonell-Caballero, J and Puig-Butill{\'e}, J A and Maseda, R and Puig, S and de Lucas, R and Baselga, E and Larcher, F and Dopazo, J and Del Rio, M} } @article {490, title = {Novel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree.}, journal = {BMC Genet}, volume = {15}, year = {2014}, month = {2014 Dec 14}, pages = {143}, abstract = {

BACKGROUND: Molecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP).

RESULTS: Exome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co-segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet-Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family.

CONCLUSIONS: The combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1.

}, keywords = {Bardet-Biedl Syndrome, Base Sequence, Case-Control Studies, DNA Mutational Analysis, Eye Proteins, Genes, Recessive, Genetic Association Studies, Humans, Microsatellite Repeats, Microtubule-Associated Proteins, Mutation, Missense, Pedigree, Phenotype, Retina, Retinitis pigmentosa}, issn = {1471-2156}, doi = {10.1186/s12863-014-0143-2}, author = {M{\'e}ndez-Vidal, Cristina and Bravo-Gil, Nereida and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Vela-Boza, Alicia and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {549, title = {Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Nov 22}, pages = {e14078}, abstract = {

Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95\% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95\% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95\% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.

}, keywords = {Adult, Bone Morphogenetic Protein Receptors, Type I, Breast, Breast Neoplasms, Calcium-Calmodulin-Dependent Protein Kinases, Case-Control Studies, Cyclin-Dependent Kinases, Disease Progression, Estrogen Receptor alpha, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Germ-Line Mutation, Humans, Odds Ratio, Poland, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Receptor, EphA3, Receptor, EphA7, Receptor, EphB1, Risk Factors}, issn = {1932-6203}, doi = {10.1371/journal.pone.0014078}, author = {Bonifaci, N{\'u}ria and G{\'o}rski, Bohdan and Masoj{\'c}, Bartlomiej and Woko{\l}orczyk, Dominika and Jakubowska, Anna and D{\k e}bniak, Tadeusz and Berenguer, Antoni and Serra Musach, Jordi and Brunet, Joan and Dopazo, Joaquin and Narod, Steven A and Lubi{\'n}ski, Jan and L{\'a}zaro, Conxi and Cybulski, Cezary and Pujana, Miguel Angel} } @article {575, title = {Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.}, journal = {Hum Mutat}, volume = {31}, year = {2010}, month = {2010 Nov}, pages = {E1772-800}, abstract = {

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9\% (12/28) are very likely pathogenic, 17.9\% (5/28)are possibly pathogenic, whereas 39.3\% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9\% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.

}, keywords = {Amino Acid Sequence, Animals, Case-Control Studies, DNA Mutational Analysis, Drosophila Proteins, Evolution, Molecular, Eye Proteins, Female, Genes, Recessive, Genetic Variation, Humans, Male, Molecular Sequence Data, mutation, Pedigree, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Retinitis pigmentosa, Spain, Structural Homology, Protein}, issn = {1098-1004}, doi = {10.1002/humu.21334}, author = {Barrag{\'a}n, Isabel and Borrego, Salud and Pieras, Juan Ignacio and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Santoyo, Javier and Ayuso, Carmen and Baiget, Montserrat and Mill{\'a}n, Jos{\'e} M and Mena, Marcela and Abd El-Aziz, Mai M and Audo, Isabelle and Zeitz, Christina and Littink, Karin W and Dopazo, Joaquin and Bhattacharya, Shomi S and Anti{\v n}olo, Guillermo} }