Osteogenesis imperfecta in Brazilian patients.

Osteogenesis Imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and fracture. Mutations in 20 distinct genes can cause OI, and therefore, the genetic diagnosis of OI is frequently difficult to obtain because of the great number of genes that can be related with this disease. Studies that report the most frequently mutated genes in OI patients can help to improve molecular strategies for diagnosis of the disease. In order to characterize the mutation profile of OI in Brazilian patients, we analyzed 30 unrelated patients through SSCP screening, NGS gene panel, and/or Sanger sequencing for the 11 most frequently mutated genes in the database of mutations, including COL1A1, COL1A2, P3H1, CRTAP, PPIB, SERPINH1, SERPINF1, FKBP10, SP7, WNT1 and IFITM5. Disease-causing variants were identified in COL1A1, COL1A2, FKBP10, P3H1, and IFITM5. A total of 28 distinct mutations were identified, including seven novel changes. Our data show that the analysis of these five genes is able to detect at least 95% of causative mutations in OI disorder from Brazilian population. However, it has to be taken into considerations that distinct populations can have different frequencies of disease-causing variants. Hence, it is important to replicate this study in other groups.

Analysis of 12 X-STRs loci in a population from southeastern Brazil.

Short tandem repeat (STR) markers on the X chromosome have a high potential for solving complex kinship analysis and individual identification cases. To achieve such purposes, allele and haplotype frequencies for the specific population are necessary. Nonetheless, such frequencies are not always available. Therefore, we obtained haplotypes from 520 unrelated males from four different geographic regions of Espírito Santo - Brazil, using the Investigator Argus X-12 kit. Forensic parameters for linked groups of four X-STR loci are reported. Genetic distance analyzes suggest that ES population is genetically closer to the Italian population and farther from the Mexican one, among the populations analyzed in this study.

Functional vascular endothelial growth factor -634G>C SNP is associated with proliferative diabetic retinopathy: a case-control study in a Brazilian population of European ancestry.

OBJECTIVE: The purpose of this study was to evaluate the effect of the single nucleotide polymorphism (SNP) -634G>C at the 5' regulatory region of the vascular endothelial growth factor (VEGF) in the risk of proliferative diabetic retinopathy (PDR) in the Brazilian population of European ancestry with type 2 diabetes. RESEARCH DESIGN AND METHODS: A case-control study was conducted in 501 type 2 diabetic patients of European ancestry. Patients underwent a standardized clinical, ophthalmological, and laboratory evaluation. Of these, 167 patients had PDR (case patients), and 334 were considered as control subjects (patients without PDR) for PDR. A reference population (110 individuals of European ancestry) was also evaluated. RESULTS: No evidence of association between -634G>C/VEGF and the presence of diabetic retinopathy or type 2 diabetes was observed (P > 0.05). However, CC homozygous for the SNP -634G>C was significantly more frequent in patients with PDR (37 of 167; 22.2%) than in the corresponding control group (40 of 334; 12%) in accordance with a recessive model (P = 0.003). This effect was further observed when creatinine, BMI, sex, duration of type 2 diabetes, HDL cholesterol, and systolic blood pressure were taken into account (odds ratio 1.9 [95% CI 1.01-3.79], P = 0.04). CONCLUSIONS: The presence of the allele -634C/VEGF in homozygosity is an independent risk factor for the development of PDR in type 2 diabetic patients of European ancestry.

COL18A1 is highly expressed during human adipocyte differentiation and the SNP c.1136C > T in its "frizzled" motif is associated with obesity in diabetes type 2 patients.

Collagen XVIII can generate two fragments, NC11-728 containing a frizzled motif which possibly acts in Wnt signaling and Endostatin, which is cleaved from the NC1 and is a potent inhibitor of angiogenesis. Collagen XVIII and Wnt signaling have recently been associated with adipogenic differentiation and obesity in some animal models, but not in humans. In the present report, we have shown that COL18A1 expression increases during human adipogenic differentiation. We also tested if polymorphisms in the Frizzled (c.1136C>T; Thr379Met) and Endostatin (c.4349G>A; Asp1437Asn) regions contribute towards susceptibility to obesity in patients with type 2 diabetes (113 obese, BMI > or =30; 232 non-obese, BMI < 30) of European ancestry. No evidence of association was observed between the allele c.4349G>A and obesity, but we observed a significantly higher frequency of homozygotes c.1136TT in obese (19.5%) than in non-obese individuals (10.9%) [P = 0.02; OR = 2.0 (95%CI: 1.07-3.73)], suggesting that the allele c.1136T is associated to obesity in a recessive model. This genotype, after controlling for cholesterol, LDL cholesterol, and triglycerides, was independently associated with obesity (P = 0.048), and increases the chance of obesity in 2.8 times. Therefore, our data suggest the involvement of collagen XVIII in human adipogenesis and susceptibility to obesity.

Mutations in collagen 18A1 and their relevance to the human phenotype.

