A novel mutation, outside of the candidate region for diagnosis, in the inverted formin 2 gene can cause focal segmental glomerulosclerosis

Focal and segmental glomerulosclerosis (FSGS) is a histological pattern that has several etiologies, including genetics. The autosomal dominant form of FSGS is a heterogenic disease caused by mutations within three known genes: alpha-actinin 4 (ACTN4), canonical transient receptor potential 6 (TRPC6), and the inverted formin 2 (INF2) gene. More recently, INF2 mutations have also been attributed to Charcot-Marie-Tooth neuropathy associated with FSGS. Here we performed direct sequencing, histological characterization, and functional studies in a cohort of families with autosomal dominant FSGS. We detected a novel mutation in exon 6 of the INF2 gene outside of the exon 2-4 candidate region used for rapid diagnosis of autosomal dominant FSGS. This new mutation is predicted to alter a highly conserved amino-acid residue within the 17th alpha-helix of the diaphanous inhibitory domain of the protein. A long-term follow-up of this family indicated that all patients were diagnosed in adulthood, as opposed to early childhood, and progression to end-stage renal disease was at different times without clinical or electrodiagnostic evidence of neuropathy. Thus, this novel mutation in INF2 linked to nonsyndromic FSGS indicates the necessity for full gene sequencing if no mutation is found in the current rapid-screen region of the gene. 2012 International Society of Nephrology

Comparison between siblings and twins supports a role for modifier genes in ADPKD.

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by intrafamilial variability in renal disease progression, which could result from a combination of environmental and genetic factors. Although a role for modifier genes has been evidenced in mouse models, direct evidence in ADPKD patients is lacking. The analysis of variability in affected siblings and monozygotic (MZ) twins would help evaluate the relative contribution of environment and genetic factors on renal disease progression in ADPKD. METHODS: The difference in the age at end-stage renal disease (ESRD) and the intraclass correlation coefficient (ICC) were quantified in a large series of ADPKD siblings from western Europe and compared with the values obtained in a series of MZ ADPKD twins from the same geographic area. RESULTS: Fifty-six sibships (including 129 patients) and nine pairs of MZ twins were included. The difference in the age at ESRD was significantly higher in siblings (6.9 +/- 6.0 years, range 2 months to 23 years) than in MZ twins (2.1 +/- 1.9 years, range 1 month to 6 years; P = 0.02). Furthermore, the intraclass correlation coefficient was significantly lower in siblings than in MZ twins (0.49 vs. 0.92, respectively; P = 0.003). The intrafamilial difference in the age at ESRD was not influenced by gender. CONCLUSION: These data substantiate the existence of a large intrafamilial variability in renal disease progression in ADPKD siblings. The fact that the variability in siblings is in a significant excess of that found in MZ twins strongly suggests that modifier genes account for a significant part of this variability

La Ría de Vigo : una aproximación integral al ecosistema marino de la Ría de Vigo

414 pagesLos fondos de la ría de Vigo : composición, distribución y origen del sedimento / Federico Vilas Martín, Daniel Rey García, Belén Rubio Armesto, Ana M. Bernabeu Tello, Gonzalo Méndez Martínez, Ruth Durán Gallego, Kais Jacob Mohamed Falcón. Hidrografía y dinámica de la ría de Vigo : un sistema de afloramiento / Gabriel Rosón Porto, José Manuel Cabanas, Fiz Fernández Pérez (http://hdl.handle.net/10261/115885). Biogeoquímica de la ría de Vigo: ciclo de las sales nutrientes ; trampa/sumidero de CO2 / Carmen González Castro, Aida Fernández Ríos (http://hdl.handle.net/10261/116063). El plancton de la ría de Vigo / Francisco Gómez Figueiras, Ana Miranda, Isabel Riveiro Alarcón, Alba Ruth Vergara Castaño, Cástor Guisande (http://hdl.handle.net/10261/116072). Episodios de fitoplancton tóxico en la ría de Vigo / Beatriz Reguera Ramírez, Laura Escalera, Yolanda Pazos, Ángeles Moroño. Contaminación / Juan José González, Cristina Álvarez, Ricardo Beiras García-Sabell, Maria Victoria Besada Montenegro, José Fumega, María Ángeles Franco Hernández, Mariano Gómez, Amelia González Quijano, Teresa Nunes, Ricardo Prego Reboredo, José Antonio Soriano Sanz, Lucia Elisa Viñas Diéguez (http://hdl.handle.net/10261/116066). Explotación: pesca, marisqueo y acuicultura en la ría de Vigo / José Benito Peleteiro, Valentín Trujillo, Rafael Bañón Díaz, Jorge Ribó, Mercedes Olmedo, Blanca Álvarez Blázquez, José Luis Rodríguez, Juan Pazó, Juan José Otero. Impacto del hombre sobre el ecosistema de la ría de Vigo: hacia una gestión integrada / Ángel Guerra Sierra, Santiago Lens, Francisco Rocha Valdés (http://hdl.handle.net/10261/116069). Valoración económica del uso recreativo y la conservación / María Xosé Vázquez Rodríguez, Albino Prada BlancoN

Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis

Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.This work-was supported by the Marie Curie activities of the European Commission (Oncotrain program; fellowship to P.W), the Spanish Ministry of Economy and Competitiveness (MINECO; fellowship to A.G.-L.), the CENIT AMIT Project "Advanced Molecular Imaging Technologies" (TEC2008-06715-C02-1, RD07/0014/2009 to F.M.), the Red de investigacion Cardiovascular (RIC), cofunded by FEDER (grant RD12/004240022 to J.M.R.; grant RD12/0042/0056 to L.J.J.-B), Fundacio La Marato TV3 (grant 20151331 to J.M.R.), the Castilla-Leon Autonomous Government (BIO/SA01/15, CS049U16 to X.R.B.), the Solorzano and Ramon Areces Foundations (to X.R.B.), MINECO (grants RD12/0036/0002 and SAF2015-64556-R to X.R.B.; SAF2015-63633-R to J.M.R.; and SAF2015-69920-R to M.M.), Consolider-Ingenio 2010 Programme (grant SAF2014-57791-REDC to M.M.), Red Tematica CellSYS (grant BFU2014-52125-REDT to M.M.), Comunidad de Madrid (OncoCycle Programme; grant S2010/BMD-2470 to M.M.), Worldwide Cancer Research (grants 14-1248 to X.R.B., and 15-0278 to M.M.) and the MitoSys project (European Union Seventh Framework Programme; grant HEALTH-F5-2010-241548 to M.M.). CNIC is supported by MINECO and the Pro-CNIC Foundation. CNIO and CNIC are Severo Ochoa Centers of Excellence (MINECO awards SEV-2015-0510 and SEV-2015-0505, respectively).S