Collagen XVIII, a proteoglycan, is a component of basement membranes (BMs). There are three distinct isoforms that differ only by their N-terminal, but with a specific pattern of tissue and developmental expression. Cleavage of its C-terminal produces endostatin, an inhibitor of angiogenesis. In its N-terminal, there is a frizzled motif which seems to be involved in Wnt signaling. Mutations in this gene cause Knobloch syndrome KS), an autosomal recessive disorder characterized by vitreoretinal and macular degeneration and occipital encephalocele. This review discusses the effect of both rare and polymorphic alleles in the human phenotype, showing that deficiency of one of the collagen XVIII isoforms is sufficient to cause KS and that null alleles causing deficiency of all collagen XVIII isoforms are associated with a more severe ocular defect. This review besides illustrating the functional importance of collagen XVIII in eye development and its structure maintenance throughout life, it also shows its role in other tissues and organs, such as nervous system and kidney.

COL18A1 is highly expressed during human adipocyte differentiation and the SNP c.1136C > T in its "frizzled" motif is associated with obesity in diabetes type 2 patients

Collagen XVIII can generate two fragments, NC11-728 containing a frizzled motif which possibly acts in Wnt signaling and Endostatin, which is cleaved from the NC1 and is a potent inhibitor of angiogenesis. Collagen XVIII and Wnt signaling have recently been associated with adipogenic differentiation and obesity in some animal models, but not in humans. In the present report, we have shown that COL18A1 expression increases during human adipogenic differentiation. We also tested if polymorphisms in the Frizzled (c.1136C>T; Thr379Met) and Endostatin (c.4349G>A; Asp1437Asn) regions contribute towards susceptibility to obesity in patients with type 2 diabetes (113 obese, BMI =30; 232 non-obese, BMI < 30) of European ancestry. No evidence of association was observed between the allele c.4349G>A and obesity, but we observed a significantly higher frequency of homozygotes c.1136TT in obese (19.5 percent) than in non-obese individuals (10.9 percent) [P = 0.02; OR = 2.0 (95 percentCI: 1.07-3.73)], suggesting that the allele c.1136T is associated to obesity in a recessive model. This genotype, after controlling for cholesterol, LDL cholesterol, and triglycerides, was independently associated with obesity (P = 0.048), and increases the chance of obesity in 2.8 times. Therefore, our data suggest the involvement of collagen XVIII in human adipogenesis and susceptibility to obesity.

Colágeno XVIII pode gerar dois fragmentos, um correspondendo à região NC11-728 contendo o motivo ''frizzled'', o qual possivelmente atua na sinalização Wnt, e outro correspondendo a Endostatina, que é clivada a partir da região NC1 e é uma potente inibidora de angiogênese. Colágeno XVIII e a via de sinalização Wnt foram recentemente associados à diferenciação adipogênica e obesidade em alguns modelosanimais, porém ainda não em humanos. No presente trabalho, mostramos que os níveis de expressão gênica do COL18A1 aumentam durante o processo de diferenciação adipogênica em humanos. Também testamos se polimorfismos localizados no motivo ''Frizzled'' (c.1136C > T; Thr379Met) e na região da Endostatina (c.4349G > A; Asp1437Asn) contribuem na predisposição a obesidade em pacientes com diabetes tipo 2. (113 obesos, BMI > 30; 232 não-obesos, BMI < 30) de ancestralidade Européia. Nenhuma evidência de associação entre o alelo c.4349G > A e obesidade foi observada, contudo, observamos uma freqüência significativamente maior de homozigotos c.1136TT em obesos (19.5 por cento) do que em não-obesos (10.9 por cento)[P = 0.02; OR = 2.0 (95 por centoCI: 1.07-3.73)], sugerindo que o alelo c.1136T está associado com obesidade conforme ummodelo recessivo. Este genótipo manteve-se associado à obesidade (P = 0.048) mesmo após o controle das variáveis colesterol, LDL e triglicérides, e confere um risco 2.8 vezes maior de obesidade. Portanto, nossos dados sugerem o envolvimento do colágeno XVIII em adipogênese humana e predisposição a obesidade.

Mutations in collagen 18A1 (COL18A1) and their relevance to the human phenotype

Colágeno XVIII, uma proteoglicana, é um componente das membranas basais (MBs). Existem três isoformas distintas que diferem apenas na região N-terminal, mas que apresentam um padrão específico de expressão nos diferentes tecidos e durante o desenvolvimento. A clivagem da região C-terminal produz endostatina, um inibidor de angiogênese. Na sua região N-terminal, há um motivo "frizzled'', o qual parece estar envolvido com a sinalização de Wnt. Mutações no gene COL18A1 causam a síndrome de Knobloch (SK), uma condição de herança autossômica recessiva caracterizada por degeneração vítreo - retiniana, degeneração de mácula e encefalocele occipital. Esta revisão discute o efeito tanto de alelos raros como polimórficos no fenótipo, mostrando que deficiência de uma das isoformas de colágeno XVIII é suficiente para causar SK e que alelos nulos causando deficiência de todas as isoformas de colágeno XVIII estão associadas a alterações oculares mais graves. Esta revisão, além de ilustrar a importância funcional do colágeno XVIII no desenvolvimento do olho e na manutenção de sua estrutura, também mostra que esta proteína tem um papel funcional importante em outros tecidos e órgão, como no sistema nervoso central e rim.